Publications by authors named "Jonathan M Carlson"

83 Publications

Elevated HIV Infection of CD4 T Cells in MRKAd5 Vaccine Recipients Due to CD8 T Cells Targeting Adapted Epitopes.

J Virol 2021 Jul 26;95(16):e0016021. Epub 2021 Jul 26.

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

HIV frequently escapes CD8 T cell responses, leading to the accumulation of viral adaptations. We recently demonstrated that during chronic HIV infection, adapted epitopes can promote maturation of dendritic cells (DCs) through direct CD8 T cell interactions and lead to enhanced HIV -infection of CD4 T cells. Here, we sought to determine the role of such adaptations following HIV MRKAd5 vaccination. We observed that vaccine-induced adapted epitope-specific CD8 T cells promoted higher levels of DC maturation than nonadapted ones and that these matured DCs significantly enhanced HIV -infection. These matured DCs were associated with higher levels of interleukin 5 (IL-5) and IL-13 and a lower level of CXCL5, which have been shown to impact DC maturation, as well as a lower level of CXCL16. Finally, we observed that vaccine recipients with high HLA-I-associated adaptation became HIV infected more quickly. Our results offer another possible mechanism for enhanced infection among MRKAd5 vaccinees. Despite the well-established contribution of CD8 T cells in HIV control, prior CD8 T cell-based HIV vaccines have failed to demonstrate any efficacy in preventing viral infection. One such vaccine, known as the MRKAd5 vaccine, showed a potential increased risk of viral infection among vaccine recipients. However, the underlying mechanism(s) remains unclear. In this study, we observed that vaccine recipients with high adaptation to their HLA-I alleles were associated with an increased HIV infection risk in comparison to the others. Similar to what we observed in HIV infection in the prior study, adapted epitope-specific CD8 T cells obtained from vaccine recipients exhibit a greater capacity in facilitating viral infection by promoting dendritic cell maturation. Our findings provide a possible explanation for the enhanced viral acquisition risk among MRKAd5 vaccine recipients and highlight the importance of optimizing vaccine design with consideration of HLA-I-associated HIV adaptation.
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http://dx.doi.org/10.1128/JVI.00160-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312883PMC
July 2021

Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein.

PLoS One 2021 28;16(4):e0250780. Epub 2021 Apr 28.

Fractal Therapeutics, Cambridge, MA, United States of America.

The spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the molecular target for many vaccines and antibody-based prophylactics aimed at bringing COVID-19 under control. Such a narrow molecular focus raises the specter of viral immune evasion as a potential failure mode for these biomedical interventions. With the emergence of new strains of SARS-CoV-2 with altered transmissibility and immune evasion potential, a critical question is this: how easily can the virus escape neutralizing antibodies (nAbs) targeting the spike RBD? To answer this question, we combined an analysis of the RBD structure-function with an evolutionary modeling framework. Our structure-function analysis revealed that epitopes for RBD-targeting nAbs overlap one another substantially and can be evaded by escape mutants with ACE2 affinities comparable to the wild type, that are observed in sequence surveillance data and infect cells in vitro. This suggests that the fitness cost of nAb-evading mutations is low. We then used evolutionary modeling to predict the frequency of immune escape before and after the widespread presence of nAbs due to vaccines, passive immunization or natural immunity. Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection. Predicted resistance timelines are comparable to those of the decay kinetics of nAbs raised against vaccinal or natural antigens, raising a second potential mechanism for loss of immunity in the population. Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250780PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081162PMC
May 2021

T-cell receptor sequencing identifies prior SARS-CoV-2 infection and correlates with neutralizing antibody titers and disease severity.

medRxiv 2021 Mar 22. Epub 2021 Mar 22.

Measuring the adaptive immune response to SARS-CoV-2 can enable the assessment of past infection as well as protective immunity and the risk of reinfection. While neutralizing antibody (nAb) titers are one measure of protection, such assays are challenging to perform at a large scale and the longevity of the SARS-CoV-2 nAb response is not fully understood. Here, we apply a T-cell receptor (TCR) sequencing assay that can be performed on a small volume standard blood sample to assess the adaptive T-cell response to SARS-CoV-2 infection. Samples were collected from a cohort of 302 individuals recovered from COVID-19 up to 6 months after infection. Previously published findings in this cohort showed that two commercially available SARS-CoV-2 serologic assays correlate well with nAb testing. We demonstrate that the magnitude of the SARS-CoV-2-specific T-cell response strongly correlates with nAb titer, as well as clinical indicators of disease severity including hospitalization, fever, or difficulty breathing. While the depth and breadth of the T-cell response declines during convalescence, the T-cell signal remains well above background with high sensitivity up to at least 6 months following initial infection. Compared to serology tests detecting binding antibodies to SARS-CoV-2 spike and nucleoprotein, the overall sensitivity of the TCR-based assay across the entire cohort and all timepoints was approximately 5% greater for identifying prior SARS-CoV-2 infection. Notably, the improved performance of T-cell testing compared to serology was most apparent in recovered individuals who were not hospitalized and were sampled beyond 150 days of their initial illness, suggesting that antibody testing may have reduced sensitivity in individuals who experienced less severe COVID-19 illness and at later timepoints. Finally, T-cell testing was able to identify SARS-CoV-2 infection in 68% (55/81) of convalescent samples having nAb titers below the lower limit of detection, as well as 37% (13/35) of samples testing negative by all three antibody assays. These results demonstrate the utility of a TCR-based assay as a scalable, reliable measure of past SARS-CoV-2 infection across a spectrum of disease severity. Additionally, the TCR repertoire may be useful as a surrogate for protective immunity with additive clinical value beyond serologic or nAb testing methods.
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http://dx.doi.org/10.1101/2021.03.19.21251426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010755PMC
March 2021

HLA-associated preadaptation in HIV Vif is associated with higher set point viral load and faster CD4+ decline in Zambian transmission pairs.

AIDS 2021 07;35(8):1157-1165

Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia.

Objective S: We investigated the relationship between human leukocyte antigen (HLA)-associated preadaptation for the entire subtype C HIV-1 proteome of the transmitted founder virus and subsequent HIV-1 disease progression in a cohort of heterosexual linked transmission pairs in Zambia.

