Rare HLA Drive Additional HIV Evolution Compared to More Frequent Alleles

Rousseau, Christine; Lockhart, David; Maley, Stephen N.; Kadie, Carl; Learn, Gerald H.; Nickle, David C.; Heckerman, David; Deng, Wenjie; Berthou, Christian; Ndung’u, Thumbi; Coovadia, Hoosen M.; Goulder, Philip; Korber, Bette T.; Walker, Bruce D.; Mullins, James I.

doi:10.1089/aid.2008.0208

Cited by 10 publications

(11 citation statements)

References 37 publications

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“…This phenomenon has been intensively studied for HLA B*5701/B*5703-presented epitopes, since these alleles are strongly associated with viral control [21], but analysis of associations of other HLAs with mutational patterns at the population level suggests it may be a widespread phenomenon [22], [23]. To determine if rapid reversion towards the B subtype consensus was evident in the any of the regions under study here, we tracked mutational patterns in all positions where the transmitted form of the virus differed from the B subtype consensus amino acid.…”

Section: Resultsmentioning

confidence: 99%

Transmission of Single HIV-1 Genomes and Dynamics of Early Immune Escape Revealed by Ultra-Deep Sequencing

et al. 2010

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We used ultra-deep sequencing to obtain tens of thousands of HIV-1 sequences from regions targeted by CD8+ T lymphocytes from longitudinal samples from three acutely infected subjects, and modeled viral evolution during the critical first weeks of infection. Previous studies suggested that a single virus established productive infection, but these conclusions were tempered because of limited sampling; now, we have greatly increased our confidence in this observation through modeling the observed earliest sample diversity based on vastly more extensive sampling. Conventional sequencing of HIV-1 from acute/early infection has shown different patterns of escape at different epitopes; we investigated the earliest escapes in exquisite detail. Over 3–6 weeks, ultradeep sequencing revealed that the virus explored an extraordinary array of potential escape routes in the process of evading the earliest CD8 T-lymphocyte responses – using 454 sequencing, we identified over 50 variant forms of each targeted epitope during early immune escape, while only 2–7 variants were detected in the same samples via conventional sequencing. In contrast to the diversity seen within epitopes, non-epitope regions, including the Envelope V3 region, which was sequenced as a control in each subject, displayed very low levels of variation. In early infection, in the regions sequenced, the consensus forms did not have a fitness advantage large enough to trigger reversion to consensus amino acids in the absence of immune pressure. In one subject, a genetic bottleneck was observed, with extensive diversity at the second time point narrowing to two dominant escape forms by the third time point, all within two months of infection. Traces of immune escape were observed in the earliest samples, suggesting that immune pressure is present and effective earlier than previously reported; quantifying the loss rate of the founder virus suggests a direct role for CD8 T-lymphocyte responses in viral containment after peak viremia. Dramatic shifts in the frequencies of epitope variants during the first weeks of infection revealed a complex interplay between viral fitness and immune escape.

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Section: Resultsmentioning

confidence: 99%

Transmission of Single HIV-1 Genomes and Dynamics of Early Immune Escape Revealed by Ultra-Deep Sequencing

et al. 2010

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“…Recently, investigations on the epitope mapping of HLA‐specific viral mutants have led to a conclusion that rare HLA alleles might drive additional viral evolution compared with the more common alleles particularly in relation to env , nef , and pol HIV‐1 genes (12). Furthermore, individuals with rare HLA alleles are more likely to be heterozygous at HLA loci.…”

Section: Major Histocompatibility Complexmentioning

confidence: 99%

Genetic determinants of HIV‐1 infection and progression to AIDS: immune response genes

