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25 pages, 4460 KiB  
Article
A Pentavalent HIV-1 Subtype C Vaccine Containing Computationally Selected gp120 Strains Improves the Breadth of V1V2 Region Responses
by Xiaoying Shen, Bette Korber, Rachel L. Spreng, Sheetal S. Sawant, Allan deCamp, Arthur S. McMillan, Ryan Mathura, Susan Zolla-Pazner, Abraham Pinter, Robert Parks, Cindy Bowman, Laura Sutherland, Richard Scearce, Nicole L. Yates, David C. Montefiori, Barton F. Haynes and Georgia D. Tomaras
Vaccines 2025, 13(2), 133; https://doi.org/10.3390/vaccines13020133 - 28 Jan 2025
Viewed by 546
Abstract
Background: HIV-1 envelope (Env) variable loops 1 and 2 (V1V2) directed non-neutralizing antibodies were a correlate of decreased transmission risk in the RV144 vaccine trial. Thus, the elicitation and breadth of antibody responses against the V1V2 of HIV-1 Env are important considerations for [...] Read more.
Background: HIV-1 envelope (Env) variable loops 1 and 2 (V1V2) directed non-neutralizing antibodies were a correlate of decreased transmission risk in the RV144 vaccine trial. Thus, the elicitation and breadth of antibody responses against the V1V2 of HIV-1 Env are important considerations for HIV-1 vaccine candidates. The V1V2 region’s highly variable nature and the extensive diversity of subtype C HIV-1 Envelopes (Envs) make the V1V2 response breadth a high priority for HIV-1 vaccine regimens aiming for V1V2-mediated protection in Southern Africa. Here, we determined whether the breadth of the anti-V1V2 vaccine response can be broadened by including HIV-1 Env strains computationally designed to enhance the coverage of subtype C V1V2 sequence diversity. Methods: Three subtype C Env strains were selected to maximize antibody binding coverage while complementing subtype C vaccine gp120s that were given in human clinical trials in South Africa, as well as to improve epitope accessibility. Humoral immunogenicity of a novel trivalent gp120 vaccine immunogen, a bivalent gp120 boost already in clinical trials (1086C and TV1), and a pentavalent (all five gp120s combined) were evaluated in a preclinical immunization study in guinea pigs. The pentavalent combination was further evaluated with alum versus glucopyranosyl lipid adjuvants formulated in squalene-in-water emulsion (GLA-SE) adjuvants in non-human primates. The breadth of the anti-V1V2 response was assessed using an array of cross-subtype variable loops 1&2 (V1V2) scaffold proteins and linear V2 peptides. Results: The breadth of the IgG response against V1V2 antigens of the trivalent and pentavalent groups was comparable, and both were greater than the breadth of the bivalent group. Linear epitope mapping showed that two linear epitopes in V2 were targeted by the vaccinated animals: the V2 hotspot focused at 169K that potentially correlated with decreased HIV-1 risk in RV144 and the V2.2 site (179LDV/I181) that is part of the integrin α4β7 binding site. The bivalent vaccine elicited a significantly higher magnitude of binding to the V2 hotspot compared to the trivalent vaccine whereas the trivalent vaccine elicited significantly higher binding to the V2.2 epitope compared to the bivalent vaccine, while the pentavalent recognized both regions. Conclusions: These results demonstrate that the three new computationally selected subtype C Envs successfully complemented 1086C and TV1 for broader V1V2 antibody responses, and, in concert with adjuvants that stimulate V1V2 responses, can be considered as part of a rationale immunogen design to improve V1V2 IgG coverage in future vaccine trials in South Africa. Full article
(This article belongs to the Special Issue Advances in HIV Vaccine Development)
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<p>Diversity of subtype C HIV-1 Env and vaccine coverage. (<b>A</b>) An unrooted phylogenetic tree of 995 subtype C Env complete sequences available through the Los Alamos HIV database web alignment, <a href="http://www.hiv.lanl.gov" target="_blank">www.hiv.lanl.gov</a>, circa 2016 when this vaccine design was originally undertaken. South Africa, a key nation for vaccine trials and the focus of this study, is compared to C clade viruses globally, with two distinctive subtype C clusters originating in India and Brazil highlighted. This tree was generated with FastTree [<a href="#B31-vaccines-13-00133" class="html-bibr">31</a>] and the figure made with Rainbow Tree (<a href="http://www.hiv.lanl.gov" target="_blank">www.hiv.lanl.gov</a>). (<b>B</b>) The net charge distribution of the combined V1 h and V2 h hypervariable regions across the acute subtype C sequences included in (<b>A</b>). The original P5 vaccine V1 h and V2 h hypervariable regions were all relatively negatively charged (−3), while the trivalent selections were neutral or positive. (<b>C</b>) V1 h and V2 h length distributions. Two of the tree original vaccines had very long V1 h and V2 h regions; the three complementary strains selected ranged from short to average. (<b>D</b>) LOGOS showing the amino acid frequencies in each position between Env 153–184. The relative size of each amino acid reflects the proportion of the variant in the virus population as indicated (C acute, C global, and Not-C). The top figure shows the amino acid frequencies found in the pentavalent vaccine, with the bivalent coverage indicated in black, and the augmented diversity coverage of the trivalent vaccine shown in blue. The next three figures show the diversity coverage of the vaccine in gray for the bivalent, blue for the augmented coverage of the trivalent, and red for the missed amino acids in the pentavalent combinations. The most common missed amino acids would have been covered by the inclusion of ZM651, which was the assumed prime vaccine strain in the initial design. (<b>E</b>) Sequence alignment of the V2 epitope region and properties across the combined V1 and V2 hypervariable regions for the subtype C vaccine candidates.</p>
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<p>Heatmap of binding magnitude (EC50) for V1V2 gp70 scaffolds by guinea pigs in the 3 vaccine groups. V1V2 antigens in red showed higher binding (<span class="html-italic">p</span> &lt; 0.05, two-tailed Wilcoxon rank sum test) by the trivalent group compared to the bivalent group, and green indicated higher binding by the bivalent group compared to the trivalent group. Antigens are ordered by subtypes. Antigens above the horizontal line are heterologous strains, and the ones below the line are vaccine-matched strains.</p>
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<p>Magnitude–breadth curves for binding to 20 heterologous gp70 V1V2 (<b>A</b>) or 12 subtype C heterologous gp70 V1V2 scaffolded proteins (<b>B</b>) by guinea pigs in each group post 4th immunization. Each curve is plotted as the proportion of V1V2 antigens in the respective panel that the animal responded to with a magnitude (Log<sub>10</sub> EC<sub>50</sub>) within the interval indicated on the x-axis. Thin dotted lines represent individual animals, and thick solid lines represent the group median values.</p>
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<p>gp120 (<b>A</b>) and V1V2 region (<b>B</b>) linear epitope binding profiles for the 3 guinea pig vaccine groups. For the gp120 binding magnitude heatmap (<b>A</b>), each line represents a different HIV-1 Env strain in the array library, and values plotted are group median intensity values. The dotted lines separate subtype C strains from other strains. Relevant Env regions are labeled by bars on the top of the heatmap. For V1V2 binding profiles (<b>B</b>), thin dashed lines represent the binding magnitude of individual animals to virus strains indicated by color. Thick solid lines represent the group median binding magnitude for the respective strains. Regions within V1V2 are indicated as gray bars on top of the plots.</p>
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<p>Spider plots showing the coverage Env strains for the two V2 linear epitopes by the 3 groups of guinea pigs (<b>A</b>,<b>B</b>), and the magnitude–breadth curves for binding to V2 linear peptides for the 3 vaccine groups. For the spider plots (<b>A</b>,<b>B</b>), labeled around each spider plot are the Env strains that showed responses for the respective epitope. The magnitude of binding to each epitope is the highest binding signal (Log<sub>2</sub> fold post-/pre-immunization) to a single peptide within the epitope region for the strain. The epitope region covers peptide #53–54 for V2.hostpot, and peptide #57–58 for V2.2. Plotted are the group median magnitude values. For the magnitude–breadth curve plot (<b>C</b>), each curve is plotted as the proportion of linear V2 peptides (shown in <a href="#app1-vaccines-13-00133" class="html-app">Figure S5</a>) that the animal responded to with a magnitude (Log<sub>2</sub> fold post-/pre-immunization) within the interval indicated on the x-axis. Thin dotted lines represent individual animals, and thick solid lines represent the group median values.</p>
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<p>Magnitude of blocking by sera of immunized guinea pigs against binding of mAbs to Env antigens. The mAb by Env antigen pairs are indicated above each panel. Each symbol represents the response of one animal. Thick bars indicated the group median magnitude of blocking.</p>
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<p>Serum IgG titers (EC<sub>50</sub>) of 2 pentavalent E/C immunized macaque groups measured in BAMA for binding to V1V2 gp70 scaffolds (<b>A</b>) and Env (<b>B</b>) antigens. Spots represent individual animals and are color-coded by group. Thick black bars represent the group median EC<sub>50</sub>.</p>
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<p>Magnitude–breadth curves for binding to all 23 gp70 V1V2 scaffolds (<b>A</b>) or 12 subtype C heterologous gp70 V1V2 (<b>B</b>) by 2 groups of pentavalent E/C immunized macaques at wk10. Each curve is plotted as the proportion of V1V2 antigens in the respective panel that the animal responded to with a magnitude (Log<sub>10</sub> EC<sub>50</sub>) within the interval indicated on the x-axis. Thin dotted lines represent individual animals, and thick solid lines represent the group median values.</p>
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<p>gp120 (<b>A</b>) and V1V2 region (<b>B</b>) linear epitope binding profiles for the 2 pentavalent E/C immunized macaque groups, and longitudinal blocking activity of serum antibodies to CH58 (<b>C</b>) and A32 (<b>D</b>) binding. For the gp120 binding magnitude heatmap (<b>A</b>), each line represents a different HIV-1 Env strain in the array library, and values plotted are group median intensity values. The dotted lines separate subtype C strains from other strains. Relevant Env regions are labeled by bars on the top of the heatmap. For V1V2 binding profiles (<b>B</b>), thin dashed lines represent the binding magnitude of individual animals to virus strains indicated by color. Thick solid lines represent the group median binding magnitude for the respective strains. Regions within V1V2 are indicated as gray bars on top of the plots.</p>
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14 pages, 520 KiB  
Review
Approaches to Next-Generation Capripoxvirus and Monkeypox Virus Vaccines
by Anna-Lise Williamson
Viruses 2025, 17(2), 186; https://doi.org/10.3390/v17020186 - 27 Jan 2025
Viewed by 456
Abstract
Globally, there are two major poxvirus outbreaks: mpox, caused by the monkeypox virus, and lumpy skin disease, caused by the lumpy skin disease virus. While vaccines for both diseases exist, there is a need for improved vaccines. The original vaccines used to eradicate [...] Read more.