Design: An adaptation model was used to calculate an adaptation score for each virus-HLA combination in order to quantify the degree of preadaptation of the transmitted virus to the linked recipient's HLA alleles. These scores were then assessed for their relationship to viral load and longitudinal CD4+ decline in the recipient.

Methods: Viral RNA was extracted from the plasma of the donor partner and the linked recipient near the time of transmission, as well as longitudinally from the linked recipient. Viral adaptation scores were calculated for each individual and each protein in the subtype C HIV-1 proteome.

Results: The majority of HLA-associated sites were located in Gag, Pol and Nef; however, proportional to protein length, the accessory and regulatory proteins contained a relatively high proportion of HLA-associated sites. Over the course of infection, HLA-mediated immune adaptation increased for all proteins except Vpu and gp120. Preadaptation was positively associated with higher early set point viral load and faster CD4+ decline. When examined by protein, preadaptation in Pol and Vif were statistically significantly associated with these markers of disease progression.

Conclusion: Adaptation in Pol had the greatest impact on viral control. Despite containing a large proportion of HLA-associated sites, Vif was the only regulatory or accessory protein for which preadaptation significantly correlated with disease progression.
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http://dx.doi.org/10.1097/QAD.0000000000002868DOI Listing
July 2021

Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection at Both Individual and Population Levels.

medRxiv 2020 Sep 17. Epub 2020 Sep 17.

Immunotherapy, Cell Therapy and Biobank (ITCB), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy.

T cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection. Here, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides (class II data in a forthcoming study). Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared "public" T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells. Collectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3-7 = 85.1% [95% CI = 79.9-89.7]; Day 8-14 = 94.8% [90.7-98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1-98.3]). These results demonstrate an approach to reliably assess the adaptive immune response both soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points. This blood-based molecular approach to characterizing the cellular immune response has applications in clinical diagnostics as well as in vaccine development and monitoring.
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http://dx.doi.org/10.1101/2020.07.31.20165647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418734PMC
September 2020

A large-scale database of T-cell receptor beta (TCRβ) sequences and binding associations from natural and synthetic exposure to SARS-CoV-2.

Res Sq 2020 Aug 4. Epub 2020 Aug 4.

We describe the establishment and current content of the ImmuneCODE™ database, which includes hundreds of millions of T-cell Receptor (TCR) sequences from over 1,400 subjects exposed to or infected with the SARS-CoV-2 virus, as well as over 135,000 high-confidence SARS-CoV-2-specific TCRs. This database is made freely available, and the data contained in it can be downloaded and analyzed online or offline to assist with the global efforts to understand the immune response to the SARS-CoV-2 virus and develop new interventions.
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http://dx.doi.org/10.21203/rs.3.rs-51964/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418738PMC
August 2020

CD8 T cells targeting adapted epitopes in chronic HIV infection promote dendritic cell maturation and CD4 T cell trans-infection.

PLoS Pathog 2019 08 9;15(8):e1007970. Epub 2019 Aug 9.

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

HIV-1 frequently escapes from CD8 T cell responses via HLA-I restricted adaptation, leading to the accumulation of adapted epitopes (AE). We previously demonstrated that AE compromise CD8 T cell responses during acute infection and are associated with poor clinical outcomes. Here, we examined the impact of AE on CD8 T cell responses and their biological relevance in chronic HIV infection (CHI). In contrast to acute infection, the majority of AE are immunogenic in CHI. Longitudinal analyses from acute to CHI showed an increased frequency and magnitude of AE-specific IFNγ responses compared to NAE-specific ones. These AE-specific CD8 T cells also were more cytotoxic to CD4 T cells. In addition, AE-specific CD8 T cells expressed lower levels of PD1 and CD57, as well as higher levels of CD28, suggesting a more activated and less exhausted phenotype. During CHI, viral sequencing identified AE-encoding strains as the dominant quasispecies. Despite increased CD4 T cell cytotoxicity, CD8 T cells responding to AE promoted dendritic cell (DC) maturation and CD4 T cell trans-infection perhaps explaining why AE are predominant in CHI. Taken together, our data suggests that the emergence of AE-specific CD8 T cell responses in CHI confers a selective advantage to the virus by promoting DC-mediated CD4 T cell trans-infection.
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http://dx.doi.org/10.1371/journal.ppat.1007970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703693PMC
August 2019

Clinical and evolutionary consequences of HIV adaptation to HLA: implications for vaccine and cure.

Curr Opin HIV AIDS 2019 05;14(3):194-204

Faculty of Health Sciences, Simon Fraser University, Burnaby.

Purpose Of Review: The purpose of this review is to summarize recent advances in our understanding of HIV adaptation to human leukocyte antigen (HLA)-associated immune pressures and its relevance to HIV prevention and cure research.

Recent Findings: Recent research has confirmed that HLA is a major driver of individual and population-level HIV evolution, that HIV strains are adapting to the immunogenetic profiles of the different human ethnic groups in which they circulate, and that HIV adaptation has substantial clinical and immunologic consequences. As such, adaptation represents a major challenge to HIV prevention and cure. At the same time, there are opportunities: Studies of HIV adaptation are revealing why certain HLA alleles are protective in some populations and not others; they are identifying immunogenic viral epitopes that harbor high mutational barriers to escape, and they may help illuminate novel, vaccine-relevant HIV epitopes in regions where circulating adaptation is extensive. Elucidation of HLA-driven adapted and nonadapted viral forms in different human populations and HIV subtypes also renders 'personalized' immunogen selection, as a component of HIV cure strategies, conceptually feasible.

Summary: Though adaptation represents a major challenge to HIV prevention and cure, achieving an in-depth understanding of this phenomenon can help move the design of such strategies forward.
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http://dx.doi.org/10.1097/COH.0000000000000541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457261PMC
May 2019

Genotypic and Mechanistic Characterization of Subtype-Specific HIV Adaptation to Host Cellular Immunity.

J Virol 2019 01 10;93(1). Epub 2018 Dec 10.

Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada

The extent to which viral genetic context influences HIV adaptation to human leukocyte antigen (HLA) class I-restricted immune pressures remains incompletely understood. The Ugandan HIV epidemic, where major pandemic group M subtypes A1 and D cocirculate in a single host population, provides an opportunity to investigate this question. We characterized plasma HIV RNA , , and sequences, along with host HLA genotypes, in 464 antiretroviral-naive individuals chronically infected with HIV subtype A1 or D. Using phylogenetically informed statistical approaches, we identified HLA-associated polymorphisms and formally compared their strengths of selection between viral subtypes. A substantial number (32%) of HLA-associated polymorphisms identified in subtype A1 and/or D had previously been reported in subtype B, C, and/or circulating recombinant form 01_AE (CRF01_AE), confirming the shared nature of many HLA-driven escape pathways regardless of viral genetic context. Nevertheless, 34% of the identified HLA-associated polymorphisms were significantly differentially selected between subtypes A1 and D. Experimental investigation of select examples of subtype-specific escape revealed distinct underlying mechanisms with important implications for vaccine design: whereas some were attributable to subtype-specific sequence variation that influenced epitope-HLA binding, others were attributable to differential mutational barriers to immune escape. Overall, our results confirm that HIV genetic context is a key modulator of viral adaptation to host cellular immunity and highlight the power of combined bioinformatic and mechanistic studies, paired with knowledge of epitope immunogenicity, to identify appropriate viral regions for inclusion in subtype-specific and universal HIV vaccine strategies. The identification of HIV polymorphisms reproducibly selected under pressure by specific HLA alleles and the elucidation of their impact on viral function can help identify immunogenic viral regions where immune escape incurs a fitness cost. However, our knowledge of HLA-driven escape pathways and their functional costs is largely limited to HIV subtype B and, to a lesser extent, subtype C. Our study represents the first characterization of HLA-driven adaptation pathways in HIV subtypes A1 and D, which dominate in East Africa, and the first statistically rigorous characterization of differential HLA-driven escape across viral subtypes. The results support a considerable impact of viral genetic context on HIV adaptation to host HLA, where HIV subtype-specific sequence variation influences both epitope-HLA binding and the fitness costs of escape. Integrated bioinformatic and mechanistic characterization of these and other instances of differential escape could aid rational cytotoxic T-lymphocyte-based vaccine immunogen selection for both subtype-specific and universal HIV vaccines.
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http://dx.doi.org/10.1128/JVI.01502-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288327PMC
January 2019

Antisense-Derived HIV-1 Cryptic Epitopes Are Not Major Drivers of Viral Evolution during the Acute Phase of Infection.

J Virol 2018 10 12;92(19). Epub 2018 Sep 12.

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

While prior studies have demonstrated that CD8 T cell responses to cryptic epitopes (CE) are readily detectable during HIV-1 infection, their ability to drive escape mutations following acute infection is unknown. We predicted 66 CE in a Zambian acute infection cohort based on escape mutations occurring within or near the putatively predicted HLA-I-restricted epitopes. The CE were evaluated for CD8 T cell responses for patients with chronic and acute HIV infections. Of the 66 predicted CE, 10 were recognized in 8/32 and 4/11 patients with chronic and acute infections, respectively. The immunogenic CE were all derived from a single antisense reading frame within However, when these CE were tested using longitudinal study samples, CE-specific T cell responses were detected but did not consistently select for viral escape mutations. Thus, while we demonstrated that CE are immunogenic in acute infection, the immune responses to CE are not major drivers of viral escape in the initial stages of HIV infection. The latter finding may be due to either the subdominant nature of CE-specific responses, the low antigen sensitivity, or the magnitude of CE responses during acute infections. Although prior studies demonstrated that cryptic epitopes of HIV-1 induce CD8 T cell responses, evidence that targeting these epitopes drives HIV escape mutations has been substantially limited, and no studies have addressed this question following acute infection. In this comprehensive study, we utilized longitudinal viral sequencing data obtained from three separate acute infection cohorts to predict potential cryptic epitopes based on HLA-I-associated viral escape. Our data show that cryptic epitopes are immunogenic during acute infection and that many of the responses they elicit are toward translation products of HIV-1 antisense reading frames. However, despite cryptic epitope targeting, our study did not find any evidence of early CD8-mediated immune escape. Nevertheless, improving cryptic epitope-specific CD8 T cell responses may still be beneficial in both preventative and therapeutic HIV-1 vaccines.
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http://dx.doi.org/10.1128/JVI.00711-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146806PMC
October 2018

Killer cell immunoglobulin-like receptor 3DL1 variation modifies HLA-B*57 protection against HIV-1.

J Clin Invest 2018 05 3;128(5):1903-1912. Epub 2018 Apr 3.

Cardiff University School of Medicine, Heath Park, University Hospital of Wales, Cardiff, United Kingdom.

HLA-B*57 control of HIV involves enhanced CD8+ T cell responses against infected cells, but extensive heterogeneity exists in the level of HIV control among B*57+ individuals. Using whole-genome sequencing of untreated B*57+ HIV-1-infected controllers and noncontrollers, we identified a single variant (rs643347A/G) encoding an isoleucine-to-valine substitution at position 47 (I47V) of the inhibitory killer cell immunoglobulin-like receptor KIR3DL1 as the only significant modifier of B*57 protection. The association was replicated in an independent cohort and across multiple outcomes. The modifying effect of I47V was confined to B*57:01 and was not observed for the closely related B*57:03. Positions 2, 47, and 54 tracked one another nearly perfectly, and 2 KIR3DL1 allotypes differing only at these 3 positions showed significant differences in binding B*57:01 tetramers, whereas the protective allotype showed lower binding. Thus, variation in an immune NK cell receptor that binds B*57:01 modifies its protection. These data highlight the exquisite specificity of KIR-HLA interactions in human health and disease.
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http://dx.doi.org/10.1172/JCI98463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919796PMC
May 2018

Elevated expression impairs HIV control through inhibition of NKG2A-expressing cells.

Science 2018 01 4;359(6371):86-90. Epub 2018 Jan 4.

Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.

The highly polymorphic human leukocyte antigen () locus encodes cell surface proteins that are critical for immunity. expression levels vary in an allele-dependent manner, diversifying allele-specific effects beyond peptide-binding preference. Analysis of 9763 HIV-infected individuals from 21 cohorts shows that higher levels confer poorer control of HIV. Elevated expression provides enhanced levels of an HLA-A-derived signal peptide that specifically binds and determines expression levels of HLA-E, the ligand for the inhibitory NKG2A natural killer (NK) cell receptor. haplotypes that favor NKG2A-mediated NK cell licensing (i.e., education) exacerbate the deleterious effect of high on HIV control, consistent with NKG2A-mediated inhibition impairing NK cell clearance of HIV-infected targets. Therapeutic blockade of HLA-E:NKG2A interaction may yield benefit in HIV disease.
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http://dx.doi.org/10.1126/science.aam8825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933048PMC
January 2018

Weaker HLA Footprints on HIV in the Unique and Highly Genetically Admixed Host Population of Mexico.