Kaur

Mehra

2009

Tissue Antigens

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Genomic studies involving well‐defined multicenter cohorts of HIV‐1/AIDS covering multiple populations have led to a greater understanding of the role of host determinants in viral acquisition, disease progression, transmission, and response to anti‐retroviral therapy. Similarly, recent knowledge on the virus genetic diversity has helped in elucidating mechanisms leading to the evolution of viral escape mutants and the role played by host immune determinants, in particular the major histocompatibility complex (MHC) associated genes. At least two alleles, HLA‐B*27 and B*57, have been identified as ‘protective’ against HIV‐1 while B*35 and B*53 act as susceptibility favoring factors. How human leukocyte antigen (HLA)‐mediated selection drives the evolution of HIV‐1 and which circulating variants are more likely to evade immune surveillance of the population are now beginning to become clear. Importantly, the rare HLA alleles in a population bear a selective advantage to the host because these can induce immune responses against pre‐adapted viruses. It is conceivable that previously established protective HLA associations are shifting with the evolving cytotoxic T lymphocyte (CTL) epitopes and may not remain protective in future. At the same time, this process is unraveling novel sub‐dominant epitopes of the virus which could now be incorporated as the dominant target CTL epitopes. An insight into the population‐specific correlates of protection is hence necessary for designing future anti‐HIV therapeutic and/or prophylactic vaccine formulation(s).

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“…Interestingly, mutations at sites that remain conserved through time have been shown to have greater fitness cost than mutations of amino acids that became dominant (and hence calculated to be conserved) later in the pandemic [ 14 ]. Indeed, HIV strains are continuously being imprinted by the human HLA types encountered in different human populations [ 18 , 19 ]. Thus, sequence conservation may change as the virus continues to evolve and adapt to host immunity, and contemporary sequence conservation may not be sufficient for pinpointing sites with crucial functional or structural roles.…”

Section: Introductionmentioning

confidence: 99%

Composite Sequence–Structure Stability Models as Screening Tools for Identifying Vulnerable Targets for HIV Drug and Vaccine Development

Manocheewa

Mittler

Samudrala

et al. 2015

Viruses

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Rapid evolution and high sequence diversity enable Human Immunodeficiency Virus (HIV) populations to acquire mutations to escape antiretroviral drugs and host immune responses, and thus are major obstacles for the control of the pandemic. One strategy to overcome this problem is to focus drugs and vaccines on regions of the viral genome in which mutations are likely to cripple function through destabilization of viral proteins. Studies relying on sequence conservation alone have had only limited success in determining critically important regions. We tested the ability of two structure-based computational models to assign sites in the HIV-1 capsid protein (CA) that would be refractory to mutational change. The destabilizing mutations predicted by these models were rarely found in a database of 5811 HIV-1 CA coding sequences, with none being present at a frequency greater than 2%. Furthermore, 90% of variants with the low predicted stability (from a set of 184 CA variants whose replication fitness or infectivity has been studied in vitro) had aberrant capsid structures and reduced viral infectivity. Based on the predicted stability, we identified 45 CA sites prone to destabilizing mutations. More than half of these sites are targets of one or more known CA inhibitors. The CA regions enriched with these sites also overlap with peptides shown to induce cellular immune responses associated with lower viral loads in infected individuals. Lastly, a joint scoring metric that takes into account both sequence conservation and protein structure stability performed better at identifying deleterious mutations than sequence conservation or structure stability information alone. The computational sequence–structure stability approach proposed here might therefore be useful for identifying immutable sites in a protein for experimental validation as potential targets for drug and vaccine development.

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Rare HLA Drive Additional HIV Evolution Compared to More Frequent Alleles

Cited by 10 publications

References 37 publications

Transmission of Single HIV-1 Genomes and Dynamics of Early Immune Escape Revealed by Ultra-Deep Sequencing

Transmission of Single HIV-1 Genomes and Dynamics of Early Immune Escape Revealed by Ultra-Deep Sequencing

Genetic determinants of HIV‐1 infection and progression to AIDS: immune response genes

Composite Sequence–Structure Stability Models as Screening Tools for Identifying Vulnerable Targets for HIV Drug and Vaccine Development

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