Globally, there are two major poxvirus outbreaks: mpox, caused by the monkeypox virus, and lumpy skin disease, caused by the lumpy skin disease virus. While vaccines for both diseases exist, there is a need for improved vaccines. The original vaccines used to eradicate smallpox, which also protect from the disease now known as mpox, are no longer acceptable. This is mainly due to the risk of serious adverse events, particularly in HIV-positive people. The next-generation vaccine for mpox prevention is modified vaccinia Ankara, which does not complete the viral replication cycle in humans and, therefore, has a better safety profile. However, two modified vaccinia Ankara immunizations are needed to give good but often incomplete protection, and there are indications that the immune response will wane over time. A better vaccine that induces a long-lived response with only one immunization is desirable. Another recently available smallpox vaccine is LC16m8. While LC16m8 contains replicating vaccinia virus, it is a more attenuated vaccine than the original vaccines and has limited side effects. The commonly used lumpy skin disease vaccines are based on attenuated lumpy skin disease virus. However, an inactivated or non-infectious vaccine is desirable as the disease spreads into new territories. This article reviews novel vaccine approaches, including mRNA and subunit vaccines, to protect from poxvirus infection. Full article
18 pages, 1511 KiB  
Review
The Role of Sustained Type I Interferon Secretion in Chronic HIV Pathogenicity: Implications for Viral Persistence, Immune Activation, and Immunometabolism
by Eman Teer, Nyasha C. Mukonowenzou and M. Faadiel Essop
Viruses 2025, 17(2), 139; https://doi.org/10.3390/v17020139 - 22 Jan 2025
Viewed by 639
Abstract
Human immunodeficiency virus (HIV) infection induces chronic immune activation by stimulating both the innate and adaptive immune systems, resulting in persistent inflammation and immune cell exhaustion. Of note, the modulation of cytokine production and its release can significantly influence the immune response. Type [...] Read more.
Human immunodeficiency virus (HIV) infection induces chronic immune activation by stimulating both the innate and adaptive immune systems, resulting in persistent inflammation and immune cell exhaustion. Of note, the modulation of cytokine production and its release can significantly influence the immune response. Type I interferons (IFN-Is) are cytokines that play a crucial role in innate immunity due to their potent antiviral effects, regulation of IFN-stimulated genes essential for viral clearance, and the initiation of both innate and adaptive immune responses. Thus, an understanding of the dual role of IFN-I (protective versus harmful) during HIV-1 infections and elucidating its contributions to HIV pathogenesis is crucial for advancing HIV therapeutic interventions. This review therefore delves into the intricate involvement of IFN-I in both the acute and chronic phases of HIV infection and emphasizes its impact on viral persistence, immune activation, and immunometabolism in treated HIV-infected individuals. Full article
(This article belongs to the Special Issue Innate Immunity to Virus Infection 2nd Edition)
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Graphical abstract
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<p>General IFN-I signaling cascade and downstream immune cell responses in HIV infection. HIV sensing and signaling by various cells (primarily plasma dendritic cells) result in protein factors’ recruitment, activation, and transcription. This triggers the release of IFN-I which induces the expression of ISGs via the JAK/STAT signal transduction pathway. Downstream effector immune cells including natural killer cells, B-, and T-cells are responsible for a diverse range of antiviral activity. HIV: human immunodeficiency virus; TLRs: Toll-like receptors; cGAS: cyclic GMP-AMP synthase; IFI16: interferon-inducible protein 16; JAK: Janus kinase; STAT: signal transducers and activators of transcription; IRF9: interferon regulatory transcription factor 9; ISRE: interferon-sensitive response element; ISGs: interferon-stimulated genes; ISGF3: IFN-stimulated gene factor 3; NK cells: natural killer cells; P: phosphorylation. Created in BioRender <a href="https://biorender.com/" target="_blank">https://biorender.com/</a>.</p>
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<p>Acute and chronic effects of IFN-I and possible effects of immunometabolism during HIV infection. Despite the beneficial role of IFN-I secretion in acute HIV infection, sustained IFN-I secretion during HIV infection leads to a persistent viral phenotype and immune activation. Furthermore, it indirectly promotes alterations in immunometabolism which may fuel immune dysfunction. APC: antigen-presenting cells; HIV: human immunodeficiency virus; pDCs: plasma dendritic cells; and IFN-I: interferon-1. Created in BioRender <a href="https://biorender.com/" target="_blank">https://biorender.com/</a>.</p>
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15 pages, 3580 KiB  
Article
Immunogenicity of HIV-1 Env mRNA and Env-Gag VLP mRNA Vaccines in Mice
by Qi Ma, Jing Yang, Xiaoguang Zhang, Hongxia Li, Yanzhe Hao and Xia Feng
Vaccines 2025, 13(1), 84; https://doi.org/10.3390/vaccines13010084 - 17 Jan 2025
Viewed by 668
Abstract
Background: The development of a protective vaccine is critical for conclusively ending the human immunodeficiency virus (HIV) epidemic. Methods: We constructed nucleotide-modified mRNA vaccines expressing HIV-1 Env and Gag proteins. Env–gag virus-like particles (VLPs) were generated through co-transfection with env and gag mRNA [...] Read more.