J Virol 2018 01 2;92(2). Epub 2018 Jan 2.

Center for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico

HIV circumvents HLA class I-restricted CD8 T-cell responses through selection of escape mutations that leave characteristic mutational "footprints," also known as HLA-associated polymorphisms (HAPs), on HIV sequences at the population level. While many HLA footprints are universal across HIV subtypes and human populations, others can be region specific as a result of the unique immunogenetic background of each host population. Using a published probabilistic phylogenetically informed model, we compared HAPs in HIV Gag and Pol (PR-RT) in 1,612 subtype B-infected, antiretroviral treatment-naive individuals from Mexico and 1,641 individuals from Canada/United States. A total of 252 HLA class I allele subtypes were represented, including 140 observed in both cohorts, 67 unique to Mexico, and 45 unique to Canada/United States. At the predefined statistical threshold of a q value of <0.2, 358 HAPs (201 in Gag, 157 in PR-RT) were identified in Mexico, while 905 (534 in Gag and 371 in PR-RT) were identified in Canada/United States. HAPs identified in Mexico included both canonical HLA-associated escape pathways and novel associations, in particular with HLA alleles enriched in Amerindian and mestizo populations. Remarkably, HLA footprints on HIV in Mexico were not only fewer but also, on average, significantly weaker than those in Canada/United States, although some exceptions were noted. Moreover, exploratory analyses suggested that the weaker HLA footprint on HIV in Mexico may be due, at least in part, to weaker and/or less reproducible HLA-mediated immune pressures on HIV in this population. The implications of these differences for natural and vaccine-induced anti-HIV immunity merit further investigation. HLA footprints on HIV identify viral regions under intense and consistent pressure by HLA-restricted immune responses and the common mutational pathways that HIV uses to evade them. In particular, HLA footprints can identify novel immunogenic regions and/or epitopes targeted by understudied HLA alleles; moreover, comparative analyses across immunogenetically distinct populations can illuminate the extent to which HIV immunogenic regions and escape pathways are shared versus population-specific pathways, information which can in turn inform the design of universal or geographically tailored HIV vaccines. We compared HLA-associated footprints on HIV in two immunogenetically distinct North American populations, those of Mexico and Canada/United States. We identify both shared and population-specific pathways of HIV adaptation but also make the surprising observation that HLA footprints on HIV in Mexico overall are fewer and weaker than those in Canada/United States, raising the possibility that HLA-restricted antiviral immune responses in Mexico are weaker, and/or escape pathways somewhat less consistent, than those in other populations.
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http://dx.doi.org/10.1128/JVI.01128-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752930PMC
January 2018

Brief Report: Selection of HIV-1 Variants With Higher Transmission Potential by 1% Tenofovir Gel Microbicide.

J Acquir Immune Defic Syndr 2017 09;76(1):43-47

*Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town and National Health Laboratory Services, Cape Town, South Africa;†Currently, Health Systems Research Unit, South African Medical Research Council, Cape Town, South Africa;‡Microsoft Research, Redmond, WA; and§Centre for the AIDS Programme of Research in South Africa, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.

Background: Women in the CAPRISA 004 trial assigned to use 1% tenofovir (TFV) microbicide gel, who became HIV-1 infected, had higher viral load set-point and slower antibody avidity maturation compared with placebo participants. We investigated whether TFV gel was selected for viruses with altered genetic characteristics.

Setting: The participants of the CAPRISA 004 trial (n = 28 TFV and 43 placebo) were from KwaZulu-Natal Province, South Africa and were infected with HIV-1 subtype C. After HIV-1 diagnosis, they were recruited into the CAPRISA 002 cohort.

Methods: We analyzed gag sequences from the earliest time point post infection (within 3 months of estimated time of infection). Transmission index was measured using a model which predicts the likelihood of an amino acid to be transmitted. Phylogenetic distance from a regional consensus sequence was calculated from a maximum likelihood phylogenetic tree.

Results: Transmission index and distance from the most common (consensus) sequence have been shown to be markers of transmission fitness. We found that viruses infecting TFV gel recipients were closer to the consensus sequence of regional strains (P = 0.003) and had higher transmission index (P = 0.01). The transmission index was weakly correlated with concomitant viral load (Spearman r = 0.22, P = 0.06).

Conclusion: Decreased acquisition risk may have increased the barrier to infection therefore selecting for fitter, more consensus-like viruses. Such virus fitness effects will need to be considered for future pre-exposure prophylaxis and vaccine trials.
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http://dx.doi.org/10.1097/QAI.0000000000001458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576519PMC
September 2017

Mother-to-Child HIV Transmission Bottleneck Selects for Consensus Virus with Lower Gag-Protease-Driven Replication Capacity.

J Virol 2017 09 10;91(17). Epub 2017 Aug 10.

HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa

In the large majority of cases, HIV infection is established by a single variant, and understanding the characteristics of successfully transmitted variants is relevant to prevention strategies. Few studies have investigated the viral determinants of mother-to-child transmission. To determine the impact of Gag-protease-driven viral replication capacity on mother-to-child transmission, the replication capacities of 148 recombinant viruses encoding plasma-derived Gag-protease from 53 nontransmitter mothers, 48 transmitter mothers, and 47 infected infants were assayed in an HIV-1-inducible green fluorescent protein reporter cell line. All study participants were infected with HIV-1 subtype C. There was no significant difference in replication capacities between the nontransmitter ( = 53) and transmitter ( = 44) mothers ( = 0.48). Infant-derived Gag-protease NL4-3 recombinant viruses ( = 41) were found to have a significantly lower Gag-protease-driven replication capacity than that of viruses derived from the mothers ( < 0.0001 by a paired test). High percent similarities to consensus subtype C Gag, p17, p24, and protease sequences were also found in the infants ( = 28) in comparison to their mothers ( = 0.07, = 0.002, = 0.03, and = 0.02, respectively, as determined by a paired test). These data suggest that of the viral quasispecies found in mothers, the HIV mother-to-child transmission bottleneck favors the transmission of consensus-like viruses with lower viral replication capacities. Understanding the characteristics of successfully transmitted HIV variants has important implications for preventative interventions. Little is known about the viral determinants of HIV mother-to-child transmission (MTCT). We addressed the role of viral replication capacity driven by Gag, a major structural protein that is a significant determinant of overall viral replicative ability and an important target of the host immune response, in the MTCT bottleneck. This study advances our understanding of the genetic bottleneck in MTCT by revealing that viruses transmitted to infants have a lower replicative ability as well as a higher similarity to the population consensus (in this case HIV subtype C) than those of their mothers. Furthermore, the observation that "consensus-like" virus sequences correspond to lower replication abilities yet appear to be preferentially transmitted suggests that viral characteristics favoring transmission are decoupled from those that enhance replicative capacity.
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http://dx.doi.org/10.1128/JVI.00518-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553170PMC
September 2017

