HIV Vaccine Research Articles

Phenotypic Characterization of Subtype A and Recombinant AC Transmitted/Founder Viruses from a Rwandan HIV-1 Heterosexual Transmission Cohort

HIV-1 subtypes have distinct geographical distributions, with subtypes A, C, and D and inter-subtype recombinants circulating in sub-Saharan Africa. Historically, individuals living with subtype A viruses exhibit slower CD4 decline and progression to AIDS diagnosis. Despite this, there are few authentic infectious molecular clones (IMCs) of subtype A or AC recombinant transmitted founder (TF) viruses with which to investigate viral impacts on pathogenesis. In this study, we constructed 16 authentic subtype A1 and 4 A1C recombinant IMCs from the IAVI Rwandan Protocol C acute infection cohort and characterized these viruses phenotypically. The virus replicative capacity (RC) scores varied over 50-fold, but the natural substitution of non-consensus amino acids in the p17(MA) domain of Gag was generally linked to higher RC levels. Sensitivity to a panel of broadly neutralizing antibodies (bNAbs) showed that all but one TF was sensitive to N6, which targets the CD4 binding site, while bNAbs PG16 and PGT 128 had a similar level of potency but reduced breadth against our panel of viruses. In contrast, bNAb 10E8V4 revealed high breadth but much lower potency. This panel of well-characterized, authentic subtype A and AC recombinant IMCs provides a resource for studies on the role of the virus subtype in HIV-1 transmission, pathogenesis, and vaccine design.

A qualitative study on experiences and perceptions of screening for enrolment in HIV clinical research among volunteers in Kenya

INTRODUCTION Screening volunteers to determine their eligibility to enrol in clinical research is an important phase in clinical research. However, little is known about how volunteers view and experience this phase of research implementation. This study explored volunteers’ perceptions and experiences of screening for enrolment into HIV clinical research studies. MATERIALS AND METHODS A qualitative study was conducted with 44 research participants purposively selected from a sample of 164 participants drawn from six research studies at the Kenya Aids Vaccine Initiative-Institute of Clinical Research (KAVI-ICR) in Nairobi, Kenya. Data was collected between March and June 2014, through in-depth interviews that were audio recorded and transcribed verbatim. Data were managed and thematically analyzed using the Atlas ti software. RESULTS Participants expressed mixed views and experiences about screening. A majority had initial fears about HIV testing and being screened for possible chronic diseases. Discomfort with physical examination, amounts of blood collected and associated pain were reported. On a positive note, participants were appreciative of the free comprehensive screening, and confirmations of being in good health. Those found with minor ailments reported receiving treatment before enrolment. HIV risk reduction behaviours following post-test counselling were also reported by some. CONCLUSIONS Evaluating participants’ experiences of screening for enrolment is important for the design of research that meets ethical requirements and responds to research participants’ fears and concerns for optimal enrolment and retention.

Footprints of innate immune activity during HIV-1 reservoir cell evolution in early-treated infection.

Antiretroviral treatment (ART) initiation during the early stages of HIV-1 infection is associated with a higher probability of maintaining drug-free viral control during subsequent treatment interruptions, for reasons that remain unclear. Using samples from a randomized-controlled human clinical trial evaluating therapeutic HIV-1 vaccines, we here show that early ART commencement is frequently associated with accelerated and efficient selection of genome-intact HIV-1 proviruses in repressive chromatin locations during the first year after treatment initiation. This selection process was unaffected by vaccine-induced HIV-1-specific T cell responses. Single-cell proteogenomic profiling demonstrated that cells harboring intact HIV-1 displayed a discrete phenotypic signature of immune selection by innate immune responses, characterized by a slight but significant upregulation of HLA-C, HLA-G, the IL-10 receptor, and other markers involved in innate immune regulation. Together, these results suggest an accelerated immune selection of viral reservoir cells during early-treated HIV-1 infection that seems at least partially driven by innate immune responses.

The Role of Peptides in Combatting HIV Infection: Applications and Insights.