Background: The development of a protective vaccine is critical for conclusively ending the human immunodeficiency virus (HIV) epidemic. Methods: We constructed nucleotide-modified mRNA vaccines expressing HIV-1 Env and Gag proteins. Env–gag virus-like particles (VLPs) were generated through co-transfection with env and gag mRNA vaccines. BALB/c mice were immunized with env mRNA, env–gag VLP mRNA, env plasmid DNA vaccine, or lipid nanoparticle (LNP) controls. HIV Env-specific binding and neutralizing antibodies in mouse sera were assessed via enzyme-linked immunosorbent assay (ELISA) and pseudovirus-based neutralization assays, respectively. Env-specific cellular immune responses in mouse splenocytes were evaluated using an Enzyme-linked immunosorbent assay (ELISpot) and in vivo cytotoxic T cell-killing assays. Results: The Env-specific humoral and cellular immune responses elicited by HIV-1 env mRNA and env–gag VLP mRNA vaccine were stronger than those induced by the DNA vaccine. Specific immune responses induced by the env mRNA vaccine were significantly stronger in the high-dose group than in the low-dose group. Immunization with co-formulated env and gag mRNAs elicited superior cellular immune responses compared to env mRNA alone. Conclusions: These findings suggest that the env–gag VLP mRNA platform holds significant promise for HIV-1 vaccine development. Full article
(This article belongs to the Special Issue Research on HIV/AIDS Vaccine)
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<p>Design and characterization of HIV-1 mRNA Vaccines: (<b>A</b>) Schematic representation of the construction of env and gag mRNA vaccines. (<b>B</b>) Electron microscopy images of LNP-env and LNP-gag vaccines. Scale bar: 100 nm. (<b>C</b>) Results of particle size (blue) and polydispersity index (red dots) analysis for LNP-env and LNP-gag vaccines. (<b>D</b>) Zeta potential measurement results for LNP-env and LNP-gag vaccines. (<b>E</b>) Detection of protein expression of env and gag mRNA in the cell membrane and cytoplasm of HEK293T cells. (<b>F</b>) Immunofluorescence analysis of Env and Gag protein expression, with ENV and Gag mRNA transfected into HEK293T cells for 48 h. Detection was performed using 2G12 and anti-P24 antibodies as primary antibodies and goat anti-human TRITC and goat anti-human FITC as secondary antibodies. Scale bar: 100 μm.</p>
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<p>Production and characteristics of Env-Gag VLPs by co-transfection with gp145 and gag mRNA: (<b>A</b>) A comparison of the mechanisms of action between mRNA vaccines (<b>top</b>) and virus-like particle (VLP) vaccines (<b>bottom</b>) within cells. (<b>B</b>) Schematic representation of VLPs (<b>left</b>) and electron microscopy images of VLPs (<b>right</b>). The VLPs were concentrated using ultracentrifugation and prepared for negative staining in electron microscopy. (<b>C</b>) ELISA results show the expression of Gag protein in VLPs produced by co-transfecting cells with gag and env mRNA at different molar ratios. Scale bar: 50 nm. ** <span class="html-italic">p</span> &lt; 0.01; *** <span class="html-italic">p</span> &lt; 0.001; ns, no significant difference.</p>
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<p>Immunogenicity of HIV mRNA Vaccine and Virus-Like Particle Vaccine in Mice (<b>A</b>) Immunization and detection timeline on day 0 and day 21. Mice (<span class="html-italic">n</span> = 5) were immunized with LNP-env, env-gag VLP, DNA vaccine control, or LNP control. On day 27, lymphocytes isolated from the spleens of naive BALB/c mice were stimulated with Env+Gag specific peptides and used as specific target cells. Splenocytes from the same source without specific stimulation served as internal controls. These two populations were labeled with different concentrations of CFSE and were injected intravenously into naïve or test mice. On day 28, mice sera and splenocytes were isolated for analysis. (<b>B</b>) Indirect ELISA was used to detect the titers of HIV Gp120-specific IgG in mice sera. (<b>C</b>) The 50% neutralizing antibody titers against the HIV-1 pseudovirus strain AE14 in mice sera. (<b>D</b>,<b>E</b>) IFN-γ ELISPOT assay was employed to assess T-cell immune responses in mice splenocytes. 5 × 10<sup>4</sup> freshly isolated splenic lymphocytes were stimulated in duplicate wells with 2 μg/mL of Env/Gag-specific peptides, and the IFN-γ secretion was detected. The mean numbers of IFN-γ spot formation cells (SFCs) per million splenic lymphocytes of each group are shown. Five mice in each group were analyzed. Error bars represent SEM for each group * <span class="html-italic">p</span> &lt; 0.05; *** <span class="html-italic">p</span> &lt; 0.001; **** <span class="html-italic">p</span> &lt; 0.0001; ns, no significant difference.</p>
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<p>In vivo cytotoxicity assay: One week post the last immunization, the killing of i.v.-transferred Env/Gag-pulsed splenocytes was monitored by flow cytometry. (<b>A</b>) Representative dot plots and histograms of CFSE<sup>low</sup> (unpulsed) and CFSE<sup>high</sup> (Env/Gag-pulsed) populations, 12 h after transfer (1:1) into vaccinated mice. (<b>B</b>) Percentage-specific killing of Env/Gag-pulsed target cells in the vaccinated mice compared to the naive control. CFSE stands for carboxy-fluorescein succinimidyl ester. * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01; *** <span class="html-italic">p</span> &lt; 0.001; **** <span class="html-italic">p</span> &lt; 0.0001.</p>
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12 pages, 707 KiB  
Review
Exploitation of Unconventional CD8 T-Cell Responses Induced by Engineered Cytomegaloviruses for the Development of an HIV-1 Vaccine
by Joseph Bruton and Tomáš Hanke
Vaccines 2025, 13(1), 72; https://doi.org/10.3390/vaccines13010072 - 14 Jan 2025
Viewed by 1171
Abstract
After four decades of intensive research, traditional vaccination strategies for HIV-1 remain ineffective due to HIV-1′s extraordinary genetic diversity and complex immune evasion mechanisms. Cytomegaloviruses (CMV) have emerged as a novel type of vaccine vector with unique advantages due to CMV persistence and [...] Read more.
After four decades of intensive research, traditional vaccination strategies for HIV-1 remain ineffective due to HIV-1′s extraordinary genetic diversity and complex immune evasion mechanisms. Cytomegaloviruses (CMV) have emerged as a novel type of vaccine vector with unique advantages due to CMV persistence and immunogenicity. Rhesus macaques vaccinated with molecular clone 68-1 of RhCMV (RhCMV68-1) engineered to express simian immunodeficiency virus (SIV) immunogens elicited an unconventional major histocompatibility complex class Ib allele E (MHC-E)-restricted CD8+ T-cell response, which consistently protected over half of the animals against a highly pathogenic SIV challenge. The RhCMV68-1.SIV-induced responses mediated a post-infection replication arrest of the challenge virus and eventually cleared it from the body. These observations in rhesus macaques opened a possibility that MHC-E-restricted CD8+ T-cells could achieve similar control of HIV-1 in humans. The potentially game-changing advantage of the human CMV (HCMV)-based vaccines is that they would induce protective CD8+ T-cells persisting at the sites of entry that would be insensitive to HIV-1 evasion. In the RhCMV68-1-protected rhesus macaques, MHC-E molecules and their peptide cargo utilise complex regulatory mechanisms and unique transport patterns, and researchers study these to guide human vaccine development. However, CMVs are highly species-adapted viruses and it is yet to be shown whether the success of RhCMV68-1 can be translated into an HCMV ortholog for humans. Despite some safety concerns regarding using HCMV as a vaccine vector in humans, there is a vision of immune programming of HCMV to induce pathogen-tailored CD8+ T-cells effective against HIV-1 and other life-threatening diseases. Full article
(This article belongs to the Special Issue Advances in Vaccines against Infectious Diseases)
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<p>Suggested intracellular trafficking of HLA-E in myeloid cells. (<b>a</b>) Relative transport efficiency of classical MHC-Ia and MHC-E between the ER and cell surface. (<b>b</b>) One possible pathway for loading MHC-E with microbial peptides in RhCMV68-1-infected myeloid cells. HC—heavy chain of HLA-Ia (green) and HLA-E (red); β<sub>2</sub>-m—β<sub>2</sub>-microglobulin; ER—the endoplasmic reticulum; VL9—peptide derived from HLA-Ia (green) and CMV (yellow).</p>
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46 pages, 1654 KiB  
Review
mRNA Vaccines Against COVID-19 as Trailblazers for Other Human Infectious Diseases
by Rossella Brandi, Alessia Paganelli, Raffaele D’Amelio, Paolo Giuliani, Florigio Lista, Simonetta Salemi and Roberto Paganelli
Vaccines 2024, 12(12), 1418; https://doi.org/10.3390/vaccines12121418 - 16 Dec 2024
Viewed by 1425
Abstract
mRNA vaccines represent a milestone in the history of vaccinology, because they are safe, very effective, quick and cost-effective to produce, easy to adapt should the antigen vary, and able to induce humoral and cellular immunity. Methods: To date, only two COVID-19 mRNA [...] Read more.