PARV4 prevalence, phylogeny, immunology and coinfection with HIV, HBV and HCV in a multicentre African cohort.

Wellcome Open Res 2017 Apr 7;2:26. Epub 2017 Apr 7.

Department of Microbiology and Infectious Diseases, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, OX3 9DU, UK.

The seroprevalence of human parvovirus-4 (PARV4) varies considerably by region. In sub-Saharan Africa, seroprevalence is high in the general population, but little is known about the transmission routes or the prevalence of coinfection with blood-borne viruses, HBV, HCV and HIV.  To further explore the characteristics of PARV4 in this setting, with a particular focus on the prevalence and significance of coinfection, we screened a cohort of 695 individuals recruited from Durban and Kimberley (South Africa) and Gaborone (Botswana) for PARV4 IgG and DNA, as well as documenting HIV, HBV and HCV status.  Within these cohorts, 69% of subjects were HIV-positive. We identified no cases of HCV by PCR, but 7.4% were positive for HBsAg. PARV4 IgG was positive in 42%; seroprevalence was higher in adults (69%) compared to children (21%) (p<0.0001) and in HIV-positive (52%) compared to HIV-negative individuals (24%) (p<0.0001), but there was no association with HBsAg status. We developed an on-line tool to allow visualization of coinfection data (https://purl.oclc.org/coinfection-viz). We identified five subjects who were PCR-positive for PARV4 genotype-3. CD8+ T cell responses spanned the entire PARV4 proteome and we propose a novel HLA-B*57:03-restricted epitope within the NS protein.  This characterisation of PARV4 infection provides enhanced insights into the epidemiology of infection and co-infection in African cohorts, and provides the foundations for planning further focused studies to elucidate transmission pathways, immune responses, and the clinical significance of this organism.
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http://dx.doi.org/10.12688/wellcomeopenres.11135.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423528PMC
April 2017

Impact of pre-adapted HIV transmission.

Nat Med 2016 06 16;22(6):606-13. Epub 2016 May 16.

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Human leukocyte antigen class I (HLA)-restricted CD8(+) T lymphocyte (CTL) responses are crucial to HIV-1 control. Although HIV can evade these responses, the longer-term impact of viral escape mutants remains unclear, as these variants can also reduce intrinsic viral fitness. To address this, we here developed a metric to determine the degree of HIV adaptation to an HLA profile. We demonstrate that transmission of viruses that are pre-adapted to the HLA molecules expressed in the recipient is associated with impaired immunogenicity, elevated viral load and accelerated CD4(+) T cell decline. Furthermore, the extent of pre-adaptation among circulating viruses explains much of the variation in outcomes attributed to the expression of certain HLA alleles. Thus, viral pre-adaptation exploits 'holes' in the immune response. Accounting for these holes may be key for vaccine strategies seeking to elicit functional responses from viral variants, and to HIV cure strategies that require broad CTL responses to achieve successful eradication of HIV reservoirs.
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http://dx.doi.org/10.1038/nm.4100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899163PMC
June 2016

Differences in the Selection Bottleneck between Modes of Sexual Transmission Influence the Genetic Composition of the HIV-1 Founder Virus.

PLoS Pathog 2016 05 10;12(5):e1005619. Epub 2016 May 10.

Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.

Due to the stringent population bottleneck that occurs during sexual HIV-1 transmission, systemic infection is typically established by a limited number of founder viruses. Elucidation of the precise forces influencing the selection of founder viruses may reveal key vulnerabilities that could aid in the development of a vaccine or other clinical interventions. Here, we utilize deep sequencing data and apply a genetic distance-based method to investigate whether the mode of sexual transmission shapes the nascent founder viral genome. Analysis of 74 acute and early HIV-1 infected subjects revealed that 83% of men who have sex with men (MSM) exhibit a single founder virus, levels similar to those previously observed in heterosexual (HSX) transmission. In a metadata analysis of a total of 354 subjects, including HSX, MSM and injecting drug users (IDU), we also observed no significant differences in the frequency of single founder virus infections between HSX and MSM transmissions. However, comparison of HIV-1 envelope sequences revealed that HSX founder viruses exhibited a greater number of codon sites under positive selection, as well as stronger transmission indices possibly reflective of higher fitness variants. Moreover, specific genetic "signatures" within MSM and HSX founder viruses were identified, with single polymorphisms within gp41 enriched among HSX viruses while more complex patterns, including clustered polymorphisms surrounding the CD4 binding site, were enriched in MSM viruses. While our findings do not support an influence of the mode of sexual transmission on the number of founder viruses, they do demonstrate that there are marked differences in the selection bottleneck that can significantly shape their genetic composition. This study illustrates the complex dynamics of the transmission bottleneck and reveals that distinct genetic bottleneck processes exist dependent upon the mode of HIV-1 transmission.
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http://dx.doi.org/10.1371/journal.ppat.1005619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862634PMC
May 2016

HLA-A is a Predictor of Hepatitis B e Antigen Status in HIV-Positive African Adults.

J Infect Dis 2016 Apr 9;213(8):1248-52. Epub 2015 Dec 9.

Nuffield Department of Medicine Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Trust NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford.