Peptide-based inhibitors represent a promising approach for the treatment of HIV-1, offering a range of potential advantages, including specificity, low toxicity, and the ability to target various stages of the viral lifecycle. This review outlines the current state of research on peptide-based anti-HIV therapies, highlighting key advancements and identifying future research directions. Over the past few years, there has been significant progress in developing synthetic peptide-based drugs that target various stages of the viral life cycle, including entry and replication. These approaches aim to create effective anti-HIV therapies. Additionally, peptides have proven valuable in the development of anti-HIV vaccines. In the quest for effective HIV vaccines, discovering potent antigens and designing suitable vaccine strategies are crucial for overcoming challenges such as low immunogenicity, safety concerns, and increased viral load. Innovative strategies for vaccine development through peptide research are, therefore, a key focus area for achieving effective HIV prevention. This review aims to explore the strategies for designing peptides with anti-HIV activity and to highlight their role in advancing both therapeutic and preventive measures against HIV.

Safety and implementation of a phase 1 randomized GLA-SE-adjuvanted CH505TF gp120 HIV vaccine trial in newborns.

The neonatal immune system is uniquely poised to generate broadly neutralizing antibodies (bnAbs) and thus infants are ideal for evaluating HIV vaccine candidates. We present the design and safety of a novel glucopyranosyl lipid A (GLA)-stable emulsion (SE) adjuvant admixed with a first-in-infant CH505 transmitter-founder (CH505TF) gp120 immunogen designed to induce precursors for bnAbs against HIV. HVTN 135 is a phase I randomized, placebo-controlled trial of CH505TF+GLA-SE or placebo. Healthy infants in South Africa aged ≤5 days, born to mothers living with HIV but HIV nucleic acid negative at birth were randomized to five doses of CH505TF + GLA-SE or placebo at birth and 8, 16, 32, and 54 weeks. 38 infants (median age = 4 days; interquartile range 4, 4.75 days) were enrolled November 2020 to January 2022. Among 28 (10) infants assigned to receive CH505TF + GLA-SE (placebo), most (32/38) completed the 5-dose immunization series and follow-up (35/38). Solicited local and systemic reactions were more frequent in vaccine (8, 28.6% local; 16, 57.1% systemic) vs. placebo recipients (1, 10% local, p = 0.25; 4, 40.0% systemic, p = 0.38). All events were Grade 1 except two Grade 2 events (pain, lethargy). Serious vaccine-related adverse events were not recorded. This study illustrates the feasibility of conducting trials of novel adjuvanted HIV vaccines in HIV-exposed infants receiving standard infant vaccinations. The safety profile of the CH505TF + GLA-SE vaccine was reassuring. ClinicalTrials.gov NCT04607408. National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH). This paper summarizes the phase 1 trial design and safety profile of an experimental CH505TF immunogen + GLA-SE HIV vaccine in infants born to mothers living with HIV.

Antiretroviral Therapy with Ritonavir-Boosted Atazanavir- and Lopinavir-Containing Regimens Correlates with Diminished HIV-1 Neutralization.

The impact of virion maturation on neutralizing antibody responses in HIV treatment is not fully understood. This study examines whether antiretroviral regimens (ART) with boosted protease inhibitors (b-PI), which increase exposure to immature virions, affect neutralization capacity compared to Non-b-PI regimens. Neutralization activity was assessed in 45 HIV-infected individuals on b-PI regimens and 56 on Non-b-PI regimens, adjusting for factors like infection duration, ART initiation, and immune markers. Individuals on b-PI regimens had significantly lower neutralization scores [mean: 6.1, 95% Confidence Interval (CI): 5.3-6.9] than those on Non-b-PI regimens (mean: 8.9, 95% CI: 8.0-9.9; p < 0.0001). This difference was not explained by infection duration or CD4+ counts. CD4+/CD8+ ratios were positively associated with neutralization, while b-PI use was negatively associated. A regression model indicated that b-PI use significantly predicted lower neutralization scores (beta = -0.30, p = 0.049). These findings suggest that exposure to immature virions via b-PI use reduces neutralizing antibody responses, highlighting the importance of virion maturation in antibody induction. ART regimens promoting exposure to mature virions may enhance neutralization, with potential implications for HIV vaccine design. Further research is needed to explore implications for HIV vaccine design, especially using virus-like particles.

Minimally Modified HIV-1 Infection of Macaques: Development, Utility, and Limitations of Current Models.