mRNA vaccines represent a milestone in the history of vaccinology, because they are safe, very effective, quick and cost-effective to produce, easy to adapt should the antigen vary, and able to induce humoral and cellular immunity. Methods: To date, only two COVID-19 mRNA and one RSV vaccines have been approved. However, several mRNA vaccines are currently under development for the prevention of human viral (influenza, human immunodeficiency virus [HIV], Epstein–Barr virus, cytomegalovirus, Zika, respiratory syncytial virus, metapneumovirus/parainfluenza 3, Chikungunya, Nipah, rabies, varicella zoster virus, and herpes simplex virus 1 and 2), bacterial (tuberculosis), and parasitic (malaria) diseases. Results: RNA viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV)-2, HIV, and influenza, are characterized by high variability, thus creating the need to rapidly adapt the vaccines to the circulating viral strain, a task that mRNA vaccines can easily accomplish; however, the speed of variability may be higher than the time needed for a vaccine to be adapted. mRNA vaccines, using lipid nanoparticles as the delivery system, may act as adjuvants, thus powerfully stimulating innate as well as adaptive immunity, both humoral, which is rapidly waning, and cell-mediated, which is highly persistent. Safety profiles were satisfactory, considering that only a slight increase in prognostically favorable anaphylactic reactions in young females and myopericarditis in young males has been observed. Conclusions: The COVID-19 pandemic determined a shift in the use of RNA: after having been used in medicine as micro-RNAs and tumor vaccines, the new era of anti-infectious mRNA vaccines has begun, which is currently in great development, to either improve already available, but unsatisfactory, vaccines or develop protective vaccines against infectious agents for which no preventative tools have been realized yet. Full article
(This article belongs to the Topic Advances in Vaccines and Antimicrobial Therapy)
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<p>Schematic representation of synthetic mRNA. Created with BioRender.com.</p>
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<p>The main steps to mRNA vaccine development. Created with BioRender.com.</p>
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<p>SARS-CoV-2 and protein S interaction with ACE2 and TMPRSS2 to enter cell. Created with BioRender.com.</p>
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<p>(<b>A</b>) The endocytic pathway of mRNA vaccine inside the antigen-presenting cell and its interaction with T-helper (Th) cells, cytotoxic T-lymphocytes (CTL), and B-lymphocytes; (<b>B</b>) the germinal center (GC) in secondary lymphoid organs and the extra-follicular pathways of B-cell maturation to memory B-cells and antibody-producing plasma cells (PCs). Created with BioRender.com.</p>
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12 pages, 283 KiB  
Article
Inclusion of Labor Migrants as a Potential Key Population for HIV: A Nationwide Study from Tajikistan
by Brian Kwan, Hamid R. Torabzadeh, Adebimpe O. Akinwalere, Julie Nguyen, Patricia Cortez, Jamoliddin Abdullozoda, Salomudin J. Yusufi, Kamiar Alaei and Arash Alaei
Trop. Med. Infect. Dis. 2024, 9(12), 304; https://doi.org/10.3390/tropicalmed9120304 - 11 Dec 2024
Viewed by 896
Abstract
Key populations are particularly vulnerable to human immunodeficiency virus (HIV) infection. Nearly half of Tajikistan’s gross domestic product (GDP) originates from labor migrant transfers. While not officially designated as a key population, over 300,000 migrants return to Tajikistan every year at increased risk [...] Read more.
Key populations are particularly vulnerable to human immunodeficiency virus (HIV) infection. Nearly half of Tajikistan’s gross domestic product (GDP) originates from labor migrant transfers. While not officially designated as a key population, over 300,000 migrants return to Tajikistan every year at increased risk for HIV due to absence or interruption of treatment, change in risky behaviors, and other factors. We analyzed cross-sectional data from the national registry system operated by the Tajikistan Ministry of Health and Social Protection of individuals (n = 10,700) who had been diagnosed with HIV from 1 January 2010 to 30 May 2023. Individual HIV cases resided in five regions: Districts of Republican Subordination (DRS), Dushanbe (Tajikistan’s capital city), Gorno-Badakhshan Autonomous Oblast (GBAO), Khatlon, and Sughd. We developed logistic regression models to investigate the relationships between key population status and demographic characteristics. GBAO has the largest proportion of labor migrants (49.59%), which is much larger than that of the other regions (<32%). In contrast to other key populations, there was a larger proportion of HIV cases in rural areas that were labor migrants (23.25%) in comparison to urban areas (16.05%). In multivariable analysis, the odds of being a labor migrant were 6.248 (95% CI: 4.811, 8.113), 2.691 (95% CI: 2.275, 3.184), and 1.388 (95% CI: 1.155, 1.668) times larger if a case was residing in GBAO, Sughd, or DRS, compared to Dushanbe, respectively. Our research contributes to the field by proposing to expand the definition of key population to include labor migrants in Central Asia who should be emphasized as a vulnerable population at high risk of HIV. We encourage policy action to provide designated HIV funding for labor migrants, increase international attention, and promote potential modifications of national regulations and/or laws regarding prevention and treatment of HIV among non-citizen populations. Full article
(This article belongs to the Special Issue Contemporary Migrant Health, 2nd Edition)
18 pages, 2427 KiB  
Article
Screening for STIs: Results of a Health-Promotion Programme in a Portuguese University
by Joana M. Oliveira, Ana Helena Martins, Daniela Veiga, Célia Lavaredas, António Queirós and Ana Miguel Matos
Microorganisms 2024, 12(12), 2479; https://doi.org/10.3390/microorganisms12122479 - 2 Dec 2024
Viewed by 826
Abstract
Sexually Transmitted Infections (STIs) are an important and growing public health concern. Implementation of screening programmes and awareness campaigns are crucial to mitigate this problem. A university in the central region of Portugal has devised a health-promotion programme, named Protection+, specifically directed [...] Read more.
Sexually Transmitted Infections (STIs) are an important and growing public health concern. Implementation of screening programmes and awareness campaigns are crucial to mitigate this problem. A university in the central region of Portugal has devised a health-promotion programme, named Protection+, specifically directed towards the sexual health of the university community. The present study aimed to evaluate the results of the different actions undertaken as part of the health-promotion programme during the 2023–2024 academic year. Chlamydia, gonorrhoea, trichomoniasis and infection with Mycoplasma genitalium were assessed through real-time polymerase chain reaction protocols. Syphilis, infection with HIV, HBV and HCV were assessed through immunological assays. The adherence to the health-promotion programme after the awareness campaigns was also evaluated. STIs have been diagnosed in 13.7% of the 475 screened participants. Chlamydia was the STI most frequently diagnosed (8.4%), followed by infection with M. genitalium (2.3%), T. pallidum (2.0%) and N. gonorrhoeae (1.1%). HIV, HBV and HCV were diagnosed in a residual number of cases, and T. vaginalis was not detected in any of the screened participants. At the time of diagnosis, more than half of the infected patients were asymptomatic. After the implementation of awareness campaigns, an increase in the adherence to STI screening was observed, with the expected simultaneous increase in STI diagnoses. The high prevalence of STIs, particularly chlamydia, in the university population, along with the asymptomatic nature of these infections, demonstrated the importance of STI screenings and the implementation of campaigns that raise awareness on the prevention and consequences of untreated STIs. Full article
(This article belongs to the Special Issue Clinical Microbial Infection and Antimicrobial Resistance)
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<p>Frequency of detection of (<b>a</b>) STIs and (<b>b</b>) STIs and others sexually transmitted microorganisms.</p>
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<p>Distribution of STIs according to age group and gender.</p>
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<p>Prevalence of STIs according to gender.</p>
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<p>Prevalence of commensal microorganisms according to gender.</p>
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<p>Prevalence of co-detection of multiple agents according to gender.</p>
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<p>Frequency of detection of HAV-specific antibodies by gender.</p>
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<p>Evolution of the number of participants and STI cases during the academic year.</p>
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17 pages, 5628 KiB  
Article
Two Disaccharide-Bearing Polyethers, K-41B and K-41Bm, Potently Inhibit HIV-1 via Mechanisms Different from That of Their Precursor Polyether, K-41A
by Jie Liu, Qiuyu Wei, Xin Liu, Jiang Chen, Yujie Zhan, Qinglian Li, Qian Wang, Bingyu Liang, Junjun Jiang, Fengxiang Qin, Zongxiang Yuan, Qiuzhen Qin, Xuehua Li, Yangping Li, Hao Liang, Li Ye and Bo Zhou
Curr. Issues Mol. Biol. 2024, 46(12), 13482-13498; https://doi.org/10.3390/cimb46120805 - 25 Nov 2024
Viewed by 930
Abstract
The screening of novel antiviral agents from marine microorganisms is an important strategy for new drug development. Our previous study found that polyether K-41A and its analog K-41Am, derived from a marine Streptomyces strain, exhibit anti-HIV activity by suppressing the activities of HIV-1 [...] Read more.