Outcomes of chronic infection with hepatitis B virus (HBV) are varied, with increased morbidity reported in the context of human immunodeficiency virus (HIV) coinfection. The factors driving different outcomes are not well understood, but there is increasing interest in an HLA class I effect. We therefore studied the influence of HLA class I on HBV in an African HIV-positive cohort. We demonstrated that virologic markers of HBV disease activity (hepatitis B e antigen status or HBV DNA level) are associated with HLA-A genotype. This finding supports the role of the CD8(+) T-cell response in HBV control, and potentially informs future therapeutic T-cell vaccine strategies.
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http://dx.doi.org/10.1093/infdis/jiv592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4799671PMC
April 2016

A strong association of human leukocyte antigen-associated Pol and Gag mutations with clinical parameters in HIV-1 subtype A/E infection.

AIDS 2016 Mar;30(5):681-9

aCenter for AIDS Research, Kumamoto University, Kumamoto, Japan beScience Group, Microsoft Research, Los Angeles, California, USA cNational Hospital of Tropical Diseases, Dong Da District, Hanoi, Vietnam dFaculty of Health Sciences, Simon Fraser University, Burnaby, BC, USA eAIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan fBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada gInternational Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan hNuffield Department of Medicine, University of Oxford, Oxford, UK. *Giang Van Tran and Takayuki Chikata contributed equally to this study.

Objectives: Identification of human leukocyte antigen-associated HIV-1 polymorphisms (HLA-APs) in different global populations furthers our understanding of HIV-1 pathogenesis and may help identify candidate immunogens for HIV vaccines targeted to these populations. Although numerous population-based studies identifying HLA-APs have been conducted in HIV-1 subtype B- and subtype C-infected cohorts, few have focused on subtype A/E.

Design: We investigated HLA-APs in a cohort of chronically HIV-1 subtype A/E-infected Vietnamese individuals.

Methods: HLA-APs in HIV-1 Gag, Pol, and Nef regions from 388 treatment-naive individuals chronically infected with HIV-1 subtype A/E were analyzed using phylogenetically informed approaches.

Results: A total of 303 HLA-APs were identified. HLA-APs occurring at six positions in Gag and six positions in Pol were significantly associated with higher plasma viral load (pVL), whereas HLA-APs occurring at two positions in Gag and 13 positions in Pol were significantly associated with lower CD4 T-cell counts. Furthermore, the proportion of Pol codons harboring an HLA-AP specific to the host's HLA correlated positively with HIV-1 pVL (R = 0.22; P < 0.0001) and inversely with CD4 T-cell counts (R = -0.32; P < 0.0001). Similarly, the proportion of HLA-associated Gag codons harboring host-specific HLA-AP correlated inversely with CD4 T-cell counts (R = -0.13; P = 0.01).

Conclusion: These significant associations between HIV-1 amino acids adapted to Vietnamese HLA alleles and higher pVL and lower CD4 T-cell counts suggests that accumulation of cytotoxic T cells escape mutations may influence clinical outcomes in HIV-1 subtype A/E-infected Vietnamese individuals.
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http://dx.doi.org/10.1097/QAD.0000000000000969DOI Listing
March 2016

Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa.

PLoS Med 2015 Nov 17;12(11):e1001900; discussion e1001900. Epub 2015 Nov 17.

Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America.

Background: Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure.

Methods And Findings: Two sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+ NK cells through sequence variations within HLA class I-presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA-C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 ± 10.45 standard deviation [SD] and variant mean 44.67 ± 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 ± 0.07 standard error of the mean [SEM] and variant mean 0.63 ± 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/peptide/HLA interactions in the context of the different viral sequence variants studied supported these results. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control.

Conclusions: These data provide novel insights into how viruses can evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance binding to inhibitory NK cell receptors. Better understanding of the mechanisms by which HIV-1 evades NK-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of NK cells.
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http://dx.doi.org/10.1371/journal.pmed.1001900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648589PMC
November 2015

Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic.

J Virol 2016 02 11;90(3):1244-58. Epub 2015 Nov 11.

Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada

Unlabelled: Human leukocyte antigen (HLA) class I-associated polymorphisms in HIV-1 that persist upon transmission to HLA-mismatched hosts may spread in the population as the epidemic progresses. Transmission of HIV-1 sequences containing such adaptations may undermine cellular immune responses to the incoming virus in future hosts. Building upon previous work, we investigated the extent of HLA-associated polymorphism accumulation in HIV-1 polymerase (Pol) through comparative analysis of linked HIV-1/HLA class I genotypes sampled during historic (1979 to 1989; n = 338) and modern (2001 to 2011; n = 278) eras from across North America (Vancouver, BC, Canada; Boston, MA; New York, NY; and San Francisco, CA). Phylogenies inferred from historic and modern HIV-1 Pol sequences were star-like in shape, with an inferred most recent common ancestor (epidemic founder virus) sequence nearly identical to the modern North American subtype B consensus sequence. Nevertheless, modern HIV-1 Pol sequences exhibited roughly 2-fold-higher patristic (tip-to-tip) genetic distances than historic sequences, with HLA pressures likely driving ongoing diversification. Moreover, the frequencies of published HLA-associated polymorphisms in individuals lacking the selecting HLA class I allele was on average ∼2.5-fold higher in the modern than in the historic era, supporting their spread in circulation, though some remained stable in frequency during this time. Notably, polymorphisms restricted by protective HLA alleles appear to be spreading to a greater relative extent than others, though these increases are generally of modest absolute magnitude. However, despite evidence of polymorphism spread, North American hosts generally remain at relatively low risk of acquiring an HIV-1 polymerase sequence substantially preadapted to their HLA profiles, even in the present era.

Importance: HLA class I-restricted cytotoxic T-lymphocyte (CTL) escape mutations in HIV-1 that persist upon transmission may accumulate in circulation over time, potentially undermining host antiviral immunity to the transmitted viral strain. We studied >600 experimentally collected HIV-1 polymerase sequences linked to host HLA information dating back to 1979, along with phylogenetically reconstructed HIV-1 sequences dating back to the virus' introduction into North America. Overall, our results support the gradual spread of many-though not all-HIV-1 polymerase immune escape mutations in circulation over time. This is consistent with recent observations from other global regions, though the extent of polymorphism accumulation in North America appears to be lower than in populations with high seroprevalence, older epidemics, and/or limited HLA diversity. Importantly, the risk of acquiring an HIV-1 polymerase sequence at transmission that is substantially preadapted to one's HLA profile remains relatively low in North America, even in the present era.
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http://dx.doi.org/10.1128/JVI.02353-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719594PMC
February 2016

Enhanced Recognition of HIV-1 Cryptic Epitopes Restricted by HLA Class I Alleles Associated With a Favorable Clinical Outcome.