Nonhuman primate (NHP) studies that utilize simian immunodeficiency virus (SIV) to model human immunodeficiency virus (HIV-1) infection have proven to be powerful, highly informative research tools. However, there are substantial differences between SIV and HIV-1. Accordingly, there are numerous research questions for which SIV-based models are not well suited, including studies of certain aspects of basic HIV-1 biology, and pre-clinical evaluations of many proposed HIV-1 treatment, prevention, and vaccination strategies. To overcome these limitations of NHP models of HIV-1 infection, several groups have pursued the derivation of a minimally modified HIV-1 (mmHIV-1) capable of establishing pathogenic infection in macaques that authentically recapitulates key features of HIV-1 in humans. These efforts have focused on three complementary objectives: (1) engineering HIV-1 to circumvent species-specific cellular restriction factors that otherwise potently inhibit HIV-1 in macaques, (2) introduction of a C chemokine receptor type 5 (CCR5)-tropic envelope, ideally that can efficiently engage macaque CD4, and (3) correction of gene expression defects inadvertently introduced during viral genome manipulations. While some progress has been made toward development of mmHIV-1 variants for use in each of the three macaque species (pigtail, cynomolgus, and rhesus), model development progress has been most promising in pigtail macaques (PTMs), which do not express an HIV-1-restricting tripartite motif-containing protein 5 α (TRIM5α). In our work, we have derived a CCR5-tropic mmHIV-1 clone designated stHIV-A19 that comprises 94% HIV-1 genome sequence and replicates to high acute-phase titers in PTMs. In animals treated with a cell-depleting CD8α antibody at the time of infection, stHIV-A19 maintains chronically elevated plasma viral loads with progressive CD4+ T-cell loss and the development of acquired immune-deficiency syndrome (AIDS)-defining clinical endpoints. However, in the absence of CD8α+ cell depletion, no mmHIV-1 model has yet displayed high levels of chronic viremia or AIDS-like pathogenesis. Here, we review mmHIV-1 development approaches, the phenotypes, features, limitations, and potential utility of currently available mmHIV-1s, and propose future directions to further advance these models.

HIV incidence and its associated factors among young adults with multiple sexual partners in Maputo, Mozambique: a vaccine preparedness study

IntroductionSub-Saharan Africa has a high burden of HIV, particularly among female sex workers (FSW) and men who have sex with men (MSM). Future clinical trials to evaluate vaccines and other interventions to prevent HIV will need to enroll populations with high HIV incidence. We conducted an observational study of HIV incidence among men and women with multiple sexual partners—including MSM and FSW—in Maputo, Mozambique, in order to prepare the country to conduct future efficacy trials of candidate HIV vaccines and other HIV prevention products.MethodsWe conducted a prospective observational HIV incidence study in Maputo, Mozambique, that enrolled adults aged 18–35 years, without HIV, who had two or more sexual partners in the preceding three months. Recruitment strategies prioritized participation of MSM and FSW. Participants were followed for 24 months with HIV-1 testing every 3 months and staff-administered behavioral questionnaires every 6 months. Cox proportional hazard modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for factors potentially associated with HIV acquisition.ResultsFrom January 2014 to October 2017, 505 adults without HIV were enrolled with median age of 21 years (interquartile range:19–24); 41% were female and 82% were single. There were 19 HIV seroconversions (10 female and 9 male) during 943 person-years (PY) of observation (overall HIV incidence 2.02/100PY; 95%CI 1.21–3.15). The highest HIV incidence was observed among sex workers (2.08/100PY; 95%CI 0.25–7.52) and MSM (19.18/100PY; 95%CI 3.96–56.06). Increased hazard of incident HIV was observed among participants who were MSM (HR = 27.95, 95%CI 4.39–117.94), p = 0.0004), reported three or more sexual partners at enrollment (HR = 7.39, 95%CI 1.64–33.25, p = 0.009), and indicated ever having a sexual partner living with HIV (HR = 9.64, 95%CI 2.23–41.71, p = 0.002).ConclusionOur findings may inform inclusion criteria for upcoming clinical trials of HIV prevention interventions, including vaccine candidates, which may prioritize enrollment of MSM, people with more than three sexual partners, and people with sexual partners who are living with HIV. These same populations are in need of further intervention to reduce HIV incidence.

Potent and broad HIV-1 neutralization in fusion peptide-primed SHIV-infected macaques.