The screening of novel antiviral agents from marine microorganisms is an important strategy for new drug development. Our previous study found that polyether K-41A and its analog K-41Am, derived from a marine Streptomyces strain, exhibit anti-HIV activity by suppressing the activities of HIV-1 reverse transcriptase (RT) and its integrase (IN). Among the K-41A derivatives, two disaccharide-bearing polyethers—K-41B and K-41Bm—were found to have potent anti-HIV-1IIIB activity in vitro. This study aimed to clarify whether K-41B and K-41Bm have inhibitory effects on different HIV-1 strains or whether these two derivatives have mechanisms of action different from that of their precursor, K-41A. An anti-HIV-1 assay indicated that K-41B and K-41Bm have potent anti-HIV-1BaL activity, with low 50% inhibitory concentrations (IC50s) (0.076 and 0.208 μM, respectively) and high selective indexes (SIs) (58.829 and 31.938, respectively) in the peripheral blood mononuclear cell (PBMC)-HIV-1BaL system. The time-of-addition (TOA) assay indicated that K-41B and K-41Bm may exert antiviral effects by activating multiple stages of HIV-1 replication. A cell protection assay indicated that the pretreatment of cells with K-41B or K-41Bm has almost no inhibitory effect on HIV-1 infection. A virus inactivation assay indicated that pretreatment of the virus with K-41B or K-41Bm inhibits HIV-1 infection by 60%. A cell–cell fusion assay showed that K-41B and K-41Bm blocked the cell fusion mediated by viral envelope proteins. The HIV-1 key enzyme experiment also indicated that both compounds have certain inhibitory effects on HIV-1 IN. Furthermore, molecular docking showed that K-41B and K-41Bm interact with several viral and host proteins, including HIV-1 IN, an envelope protein (gp120), a transmembrane protein (gp41), and cell surface receptors (CD4, CCR5, and CXCR4). Overall, in addition to having a similar anti-HIV-1 mechanism of inhibiting HIV-1 IN like the precursor polyether K-41A, the disaccharide-bearing polyether derivatives K-41B and K-41Bm may also inhibit viral entry. This suggests that they display anti-HIV-1 mechanisms that are different from those of their precursor polyethers. Full article
(This article belongs to the Section Molecular Microbiology)
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<p>Cytotoxicity and anti-HIV-1 activities of K-41B and K-41Bm in PBMC-HIV-1<sub>BaL</sub> system. (<b>A</b>–<b>C</b>) The effects of K-41B (<b>A</b>), K-41Bm (<b>B</b>), and AZT (<b>C</b>) on cell viabilities were measured in parallel mock-infected cells using CellTiter-Glo Luminescent cell viability assay, respectively. (<b>D</b>–<b>F</b>) The effects of K-41B (<b>D</b>), K-41Bm (<b>E</b>), and AZT (<b>F</b>) on HIV-1 replication, respectively. The levels of HIV-1<sub>BaL</sub> in the culture supernatants were determined with an HIV-1 p24 ELISA kit. The relative cell viabilities in compound-treated groups were presented as the percentage of control (without compound treatment, which was defined as 100%). The levels of relative HIV-1 replication were presented as the percentage of control (with HIV-1 infection, without compound treatment, which was defined as 100%). AZT treatment was used as a drug control.</p>
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<p>The effects of K-41B and K-41Bm on HIV-1-induced syncytia in MT-2 cells. MT-2 cells were infected with HIV-1<sub>IIIB</sub> virus and treated with K-41B and K-41Bm. The formation of HIV-1-induced syncytia (indicated by the red arrows) was observed with a microscope at 72 h post-infection. (<b>A</b>–<b>C</b>) HIV-1-infected cells were treated with different concentrations of K-41B. (<b>D</b>–<b>F</b>) HIV-1-infected cells were treated with different concentrations of K-41Bm. (<b>G</b>) Negative control. MT-2 cells without HIV-1 infection, without compound treatment. (<b>H</b>) Positive control. MT-2 cells with HIV-1 infection, without compound treatment.</p>
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<p>Time-of-addition assay. TZM-bl cells were infected with HIV-1<sub>IIIB</sub>, and the compounds were added to the culture at serial time points (0, 2, 4, 6, 8, 10, 12, 18, and 24 h) post HIV-1 infection, respectively. After 48 h treatment, the levels of HIV-1 were measured by luciferase activity. The percent inhibitory of HIV-1 was calculated using the following formula: [1–(E–N)/(P–N)] × 100%; “E” represents the luciferase value in the experiment group; “N” represents the luciferase value in the negative control group, to which no virus was added; “P” represents the luciferase value in the positive control group, to which no compound was added. The data presented are one representative experiment of repeated experiments. Black circles, T-20 (2.226 μM); squares, AZT (1.496 μM); perpendicular triangle, RAL (4.687 μM); inverted triangle, LPV (79.517 μM); diamond, K-41B (4.653 μM); white circles, K-41Bm (4.600 μM).</p>
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<p>Cell protection assay of K-41B and K-41Bm on TZM-bl cells. TZM-bl cells were pretreated with K-41B (<b>A</b>), K-41Bm (<b>B</b>), or LPV (<b>C</b>) at indicated concentrations for 1 h before HIV-1 infection. Then, the cells were washed with PBS to remove the compounds in the cultures and infected with the HIV-1<sub>IIIB</sub> virus (100 TCID<sub>50</sub>). At 48 h post-infection, the levels of HIV-1 were measured using a luciferase assay, and the relative HIV-1 levels were presented as a percentage of control (with HIV-1 infection, without compound treatment, which was defined as 100%). Compounds were three-fold serially diluted to four concentrations with LPV as a negative control.</p>
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<p>Virus inactivation assay of K-41B and K-41Bm on HIV-1<sub>IIIB</sub>. K-41B (<b>A</b>), K-41Bm (<b>B</b>), or Triton X-100 (<b>C</b>) were premixed with HIV-1<sub>IIIB</sub> virus (100 TCID<sub>50</sub>) for 1 h. Then, the mixtures were washed with PBS and transferred into the TZM-bl cells culture. At 48 h post-transferring, the levels of HIV-1 were measured using a luciferase assay, and the relative HIV-1 levels were presented as a percentage of control (with HIV-1 infection, without compound treatment, which was defined as 100%). Compounds were three-fold serially diluted to four concentrations with Triton X-100 as a positive drug control.</p>
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<p>The cell–cell fusion inhibition assay of K-41B and K-41Bm on H9-HIV-1<sub>IIIB</sub> cells and MT-2 cells. H9-HIV-1<sub>IIIB</sub> cells labeled with Calcein-AM dye were treated with K-41B (<b>A</b>), K-41Bm (<b>B</b>), or T-20 (<b>C</b>) and MT-2 cells. And after 2 h, cell–cell fusion (indicated by the red arrows) was observed using an inverted fluorescence microscope. Three control groups were set, including the reference compound control with T-20 (<b>C</b>), the positive control without compound (<b>D</b>), and the negative control of normal H9 cells co-cultured with MT-2 cells (<b>E</b>).</p>
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<p>Effects of K-41B and K-41Bm on HIV-1 key enzyme activities. The HIV-1 RT inhibition assay (<b>A</b>), HIV-1 IN inhibition assay (<b>B</b>), and HIV-1 PR inhibition assay (<b>C</b>) were performed using ELISA kits according to the manufacturer, and NVP, sodium azide, and Pepstatin A were used as the positive control, respectively. The relative enzyme activity levels are presented as a percentage of control (without compound treatment, which was defined as 100%). Since the concentration unit (%) of sodium azide differed from that of K-41B and K-41Bm (μM), causing incompatibility, Figure B did not display the result of sodium azide.</p>
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<p>The protein–ligand interactions of K-41B with HIV-1 key proteins. (<b>A</b>–<b>F</b>) The 3D images of protein–ligand interactions of K-41B (purple) with HIV-1 IN (<b>A</b>), gp120 (<b>B</b>), gp41 (<b>C</b>), CD4 (<b>D</b>), CCR5 (<b>E</b>), and CXCR4 (<b>F</b>). (<b>a</b>–<b>f</b>) are the corresponding 2D images. The dark blue oval in the 3D image and the dark blue rectangle in the 2D image denote the glycosylated modified structure.</p>
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<p>The protein–ligand interactions of K-41Bm with HIV-1 key proteins. A-F show the 3D images of protein–ligand interactions of K-41Bm (orange) with HIV-1 IN (<b>A</b>), gp120 (<b>B</b>), gp41 (<b>C</b>), CD4 (<b>D</b>), CCR5 (<b>E</b>), and CXCR4 (<b>F</b>). (<b>a</b>–<b>f</b>) are the corresponding 2D images. The dark blue oval in the 3D image and the dark blue rectangle in the 2D image denote the glycosylated modified structure.</p>
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13 pages, 1563 KiB  
Article
Hepatitis A Seroprevalence Among HIV-Exposed and Unexposed Pediatric Populations in South Africa
by Edina Amponsah-Dacosta, Lufuno Ratshisusu, Lorato M. Modise, Ntombifuthi Blose, Omphile E. Simani, Selokela G. Selabe, Benjamin M. Kagina and Rudzani Muloiwa
Vaccines 2024, 12(11), 1276; https://doi.org/10.3390/vaccines12111276 - 13 Nov 2024
Viewed by 1284
Abstract
Background: There is limited evidence comparing hepatitis A seroprevalence among HIV-exposed uninfected (HEU), HIV-infected (HIV), and unexposed uninfected (HUU) children. This compromises rational vaccine decision-making. Methods: This study comprised a retrospective health facility-based population of children aged 1 month–12 years. Archival sera were [...] Read more.