J Acquir Immune Defic Syndr 2015 Sep;70(1):1-8

*Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; and †Microsoft Research, Redmond, WA.

Background: Cryptic epitopes (CEs) are peptides derived from the translation of 1 or more of the 5 alternative reading frames (ARFs; 2 sense and 3 antisense) of genes. Here, we compared response rates to HIV-1-specific CE predicted to be restricted by HLA-I alleles associated with protection against disease progression to those without any such association.

Methods: Peptides (9mer to 11mer) were designed based on HLA-I-binding algorithms for B*27, B*57, or B*5801 (protective alleles) and HLA-B*5301 or B*5501 (nonprotective allele) in all 5 ARFs of the 9 HIV-1 encoded proteins. Peptides with >50% probability of being an epitope (n = 231) were tested for T-cell responses in an IFN-γ enzyme-linked immunosorbent spot (ELISpot) assay. Peripheral blood mononuclear cell samples from HIV-1 seronegative donors (n = 42) and HIV-1 seropositive patients with chronic clade B infections (n = 129) were used.

Results: Overall, 16%, 2%, and 2% of chronic HIV infected patients had CE responses by IFN-γ ELISpot in the protective, nonprotective, and seronegative groups, respectively (P = 0.009, Fischer exact test). Twenty novel CE-specific responses were mapped (median magnitude of 95 spot forming cells/10 peripheral blood mononuclear cells), and most were both antisense derived (90%) and represented ARFs of accessory proteins (55%). CE-specific CD8 T cells were multifunctional and proliferated when assessed by intracellular cytokine staining.

Conclusions: CE responses were preferentially restricted by the protective HLA-I alleles in HIV-1 infection, suggesting that they may contribute to viral control in this group of patients.
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http://dx.doi.org/10.1097/QAI.0000000000000700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556167PMC
September 2015

Prevalence and Characteristics of Hepatitis B Virus (HBV) Coinfection among HIV-Positive Women in South Africa and Botswana.

PLoS One 2015 28;10(7):e0134037. Epub 2015 Jul 28.

Nuffield Department of Medicine, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom; Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Headington, Oxford, United Kingdom; NIHR Biomedical Research Centre, John Radcliffe Hospital, Headley Way, Headington, Oxford, United Kingdom.

There is progressive concern about the evolving burden of morbidity and mortality caused by coinfection with HIV-1 and hepatitis B virus (HBV) in sub-Saharan Africa, but the epidemiology and impact of this problem are not well defined. We therefore set out to assimilate more information about the nature of HBV/HIV coinfection in this region by undertaking a retrospective observational study of southern African adult women. We used samples from previously recruited HIV-1 positive women attending antenatal clinics in three settings in South Africa and Botswana (n = 950) and added a small cohort of HIV-negative antenatal South African women for comparison (n = 72). We tested for HBsAg and followed up HBsAg-positive samples by testing for HBeAg, HBV DNA, HBV genotype, presence of drug-resistance associated mutations (RAMs) and HDV. We identified HBsAg in 72 individuals (7% of the whole cohort), of whom 27% were HBeAg-positive, and the majority HBV genotypes A1 and A2. We did not detect any HDV coinfection. HBV prevalence was significantly different between geographically distinct cohorts, but did not differ according to HIV status. Among adults from South Africa, HBV/HIV coinfected patients had lower CD4+ T cell counts compared to those with HIV-monoinfection (p = 0.02), but this finding was not replicated in the cohort from Botswana. Overall, these data provide a snapshot of the coinfection problem at the heart of the HIV/HBV co-epidemic, and are important to inform public health policy, resource allocation, education, surveillance and clinical care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134037PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517770PMC
May 2016

CD8+ TCR Bias and Immunodominance in HIV-1 Infection.

J Immunol 2015 Jun 24;194(11):5329-45. Epub 2015 Apr 24.

Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom;

Immunodominance describes a phenomenon whereby the immune system consistently targets only a fraction of the available Ag pool derived from a given pathogen. In the case of CD8(+) T cells, these constrained epitope-targeting patterns are linked to HLA class I expression and determine disease progression. Despite the biological importance of these predetermined response hierarchies, little is known about the factors that control immunodominance in vivo. In this study, we conducted an extensive analysis of CD8(+) T cell responses restricted by a single HLA class I molecule to evaluate the mechanisms that contribute to epitope-targeting frequency and antiviral efficacy in HIV-1 infection. A clear immunodominance hierarchy was observed across 20 epitopes restricted by HLA-B*42:01, which is highly prevalent in populations of African origin. Moreover, in line with previous studies, Gag-specific responses and targeting breadth were associated with lower viral load set-points. However, peptide-HLA-B*42:01 binding affinity and stability were not significantly linked with targeting frequencies. Instead, immunodominance correlated with epitope-specific usage of public TCRs, defined as amino acid residue-identical TRB sequences that occur in multiple individuals. Collectively, these results provide important insights into a potential link between shared TCR recruitment, immunodominance, and antiviral efficacy in a major human infection.
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http://dx.doi.org/10.4049/jimmunol.1400854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433859PMC
June 2015

Comprehensive sieve analysis of breakthrough HIV-1 sequences in the RV144 vaccine efficacy trial.

PLoS Comput Biol 2015 Feb 3;11(2):e1003973. Epub 2015 Feb 3.

Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.