An antibody-based HIV-1 vaccine will require the induction of potent cross-reactive HIV-1-neutralizing responses. To demonstrate feasibility toward this goal, we combined vaccination targeting the fusion-peptide site of vulnerability with infection by simian-human immunodeficiency virus (SHIV). In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45%-77% breadth (geometric mean 50% inhibitory dilution [ID50] ∼100) on a 208-strain panel. Molecular dissection of these responses by antibody isolation and cryo-electron microscopy (cryo-EM) structure determination revealed 15 of 16 antibody lineages with cross-clade neutralization to be directed toward the fusion-peptide site of vulnerability. In each macaque, isolated antibodies from memory B cells recapitulated the plasma-neutralizing response, with fusion-peptide-binding antibodies reaching breadths of 40%-60% (50% inhibitory concentration [IC50]<50μg/mL) and total lineage-concentrations estimates of 50-200μg/mL. Longitudinal mapping indicated that these responses arose prior to SHIV infection. Collectively, these results provide invivo molecular examples for one to a few B cell lineages affording potent, broadly neutralizing plasma responses.

Mosaic HIV-1 vaccine and SHIV challenge strain V2 loop sequence identity and protection in primates

The failure of human vaccine efficacy trials assessing a mosaic HIV-1 vaccine calls into question the translatability of preclinical SHIV challenge studies that demonstrated high efficacy of this vaccine in primates. Here we present a post hoc immune correlates analysis of HIV-1 Env peptide-binding antibody responses from the NHP13-19 study identifying the V2 loop as the principal correlate of protection in primates. Moreover, we found high V2 loop sequence identity between the Mos1 vaccine component and the SHIV challenge strain, while the vaccine showed considerably lower V2 identity to globally circulating HIV-1 sequences. Thus, the induction of immune responses against the V2 epitope, which had exceptional identity between the vaccine and challenge Env strains, may have contributed to the high protection in primates.

Assessing willingness to pay for children's COVID-19 vaccination among healthcare providers and users using a theory-based discrete choice experiment

Improving vaccine coverage among children is crucial to prevent the long-term consequences of COVID-19 infections and the emergence of resistant COVID-19 variants, especially in resource-scarce settings. This study determined factors influencing the willingness to take and pay for COVID-19 vaccine for children among Vietnamese healthcare professionals and the public. A Theory-Based discrete-choice experiment was focused on a different topic related to vaccines, including the COVID-19 vaccine for children, Monkeypox, the adult COVID-19 booster, the HIV vaccine, and a potential future pandemic. The recruitment period was from April to August 2022, and a total of 5700 Vietnamese individuals aged 16 and above from various regions of the country participated in the study. The data for the sub-study on the COVID-19 vaccination for children was completed by 891 of these participants. Most participants agreed on vaccination for all children. Among healthcare professionals it was 76.2% and 69.3% for the general population. Healthcare professionals were the main source of vaccine information (70.7%). Payment options of 50%, 100%, and full subsidy were the most popular. Concerns about vaccine characteristics were associated with lower acceptance among healthcare professionals and the general public. The burden of historical medical expenses negatively correlated with willingness to pay for vaccination, while service satisfaction positively correlated with willingness to pay. To develop an effective vaccination program among children in Vietnam, providing accurate information and satisfying vaccine services, primarily through knowledgeable and professional healthcare providers, can improve the willingness to vaccinate and pay for the COVID-19 vaccine.

Signal peptide exchange alters HIV-1 envelope antigenicity and immunogenicity.

HIV-1 envelope (Env) is the key target for antibodies (Abs) against the virus and thus an important HIV-1 vaccine component. Env is synthesized from a gp160 precursor with a signal peptide (SP) at its N-terminus. This study investigated the influence of the SP on Env antigenicity and immunogenicity. Env proteins from two HIV-1 isolates, AA05 and AC02, were analyzed as gp120 and gp160 in their native wild-type (WT) forms and as chimeras with swapped SPs (AA05-02 and AC02-05). The WT and chimeric Env were assessed for antigenicity and glycosylation using monoclonal antibodies (mAbs) and glycan probes. Immunogenicity was tested in mice using three vaccine types: gp120 protein, gp120 DNA+gp120 protein, and gp120 DNA+gp160 DNA. The recombinant AC02 gp120 protein was antigenically superior to AA05 as indicated by higher reactivity with most mAbs tested. When SPs were swapped, the antigenicity of the chimeric gp120s (AA05-02 and AC02-05) resembled that of the gp120s from which the SPs were derived; AA05-02 was similar to AC02 and vice versa. Glycan probe reactivity followed a similar pattern: AA05-02 and AC02 showed similar affinity to high-mannose specific mAbs and lectins. Interestingly, the antigenicity of gp160s showed an opposite pattern; membrane-bound gp160 expressed with the AA05 SP (AA05 and AC02-05) showed greater mAb binding than gp160 with the AC02 SP (AC02 and AA05-02). Mice immunized with gp120 protein showed that AA05-02 induced stronger cross-reactive binding Ab responses than AA05 WT, and AC02 elicited stronger responses than AC02-05, indicating AC02 SP enhanced gp120 immunogenicity. However, when DNA vaccines were included (gp120 DNA+gp120 protein and gp120 DNA+gp160 DNA), the use of heterologous SPs diminished the immunogenicity of the WT immunogens. Among the three vaccine regimens tested, only gp120 DNA+gp160 DNA immunization elicited low-level Tier 2 neutralizing Abs, with AA05 WT inducing Abs with greater neutralization capabilities than AA05-02. These data demonstrate that the SP can significantly impact the antigenicity and immunogenicity of HIV-1 Env proteins. Hence, while SP swapping is a common practice in constructing Env immunogens, this study highlights the importance of careful consideration of the effects of replacing native SPs on the immunogenicity of Env vaccines.