Background: There is limited evidence comparing hepatitis A seroprevalence among HIV-exposed uninfected (HEU), HIV-infected (HIV), and unexposed uninfected (HUU) children. This compromises rational vaccine decision-making. Methods: This study comprised a retrospective health facility-based population of children aged 1 month–12 years. Archival sera were tested for markers of acute (anti-HAV IgM) or past (total anti-HAV) HAV infection. Subgroup analysis was conducted based on perinatal HIV exposure or infection status. Results: Among 513 children, the median age was 10 (IQR: 4–25) months. The median maternal age was 29 (IQR: 25–34) years. An anti-HAV seropositivity of 95.1% (117/122 [95% CI 90.2–98.4]) was found among those ≤6 months of age, indicative of the rate of transplacental antibody transfer. Among 1–12-year-olds, hepatitis A seroprevalence was 19.3% (37/192 [95% CI 14.1–25.7]), while 1.1% (2/188 [95% CI 0.12–2.76]) had evidence of acute infection. Compared to HIV-exposed subgroups (HIV = 60%, 6/10 [95% CI 27.4–86.3] and HEU = 45%, 9/20 [95% CI 23.8–68]), hepatitis A seroprevalence among HUU children was low (29.2%, 47/161 [95% CI 22.4–37.0]). Conclusions: Natural immunity among HIV-exposed and unexposed children in South Africa is insufficient to protect against severe liver complications associated with HAV infection later in adulthood. Full article
(This article belongs to the Special Issue Vaccines and Vaccination: HIV, Hepatitis Viruses, and HPV)
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<p>Sample stratification and laboratory testing for serological markers and viral RNA.</p>
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<p>Seropositivity of anti-HAV stratified by age across the study population.</p>
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<p>Anti-HAV seropositivity in HIV-exposed (<span class="html-italic">n</span> = 30) vs. -unexposed (<span class="html-italic">n</span> = 161) children 1–12 years of age.</p>
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<p>Seropositivity of anti-HAV stratified by age among (<b>a</b>) HIV-exposed vs. (<b>b</b>) HIV-unexposed children.</p>
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18 pages, 2878 KiB  
Article
New Associations with the HIV Predisposing and Protective Alleles of the Human Leukocyte Antigen System in a Peruvian Population
by Daisy Obispo, Oscar Acosta, Maria L. Guevara, Susan Echavarría, Susan Espetia, María Dedios, Carlos Augusto Yabar and Ricardo Fujita
Viruses 2024, 16(11), 1708; https://doi.org/10.3390/v16111708 - 30 Oct 2024
Viewed by 1189
Abstract
The accurate determination of an individual’s unique human leukocyte antigen (HLA) allele holds important significance in evaluating the risk associated with autoimmune and infectious diseases, such as human immunodeficiency virus (HIV) infection. Several allelic variants within the HLA system have been linked to [...] Read more.
The accurate determination of an individual’s unique human leukocyte antigen (HLA) allele holds important significance in evaluating the risk associated with autoimmune and infectious diseases, such as human immunodeficiency virus (HIV) infection. Several allelic variants within the HLA system have been linked to either increased protection or susceptibility in the context of infectious and autoimmune diseases. This study aimed to determine the frequency and association of HLA alleles between people living with HIV (PLHIV) as the case group and Peruvian individuals without HIV with high-risk behaviors of sexually transmitted diseases as the control group. Whole exome sequencing (WES) was used to determine high-resolution HLA allelotypes using the OptiType and arcas HLA tools. The HLA alleles present in HLA classes I (A, B, and C loci) and II (DPB1, DQA1, DQB1, and DRB1 loci) were determined in a cohort of 59 PLHIV (cases) and 44 individuals without HIV (controls). The most frequent HLA alleles were A*02:01, DPB1*04:02, and DQB1*03:419 at 36%, 30%, and 28% prevalence in general population. We found that C*07:01 (p = 0.0101; OR = 10.222, 95% IC: 1.40–74.55), DQA1*03:02 (p = 0.0051; OR = 5.297, 95% IC: 1.48–19.02), and DRB1*09:01 (p = 0.0119; OR = 4.788, 95% IC: 1.39–16.44) showed an association with susceptibility to HIV infection, while DQB1*03:419 (p = 0.0478; OR = 0.327, 95% IC: 0.11–0.96) was associated with protection from HIV infection. Our findings contribute to the knowledge of HLA allele diversity in the Peruvian population (around 70% South American indigenous ancestry) lays the groundwork for further valuable large-scale use of HLA typing and offers a novel association with HIV infection that is relevant to vaccine studies. Full article
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<p>Frequency distribution of HLA class I alleles in PLHIV and those without HIV based on 2-field resolution HLA imputation. (<b>a</b>) Allele frequencies across 20 HLA-A loci. (<b>b</b>) Allele frequencies across 31 HLA-B loci. (<b>c</b>) Allele frequencies across 17 HLA-C loci.</p>
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<p>Frequency distribution of HLA class I alleles in PLHIV and those without HIV based on 2-field resolution HLA imputation. (<b>a</b>) Allele frequencies across 20 HLA-A loci. (<b>b</b>) Allele frequencies across 31 HLA-B loci. (<b>c</b>) Allele frequencies across 17 HLA-C loci.</p>
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<p>Frequency distribution of HLA class I alleles in PLHIV and those without HIV based on 2-field resolution HLA imputation. (<b>a</b>) Allele frequencies across 20 HLA-A loci. (<b>b</b>) Allele frequencies across 31 HLA-B loci. (<b>c</b>) Allele frequencies across 17 HLA-C loci.</p>
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<p>Frequency distribution of HLA alleles class II in PLHIV and those without HIV based on 2-field resolution HLA imputation. (<b>a</b>) Allele frequencies across 14 HLA-DPB1 loci. (<b>b</b>) Allele frequencies across 28 HLA-DRB1 loci. (<b>c</b>) Allele frequencies across 15 HLA-DQA1 loci. (<b>d</b>) Allele frequencies across 16 HLA-DQB1 loci.</p>
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<p>Frequency distribution of HLA alleles class II in PLHIV and those without HIV based on 2-field resolution HLA imputation. (<b>a</b>) Allele frequencies across 14 HLA-DPB1 loci. (<b>b</b>) Allele frequencies across 28 HLA-DRB1 loci. (<b>c</b>) Allele frequencies across 15 HLA-DQA1 loci. (<b>d</b>) Allele frequencies across 16 HLA-DQB1 loci.</p>
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<p>Frequency distribution of HLA alleles class II in PLHIV and those without HIV based on 2-field resolution HLA imputation. (<b>a</b>) Allele frequencies across 14 HLA-DPB1 loci. (<b>b</b>) Allele frequencies across 28 HLA-DRB1 loci. (<b>c</b>) Allele frequencies across 15 HLA-DQA1 loci. (<b>d</b>) Allele frequencies across 16 HLA-DQB1 loci.</p>
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<p>Frequency distribution of HLA alleles class II in PLHIV and those without HIV based on 2-field resolution HLA imputation. (<b>a</b>) Allele frequencies across 14 HLA-DPB1 loci. (<b>b</b>) Allele frequencies across 28 HLA-DRB1 loci. (<b>c</b>) Allele frequencies across 15 HLA-DQA1 loci. (<b>d</b>) Allele frequencies across 16 HLA-DQB1 loci.</p>
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17 pages, 724 KiB  
Review
Tumor Initiation and Progression in People Living on Antiretroviral Therapies
by Seun E. Olufemi, Daniel A. Adediran, Temitope Sobodu, Isaac O. Adejumo, Olumide F. Ajani and Elijah K. Oladipo
Biologics 2024, 4(4), 390-406; https://doi.org/10.3390/biologics4040024 - 25 Oct 2024
Viewed by 1277
Abstract
Antiretroviral therapy (ART) has significantly extended the lifespan of people living with Human Immunodeficiency Virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS), thereby transforming the disease into a manageable chronic condition. However, this increased longevity has led to a higher incidence of non-AIDS-defining cancers [...] Read more.