The RV144 clinical trial showed the partial efficacy of a vaccine regimen with an estimated vaccine efficacy (VE) of 31% for protecting low-risk Thai volunteers against acquisition of HIV-1. The impact of vaccine-induced immune responses can be investigated through sieve analysis of HIV-1 breakthrough infections (infected vaccine and placebo recipients). A V1/V2-targeted comparison of the genomes of HIV-1 breakthrough viruses identified two V2 amino acid sites that differed between the vaccine and placebo groups. Here we extended the V1/V2 analysis to the entire HIV-1 genome using an array of methods based on individual sites, k-mers and genes/proteins. We identified 56 amino acid sites or "signatures" and 119 k-mers that differed between the vaccine and placebo groups. Of those, 19 sites and 38 k-mers were located in the regions comprising the RV144 vaccine (Env-gp120, Gag, and Pro). The nine signature sites in Env-gp120 were significantly enriched for known antibody-associated sites (p = 0.0021). In particular, site 317 in the third variable loop (V3) overlapped with a hotspot of antibody recognition, and sites 369 and 424 were linked to CD4 binding site neutralization. The identified signature sites significantly covaried with other sites across the genome (mean = 32.1) more than did non-signature sites (mean = 0.9) (p < 0.0001), suggesting functional and/or structural relevance of the signature sites. Since signature sites were not preferentially restricted to the vaccine immunogens and because most of the associations were insignificant following correction for multiple testing, we predict that few of the genetic differences are strongly linked to the RV144 vaccine-induced immune pressure. In addition to presenting results of the first complete-genome analysis of the breakthrough infections in the RV144 trial, this work describes a set of statistical methods and tools applicable to analysis of breakthrough infection genomes in general vaccine efficacy trials for diverse pathogens.
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http://dx.doi.org/10.1371/journal.pcbi.1003973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315437PMC
February 2015

HIV-1 adaptation to HLA: a window into virus-host immune interactions.

Trends Microbiol 2015 Apr 19;23(4):212-24. Epub 2015 Jan 19.

Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada. Electronic address:

HIV-1 develops specific mutations within its genome that allow it to escape detection by human leukocyte antigen (HLA) class I-restricted immune responses, notably those of CD8(+) cytotoxic T lymphocytes (CTL). HLA thus represents a major force driving the evolution and diversification of HIV-1 within individuals and at the population level. Importantly, the study of HIV-1 adaptation to HLA also represents an opportunity to identify what qualities constitute an effective immune response, how the virus in turn adapts to these pressures, and how we may harness this information to design HIV-1 vaccines that stimulate effective cellular immunity.
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http://dx.doi.org/10.1016/j.tim.2014.12.008DOI Listing
April 2015

Immune screening identifies novel T cell targets encoded by antisense reading frames of HIV-1.

J Virol 2015 Apr 14;89(7):4015-9. Epub 2015 Jan 14.

IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Germans Trias I Pujol, Badalona, Spain Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain University of Vic and Central University of Catalonia, Vic, Catalonia, Spain Autonomous University of Barcelona, Barcelona, Catalonia, Spain

Cytotoxic-T lymphocyte (CTL) responses to epitopes in alternative HIV reading frames have been reported. However, the extent of CTL responses to putative proteins encoded in antisense reading frames is unknown. Using sequence alignments and computational approaches, we here predict five potential antisense HIV proteins and characterize common CTL responses against them. Results suggest that antisense-derived sequences are commonly transcribed and translated and could encode functional proteins that contain important targets of anti-HIV cellular immunity.
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http://dx.doi.org/10.1128/JVI.03435-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403399PMC
April 2015

Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence.

Proc Natl Acad Sci U S A 2014 Dec 1;111(50):E5393-400. Epub 2014 Dec 1.

Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom; HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa;

It is widely believed that epidemics in new hosts diminish in virulence over time, with natural selection favoring pathogens that cause minimal disease. However, a tradeoff frequently exists between high virulence shortening host survival on the one hand but allowing faster transmission on the other. This is the case in HIV infection, where high viral loads increase transmission risk per coital act but reduce host longevity. We here investigate the impact on HIV virulence of HIV adaptation to HLA molecules that protect against disease progression, such as HLA-B*57 and HLA-B*58:01. We analyzed cohorts in Botswana and South Africa, two countries severely affected by the HIV epidemic. In Botswana, where the epidemic started earlier and adult seroprevalence has been higher, HIV adaptation to HLA including HLA-B*57/58:01 is greater compared with South Africa (P = 7 × 10(-82)), the protective effect of HLA-B*57/58:01 is absent (P = 0.0002), and population viral replicative capacity is lower (P = 0.03). These data suggest that viral evolution is occurring relatively rapidly, and that adaptation of HIV to the most protective HLA alleles may contribute to a lowering of viral replication capacity at the population level, and a consequent reduction in HIV virulence over time. The potential role in this process played by increasing antiretroviral therapy (ART) access is also explored. Models developed here suggest distinct benefits of ART, in addition to reducing HIV disease and transmission, in driving declines in HIV virulence over the course of the epidemic, thereby accelerating the effects of HLA-mediated viral adaptation.
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http://dx.doi.org/10.1073/pnas.1413339111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273423PMC
December 2014

CD8 and CD4 epitope predictions in RV144: no strong evidence of a T-cell driven sieve effect in HIV-1 breakthrough sequences from trial participants.

PLoS One 2014 28;9(10):e111334. Epub 2014 Oct 28.

US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America; Henry Jackson Foundation, Bethesda, Maryland, United States of America.

The modest protection afforded by the RV144 vaccine offers an opportunity to evaluate its mechanisms of protection. Differences between HIV-1 breakthrough viruses from vaccine and placebo recipients can be attributed to the RV144 vaccine as this was a randomized and double-blinded trial. CD8 and CD4 T cell epitope repertoires were predicted in HIV-1 proteomes from 110 RV144 participants. Predicted Gag epitope repertoires were smaller in vaccine than in placebo recipients (p = 0.019). After comparing participant-derived epitopes to corresponding epitopes in the RV144 vaccine, the proportion of epitopes that could be matched differed depending on the protein conservation (only 36% of epitopes in Env vs 84-91% in Gag/Pol/Nef for CD8 predicted epitopes) or on vaccine insert subtype (55% against CRF01_AE vs 7% against subtype B). To compare predicted epitopes to the vaccine, we analyzed predicted binding affinity and evolutionary distance measurements. Comparisons between the vaccine and placebo arm did not reveal robust evidence for a T cell driven sieve effect, although some differences were noted in Env-V2 (0.022≤p-value≤0.231). The paucity of CD8 T cell responses identified following RV144 vaccination, with no evidence for V2 specificity, considered together both with the association of decreased infection risk in RV 144 participants with V-specific antibody responses and a V2 sieve effect, lead us to hypothesize that this sieve effect was not T cell specific. Overall, our results did not reveal a strong differential impact of vaccine-induced T cell responses among breakthrough infections in RV144 participants.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111334PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211711PMC
January 2016
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