The Latest Developments In HIV Vaccines

The Latest Developments In HIV Vaccines

Safety and immunogenicity after a 30-month boost of a subtype C ALVAC-HIV (vCP2438) vaccine prime plus bivalent subtype C gp120/MF59 vaccine boost (HVTN 100): A phase 1–2 randomized double-blind placebo-controlled trial

Induction of broad, durable immune responses is a challenge in HIV vaccine development. HVTN 100 Part A administered subtype C-containing ALVAC-HIV at months 0 and 1, and ALVAC-HIV with bivalent subtype C gp120/MF59 at months 3, 6 and 12. As IgG binding antibody and T-cell responses were similar or greater at month 12.5 vs. month 6.5, but waned by month 18, we investigated vaccine-elicited immune responses after a month 30 boost in this study, HVTN 100 Part B. From 13 September 2017 to 7 August 2018, a subgroup of vaccinees was randomized to receive intramuscular injections of ALVAC+gp120/MF59 (n = 32) or gp120/MF59 alone (n = 31) and a subgroup of placebo recipients was administered placebo (n = 7) at month 30. Primary outcomes were safety, IgG binding antibodies (bAbs) to vaccine-specific and V1V2 Env proteins and vaccine-specific CD4+ T cells at month 30.5. Secondary outcomes included neutralizing and antibody dependent cellular cytotoxicity functions and durability at months 30 and 36. Both vaccine groups had an acceptable safety profile. There were no statistically significant differences in the occurrence or level of IgG bAbs between the vaccine boost groups for any vaccine-specific or V1V2 antigens. IgG responses were higher to vaccine-matched gp120 than to V1V2. The booster vaccination restored the magnitude-breadth IgG bAb response to V1V2 antigens at month 30.5. However, it rapidly waned by month 36. CD4+ T-cell response rates to the 3 vaccine-matched Env antigens for the combined vaccine groups ranged from 37% at month 30, boosted to as high as 91% at month 30.5, and waned by month 36 to as low as 44%, with no significant differences between the vaccine boost groups. Because these responses waned after 6 months, additional strategies may be needed to maintain the durability of prime-boost vaccine regimens and to generate these or other immune responses that confer protection. Trial registration: South African National Clinical Trials Register (SANCTR number: DOH—27-0215-4796) and ClinicalTrials.gov (NCT02404311).

Comparison of the immunogenicity of mRNA-encoded and protein HIV-1 Env-ferritin nanoparticle designs.