Antiretroviral therapy (ART) has significantly extended the lifespan of people living with Human Immunodeficiency Virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS), thereby transforming the disease into a manageable chronic condition. However, this increased longevity has led to a higher incidence of non-AIDS-defining cancers (NADCs) among this population. In this holistic review, we explore the complex interactions between HIV, ART, and cancer development, focusing on how ART influences tumor initiation and progression in people living with HIV/AIDS (PLWHA). Our findings from this reveal several critical aspects of cancer risk in PLWHA. Firstly, while ART restores immune function, it does not fully normalize it. Chronic immune activation and persistent inflammation continue to be prevalent, creating a conducive environment for oncogenesis. Additionally, PLWHA are more susceptible to persistent infections with oncogenic viruses such as human papillomavirus (HPV) and Epstein–Barr virus (EBV), further increasing cancer risk. Some ART drugs have been implicated in genotoxicity and mitochondrial dysfunction, potentially promoting tumorigenesis. ART-induced metabolic changes, including insulin resistance and dyslipidemia, are also associated with heightened cancer risk. Common NADCs in PLWHA include lung cancer, liver cancer, anal cancer, and Hodgkin lymphoma, each with distinct etiologies linked to both HIV-related and ART-related factors. The interplay between HIV infection, chronic inflammation, immune restoration via ART, and the direct effects of ART drugs creates a unique cancer risk profile in PLWHA. Although ART reduces the incidence of AIDS-defining cancers, it does not confer the same protective effect against NADCs. Persistent HIV-related inflammation and immune activation, despite viral suppression, are key factors in cancer development. Additionally, long-term exposure to ART may introduce new oncogenic risks. These insights highlight the need for integrated cancer screening and prevention strategies tailored to PLWHA. Future research is needed to focus on identifying biomarkers for early cancer detection and developing ART regimens with lower oncogenic potential. Healthcare providers should be vigilant in monitoring PLWHA for cancer and adopt comprehensive screening protocols to mitigate the increased cancer risk associated with ART. Full article
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<p>HIV particles activate CD4+ T cells, leading to inflammation through the release of cytokines like TNF-α, IL-6, and IL-1β. This inflammation drives increased Cellular proliferation, reduced apoptosis, and enhanced angiogenesis, ultimately contributing to tumorigenesis.</p>
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<p>HIV proteins Tat and Nef activate NF-κB and MAPK pathways in host cells. NF-κB promotes VEGF production, leading to angiogenesis, while MAPK influences cell survival by regulating p53 and Bcl-2. This manipulation aids HIV replication and contributes to disease progression, including cancer and immune dysregulation.</p>
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13 pages, 565 KiB  
Article
A Virome and Proteomic Analysis of Placental Microbiota in Pregnancies with and without Fetal Growth Restriction
by Aleksandra Stupak, Maciej Kwiatek, Tomasz Gęca, Anna Kwaśniewska, Radosław Mlak, Robert Nawrot, Anna Goździcka-Józefiak and Wojciech Kwaśniewski
Cells 2024, 13(21), 1753; https://doi.org/10.3390/cells13211753 - 23 Oct 2024
Viewed by 1273
Abstract
Introduction: Metagenomic research has allowed the identification of numerous viruses present in the human body. Viruses may significantly increase the likelihood of developing intrauterine fetal growth restriction (FGR). The goal of this study was to examine and compare the virome of normal and [...] Read more.
Introduction: Metagenomic research has allowed the identification of numerous viruses present in the human body. Viruses may significantly increase the likelihood of developing intrauterine fetal growth restriction (FGR). The goal of this study was to examine and compare the virome of normal and FGR placentas using proteomic techniques. Methods: The study group of 18 women with late FGR was compared with 18 control patients with physiological pregnancy and eutrophic fetus. Proteins from the collected afterbirth placentas were isolated and examined using liquid chromatography linked to a mass spectrometer. Results: In this study, a group of 107 viral proteins were detected compared to 346 in the controls. In total, 41 proteins were common in both groups. In total, 64 proteins occurred only in the study group and indicated the presence of bacterial phages: E. coli, Bacillus, Mediterranenean, Edwardsiella, Propionibacterium, Salmonella, Paenibaciilus and amoebae Mimiviridae, Acanthamoeba polyphaga, Mimivivirus, Pandoravirdae, Miroviridae, Pepper plant virus golden mosaic virus, pol proteins of HIV-1 virus, and proteins of Pandoravirdae, Microviridae, and heat shock proteins of the virus Faustoviridae. Out of 297 proteins found only in the control group, only 2 viral proteins occurred statistically significantly more frequently: 1/hypothetical protein [uncultured Mediterranean phage uvMED] and VP4 [Gokushovirus WZ-2015a]. Discussion: The detection of certain viral proteins exclusively in the control group suggests that they may play a protective role. Likewise, the proteins identified only in the study group could indicate a potentially pathogenic function. A virome study may be used to identify an early infection, evaluate its progress, and possible association with fetal growth restriction. Utilizing this technology, an individualized patient therapy is forthcoming, e.g., vaccines. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Reproductive System Diseases)
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<p>Bar graphs showing a comparison of proteins that were present in both the study and control groups. The red square indicates statistically significant results that remained significant after applying the Bonferroni correction. (<b>A</b>) Graph showing comparisons of protein content (n = 26), for which em PAI values were significantly higher in the study group compared to the control. (<b>B</b>) Graph showing comparisons of protein content (n = 2) for which em PAI values were significantly (als03562.1) or non-significantly (bar34139.1) higher in the control compared to the study group. (<b>C</b>) Graph showing comparisons of protein content (n = 13) for which em PAI values were slightly higher in the study group compared to the control.</p>
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<p>Bar charts showing the content of proteins that occurred only in material from people from the study or control groups. (<b>A</b>) Graph showing the content of proteins found only in material from controls (proteins are sorted by decreasing em PAI value) [part 1—proteins 1–20]. (<b>B</b>) A graph showing the content of proteins found only in material from people from the study group (proteins are arranged in descending order of em PAI value) [part 1—proteins 1–20].</p>
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14 pages, 423 KiB  
Article
Impact of Immunosuppressants and Vaccination on COVID-19 Outcomes in Autoimmune Patients and Solid Organ Transplant Recipients: A Nationwide Propensity Score-Matched Study
by Mindong Sung, Young-Sam Kim, Changjin Cho, Yongeun Son, Dong-Wook Kim and Su-Hwan Lee
Vaccines 2024, 12(10), 1190; https://doi.org/10.3390/vaccines12101190 - 18 Oct 2024
Viewed by 1147
Abstract
Purpose: This study investigates the impact of varying degrees of immunosuppression on the clinical outcomes of immunocompromised individuals, particularly those with autoimmune diseases or post-solid organ transplant statuses, in the context of COVID-19. By focusing on these highly vulnerable populations, the study underscores [...] Read more.