Nucleoside-modified mRNA technology has revolutionized vaccine development with the success of mRNA COVID-19 vaccines. We used modified mRNA technology for the design of envelopes (Env) to induce HIV-1 broadly neutralizing antibodies (bnAbs). However, unlike SARS-CoV-2 neutralizing antibodies that are readily made, HIV-1 bnAb induction is disfavored by the immune system because of the rarity of bnAb B cell precursors and the cross-reactivity of bnAbs targeting certain Env epitopes with host molecules, thus requiring optimized immunogen design. The use of protein nanoparticles (NPs) has been reported to enhance B cell germinal center responses to HIV-1 Env. Here, we report our experience with the expression of Env-ferritin NPs compared with membrane-bound Env gp160 when encoded by modified mRNA. We found that well-folded Env-ferritin NPs were a minority of the protein expressed by an mRNA design and were immunogenic at 20 µg but minimally immunogenic in mice at 1 µg dose in vivo and were not expressed well in draining lymph nodes (LNs) following intramuscular immunization. In contrast, mRNA encoding gp160 was more immunogenic than mRNA encoding Env-NP at 1 µg dose and was expressed well in draining LN following intramuscular immunization. Thus, analysis of mRNA expression in vitro and immunogenicity at low doses in vivo are critical for the evaluation of mRNA designs for optimal immunogenicity of HIV-1 immunogens.IMPORTANCEAn effective HIV-1 vaccine that induces protective antibody responses remains elusive. We have used mRNA technology for designs of HIV-1 immunogens in the forms of membrane-bound full-length envelope gp160 and envelope ferritin nanoparticle. Here, we demonstrated in a mouse model that the membrane-bound form induced a better response than envelope ferritin nanoparticle because of higher in vivo protein expression. The significance of our research is in highlighting the importance of analysis of mRNA design expression and low-dose immunogenicity studies for HIV-1 immunogens before moving to vaccine clinical trials.

Regulation of the cell surface expression of classical and non-classical MHC proteins by the human cytomegalovirus UL40 and rhesus cytomegalovirus Rh67 proteins.

The protective immune response induced by a rhesus cytomegalovirus (RhCMV)-vectored simian immunodeficiency virus (SIV) vaccine in rhesus macaques depends on the presence of the viral Rh67 gene in the vaccine. The Rh67 protein contains a peptide that allows the RhCMV-infected cells to maintain expression of major histocompatibility complex (MHC) antigen E at the cell surface. We show that production of this peptide, referred to as "VL9," mirrors that of the equivalent peptide present in the human cytomegalovirus (CMV) protein UL40, despite the little sequence similarity between the two CMV proteins. We also show that the mature UL40 and Rh67 proteins, which have no previously described function, also contribute to CMV immune evasion by reducing cell surface expression of MHC proteins important for the immune system to detect infected cells. Despite these similarities, our work also reveals possible differences between Rh67 and UL40, and these may have implications for the use of human CMV as the vector for a potential HIV-1 vaccine.

HIV Vaccine Development at a Crossroads: New B and T Cell Approaches.

Despite rigorous scientific efforts over the forty years since the onset of the global HIV pandemic, a safe and effective HIV-1 vaccine remains elusive. The challenges of HIV vaccine development have proven immense, in large part due to the tremendous sequence diversity of HIV and its ability to escape from antiviral adaptive immune responses. In recent years, several phase 3 efficacy trials have been conducted, testing a similar hypothesis, e.g., that non-neutralizing antibodies and classical cellular immune responses could prevent HIV-1 acquisition. These studies were not successful. As a result, the field has now pivoted to bold novel approaches, including sequential immunization strategies to drive the generation of broadly neutralizing antibodies and human CMV-vectored vaccines to elicit MHC-E-restricted CD8+ T cell responses. Many of these vaccine candidates are now in phase 1 trials, with early promising results.

Global and regional genetic diversity of HIV-1 in 2010–21: systematic review and analysis of prevalence

The extensive global genetic diversity of HIV-1 poses a major challenge to HIV vaccine development. We aimed to determine recent estimates of and changes in the global and regional distributions of HIV-1 genetic variants. We conducted a systematic literature review by searching PubMed, Embase, Global Health, and CINAHL for studies containing country-specific HIV-1 subtyping data, published between Jan 1, 2010and Sep 16, 2022. The proportions of HIV-1 subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) in each country were weighted by UNAIDS estimates of the numbers of people living with HIV (PLHIV) in each country to obtain regional and global prevalence estimates of HIV-1 subtypes, CRFs, and URFs with 95% CIs for the time periods 2010-15and 2016-21. The protocol is registered with PROSPERO, CRD42017067164. We obtained 1044datasets, containing HIV-1 subtyping data from 653 013PLHIV from 122countries in 2010-2021. In 2016-2021, subtype Caccounted for 50·4% (95% CI 50·2-50·7; n=18 570 462of 36 823 798) of global HIV infections, subtype Afor 12·4% (12·2-12·6; n=4 571 250), subtype Bfor 11·3% (11·1-11·5; n=4 157 686), subtype Gfor 2·9% (2·9-3·0; n=1 083 568), subtype Dfor 2·6% (2·5-2·7; n=945 815), subtype Ffor 0·9% (0·8-0·9; n=316 724), CRFs for 15·1% (14·9-15·3; n=5 564 566), and URFs for 2·0% (1·9-2·1; n=733 374). Subtypes H, J, and K each accounted for 0·1% or less of infections. Compared with 2010-15, we observed significant (p<0·0001) increases in global proportions of subtype A (0·9%, 95% CI 0·7to 1·1) and subtype C (3·4%, 3·0to 3·7) and decreases in subtype D (-0·5%, -0·6to -0·4), subtype G (-0·8%, -1·0to -0·7), CRFs (-1·0%, -1·3to -0·8), and URFs (-1·8%, -1·9to -1·7), with no changes for subtypes Band F. The global proportion of infections attributed torecombinants decreased from 21·6% (95% CI 21·4 to 21·7; n=7 099 252of 32 622 808) in 2010-15to 19·3% (19·1to 19·5; n=7 094 694of 36 823 798) in 2016-21 (-2·3%, 95% CI -2·6to -2·0; p<0·0001). Regional distributions of HIV-1 variants were complex and evolving, with global trends in the prevalence of HIV-1 variants supported by trends across the regions. Global and regional HIV-1 genetic diversity are complex and continue to evolve. Continued and improved surveillance of HIV-1 variants remains vital for HIV vaccine development and implementation. None.

Immunization of cows with HIV envelope trimers generates broadly neutralizing antibodies to the V2-apex from the ultralong CDRH3 repertoire.

The generation of broadly neutralizing antibodies (bnAbs) to conserved epitopes on HIV Envelope (Env) is one of the cornerstones of HIV vaccine research. The animal models commonly used for HIV do not reliably produce a potent broadly neutralizing serum antibody response, with the exception of cows. Cows have previously produced a CD4 binding site response by homologous prime and boosting with a native-like Env trimer. In small animal models, other engineered immunogens were shown to focus antibody responses to the bnAb V2-apex region of Env. Here, we immunized two groups of cows (n = 4) with two regimens of V2-apex focusing Env immunogens to investigate whether antibody responses could be generated to the V2-apex on Env. Group 1 was immunized with chimpanzee simian immunodeficiency virus (SIV)-Env trimer that shares its V2-apex with HIV, followed by immunization with C108, a V2-apex focusing immunogen, and finally boosted with a cross-clade native-like trimer cocktail. Group 2 was immunized with HIV C108 Env trimer followed by the same HIV trimer cocktail as Group 1. Longitudinal serum analysis showed that one cow in each group developed serum neutralizing antibody responses to the V2-apex. Eight and 11 bnAbs were isolated from Group 1 and Group 2 cows, respectively, and showed moderate breadth and potency. Potent and broad responses in this study developed much later than previous cow immunizations that elicited CD4bs bnAbs responses and required several different immunogens. All isolated bnAbs were derived from the ultralong CDRH3 repertoire. The finding that cow antibodies can target more than one broadly neutralizing epitope on the HIV surface reveals the generality of elongated structures for the recognition of highly glycosylated proteins. The exclusive isolation of ultralong CDRH3 bnAbs, despite only comprising a small percent of the cow repertoire, suggests these antibodies outcompete the long and short CDRH3 antibodies during the bnAb response.

Identification of a Clade-Specific HLA-C*03:02 CTL Epitope GY9 Derived from the HIV-1 p17 Matrix Protein.

Efforts towards an effective HIV-1 vaccine have remained mainly unsuccessful. There is increasing evidence for a potential role of HLA-C-restricted CD8+ T cell responses in HIV-1 control, including our recent report of HLA-C*03:02 among African children. However, there are no documented optimal HIV-1 CD8+ T cell epitopes restricted by HLA-C*03:02; additionally, the structural influence of HLA-C*03:02 on epitope binding is undetermined. Immunoinformatics approaches provide a fast and inexpensive method to discover HLA-restricted epitopes. Here, we employed immunopeptidomics to identify HLA-C*03:02 CD8+ T cell epitopes. We identified a clade-specific Gag-derived GY9 (GTEELRSLY) HIV-1 p17 matrix epitope potentially restricted to HLA-C*03:02. Residues E62, T142, and E151 in the HLA-C*03:02 binding groove and positions p3, p6, and p9 on the GY9 epitope are crucial in shaping and stabilizing the epitope binding. Our findings support the growing evidence of the contribution of HLA-C molecules to HIV-1 control and provide a prospect for vaccine strategies.