Purpose: This study investigates the impact of varying degrees of immunosuppression on the clinical outcomes of immunocompromised individuals, particularly those with autoimmune diseases or post-solid organ transplant statuses, in the context of COVID-19. By focusing on these highly vulnerable populations, the study underscores the significant health inequalities faced by immunocompromised patients, who experience disproportionately worse outcomes in comparison to the general population. Methods: A retrospective cohort analysis of the K-COV-N dataset was conducted, comparing the effects of immunosuppression in autoimmune and transplant groups with matched control groups. Propensity score matching was employed to minimize inequalities in baseline characteristics, ensuring a more equitable comparison between immunocompromised and non-immunocompromised individuals. Outcomes included COVID-19-related in-hospital mortality, 28-day mortality, ICU admissions, and the need for respiratory support among 323,890 adults in the Republic of Korea. Patients with cancer or other immunosuppressive conditions, such as HIV, were excluded. Subgroup analyses assessed the influence of specific immunosuppressive medications and vaccination extent. Results: Significantly elevated in-hospital mortality was found for patients with autoimmune diseases (adjusted Odds Ratio [aOR] 2.749) and transplant recipients (aOR 7.567), with similar patterns in other outcomes. High-dose steroid use and a greater number of immunosuppressant medications markedly increased the risk of poor outcomes. Vaccination emerged as a protective factor, with a single dose substantially improving outcomes for autoimmune patients and at least two doses necessary for transplant recipients. Conclusions: Immunocompromised patients, particularly those with autoimmune diseases and transplant recipients, are highly vulnerable to severe COVID-19 outcomes. High-dose steroid use and multiple immunosuppressants further increase risks. Vaccination significantly improves outcomes, with at least one dose benefiting autoimmune patients and two doses necessary for transplant recipients. Personalized vaccination schedules based on immunosuppression levels are essential to mitigate healthcare inequalities and improve outcomes, particularly in underserved populations, informing both clinical and public health strategies. Full article
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<p>The subgroup analysis of each outcome with steroid doses, number of immunosuppressant, and vaccination rate.</p>
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14 pages, 1508 KiB  
Article
Immunogenicity and Determinants of Antibody Response to the BNT162b2 mRNA Vaccine: A Longitudinal Study in a Cohort of People Living with HIV
by Tatjana Baldovin, Davide Leoni, Ruggero Geppini, Andrea Miatton, Irene Amoruso, Marco Fonzo, Chiara Bertoncello, Mascia Finco, Maria Mazzitelli, Lolita Sasset, Annamaria Cattelan and Vincenzo Baldo
Vaccines 2024, 12(10), 1172; https://doi.org/10.3390/vaccines12101172 - 16 Oct 2024
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Abstract
Background: The COVID-19 pandemic posed significant challenges worldwide, with SARS-CoV-2 vaccines critical in reducing morbidity and mortality. This study evaluates the immunogenicity and antibody persistence of the BNT162b2 vaccine in people living with HIV (PLWH). Methods: We monitored anti-SARS-CoV-2 Spike IgG concentration in [...] Read more.
Background: The COVID-19 pandemic posed significant challenges worldwide, with SARS-CoV-2 vaccines critical in reducing morbidity and mortality. This study evaluates the immunogenicity and antibody persistence of the BNT162b2 vaccine in people living with HIV (PLWH). Methods: We monitored anti-SARS-CoV-2 Spike IgG concentration in a cohort of PLWH at five time points (T0–T4) using chemiluminescent microparticle immunoassays (CMIAs) at the baselined both during and after vaccination. In severely immunocompromised individuals, a boosting dose was recommended, and participants and IgG concentration were measured in the two subgroups (boosted and not boosted). Results: In total, 165 PLWH were included, and 83% were male with a median age of 55 years (IQR: 47–62). At T1, 161 participants (97.6%) showed seroconversion with a median of IgG values of 468.8 AU/mL (IQR: 200.4–774.3 AU/mL). By T2, all subjects maintained a positive result, with the median anti-SARS-CoV-2 Spike IgG concentration increasing to 6191.6 AU/mL (IQR: 3666.7–10,800.8 AU/mL). At T3, all participants kept their antibody levels above the positivity threshold with a median of 1694.3 AU/mL (IQR: 926.3–2966.4 AU/mL). At T4, those without a booster dose exhibited a marked decrease to a median of 649.1 AU/mL (IQR: 425.5–1299.8 AU/mL), whereas those with a booster experienced a significant increase to a median of 13,105.2 AU/mL (IQR: 9187.5–18,552.1 AU/mL). The immune response was negatively influenced by the presence of dyslipidaemia at T1 (aOR 4.75, 95% CI: 1.39–16.20) and diabetes at T3 (aOR 7.11, 95% CI: 1.10–46.1), while the use of protease inhibitors (aORs 0.06, 95% CI: 0.01–0.91) and being female (aOR 0.02, 95% CI: 0.01–0.32) at T3 were protective factors. Conclusions: The immunogenicity of the BNT162b2 vaccine in PLWH has been confirmed, with booster doses necessary to maintain high levels of anti-SARS-CoV-2 Spike IgG antibodies, especially in patients with comorbidities. These findings underline the importance of a personalized vaccination strategy in this population. Full article
(This article belongs to the Section COVID-19 Vaccines and Vaccination)
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Figure 1

Figure 1
<p>Study timeline indicating the timing of assessments and vaccinations.</p>
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<p>(<b>a</b>). Antibody concentrations of anti-SARS-CoV-2 Spike IgG throughout the follow-up time point (T1 to T4). Friedman test with Dunn’s post test (the <span class="html-italic">p</span>-value is reported for each pair in the figure). The boxplot shows the concentrations of anti-SARS-CoV-2 Spike IgG at five follow-up time points (T1 to T4), measured in Arbitrary Units per milliliter (AU/mL). The x-axis represents the time points, while the y-axis is on a logarithmic scale, indicating IgG concentration levels. T1 (after first dose): The antibody concentrations range from a minimum of 18.9 AU/mL to a maximum of 24,210.8 AU/mL, with a median of 468.8 AU/mL. The interquartile range (IQR) spans from 200.4 to 774.3 AU/mL. T2 (short-term): Concentrations range from a minimum of 487.7 AU/mL to a maximum of 47,441.1 AU/mL, with a median of 6191.6 AU/mL. The IQR is from 3666.7 to 10,800.8 AU/mL, showing a notable increase after the second dose. T3 (mid-term): The minimum concentration is 76.5 AU/mL, the maximum is 17,367.6 AU/mL, and the median is 1694.3 AU/mL. The IQR extends from 926.3 to 2966.4 AU/mL, showing a reduction compared to T2, but this is still above baseline. T4 (long-term, no boost): For participants who did not receive a booster, concentrations range from a minimum of 44.9 AU/mL to a maximum of 13,804.9 AU/mL, with a median of 649.1 AU/mL. The IQR is from 425.5 to 1299.8 AU/mL, indicating a significant decline in antibody levels. T4 (long-term, with boost): For participants who received a booster dose, concentrations range from 307.3 AU/mL to a maximum of 60,515.1 AU/mL. The median is 13,105.2 AU/mL, and the IQR ranges from 9187.5 to 18,552.1 AU/mL, demonstrating a substantial increase in antibody levels post-booster. The dotted line represents the positivity threshold of 50 AU/mL for the anti-SARS-CoV-2 Spike IgG concentration. (<b>b</b>). Spaghetti plot illustrating the anti-SARS-CoV-2 Spike IgG antibody concentrations (×10³ AU/mL) across the follow-up time points (T1 to T4) on a log10 scale. Each line represents an individual patient’s trajectory, with red lines indicating patients who received a booster dose. A dashed line indicates a positive cut-off at 50 AU/mL. This plot highlights the dynamic changes in antibody levels over time, comparing boosted and non-boosted groups, and facilitates better visualization through the use of log10-transformed data.</p>
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<p>CD4+ count (<b>top</b>) and CD4/CD8 ratio (<b>bottom</b>) at each follow-up time point (T0 to T3). The boxplots illustrate the distribution of both the CD4+ count and CD4/CD8 ratio across the different time points. For the CD4+ count, at pre-vaccination (T0), the median is 687.0, with an interquartile range (IQR) from 508.0 to 875.0. After the first dose (T1), the median is 654.0, with an IQR from 508.0 to 891.5. At short-term follow-up (T2), the median is 676.0, with an IQR from 518.0 to 888.5. Finally, at mid-term (T3), the median is 703.0, with an IQR from 536.0 to 921.0. For the CD4/CD8 ratio, at pre-vaccination (T0), the median is 0.91, with an IQR from 0.62 to 1.25. After the first dose (T1), the median is 0.93, with an IQR from 0.61 to 1.27. At short-term (T2), the median is 0.90, with an IQR from 0.62 to 1.32. At mid-term (T3), the median is 0.90, with an IQR from 0.62 to 1.28.</p>
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