Transmission of HIV-1 CTL Escape Variants Provides HLA-Mismatched Recipients with a Survival Advantage

Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
PLoS Pathogens (Impact Factor: 7.56). 04/2008; 4(3):e1000033. DOI: 10.1371/journal.ppat.1000033
Source: PubMed


Author Summary
Following infection with HIV, it is well established that a person's genetic makeup is a major determinant of how quickly they will progress to AIDS. Particularly important is the class I Human leukocyte antigen (HLA) gene that is responsible for alerting the immune system to HIV's presence. One of the reasons our immune systems are unable to beat HIV is that the virus can mutate to forms that our HLA genes no longer recognise. However, some people have versions of the HLA gene (for example HLA-B*57 and HLA-B*5801) that are known to force HIV to tolerate mutations that damage its ability to reproduce. Slower HIV reproduction is thought to be one reason that HLA-B*57 and HLA-B*5801 positive people progress to AIDS more slowly than most other HIV infected persons. We report here on a study of HLA-B*57 and HLA-B*5801 negative women in which better control of disease tended to be associated with their being infected with viruses carrying mutations that have been previously shown to reduce replication. These mutations characterise viruses found infecting HLA-B*57 and HLA-B*5801 positive people. This indicates for the first time that HLA-B*57 or HLA-B*5801 negative people that are infected by such reproductively compromised viruses may also experience better survival prospects.

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    • "A second line of explanations for slow immune escape that does not involve non-lytic mechanisms is that large fitness costs can explain at least some of the slow escapes observed. Several immune escapes confer severe fitness defects, which can be observed in vivo by poor replication of the virus in subsequent HLA-mismatched patients [26] or in vitro by viral competition assays [24] [22] [23]. Additionally , the reversion rates estimated in vivo also suffer from clonal interference, and could hence be markedly underestimated. "
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    ABSTRACT: Over the past few decades the extent to which cytotoxic T lymphocytes (CTLs) control human immunodeficiency virus (HIV) replication has been studied extensively, yet their role and mode of action remains controversial. In some studies, CTLs were found to kill a large fraction of the productively infected cells relative to the viral cytopathicity, whereas in others CTLs were suggested to kill only a small fraction of infected cells. In this review, we compile published estimates of CTL-mediated death rates, and examine whether these studies permit determining the rate at which CTLs kill HIV-1 infected cells. We highlight potential misinterpretations of the CTL-killing rates from the escape rates of mutants, and from perturbations of the steady state viral load during chronic infection. Our major conclusion is that CTL-mediated killing rates remain unknown. But contrary to current consensus, we argue that killing rates higher than one per day are perfectly consistent with the experimental data, which would imply that the majority of the productively infected cells could still die from CTL-mediated killing rather than from viral cytopathicity. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Aug 2015 · Immunology letters
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    • "These CTL escape mutations have been widely studied for their ability to impair viral fitness [13-17]. If fitness is reduced there may be a decrease in viral load, leading to long-term HIV-1 control and decreased probability of transmission to new hosts [7,9]. Moreover, if less fit viruses are transmitted into new hosts, viral loads may be lower and a better clinical outcome expected [9], although the effect may not be sustained into chronic infection [8]. "
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    ABSTRACT: Background A modest change in HIV-1 fitness can have a significant impact on viral quasispecies evolution and viral pathogenesis, transmission and disease progression. To determine the impact of immune escape mutations selected by cytotoxic T lymphocytes (CTL) on viral fitness in the context of the cognate transmitted/founder (T/F) genome, we developed a new competitive fitness assay using molecular clones of T/F genomes lacking exogenous genetic markers and a highly sensitive and precise parallel allele-specific sequencing (PASS) method. Results The T/F and mutant viruses were competed in CD4+ T-cell enriched cultures, relative proportions of viruses were assayed after repeated cell-free passage, and fitness costs were estimated by mathematical modeling. Naturally occurring HLA B57-restricted mutations involving the TW10 epitope in Gag and two epitopes in Tat/Rev and Env were assessed independently and together. Compensatory mutations which restored viral replication fitness were also assessed. A principal TW10 escape mutation, T242N, led to a 42% reduction in replication fitness but V247I and G248A mutations in the same epitope restored fitness to wild-type levels. No fitness difference was observed between the T/F and a naturally selected variant carrying the early CTL escape mutation (R355K) in Env and a reversion mutation in the Tat/Rev overlapping region. Conclusions These findings reveal a broad spectrum of fitness costs to CTL escape mutations in T/F viral genomes, similar to recent findings reported for neutralizing antibody escape mutations, and highlight the extraordinary plasticity and adaptive potential of the HIV-1 genome. Analysis of T/F genomes and their evolved progeny is a powerful approach for assessing the impact of composite mutational events on viral fitness.
    Full-text · Article · Oct 2012 · Retrovirology
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    • "We found no difference between levels of viral RNA load or CD4 counts in HLA-B*57/5801- negative subjects infected with 242N escape variant or with the wild type virus. This is in contrast to the recent report by Chopera et al. (Chopera et al., 2008), which is likely due to some methodological differences and confounding biases in both studies, as illustrated below. Chopera et al. (Chopera et al., 2008) analyzed nine cases with transmitted A146X (X=P or S), and six of those also showed T242N. "
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    ABSTRACT: Viral mutations at Gag residue 242 and relevant viral polymorphisms were analyzed in a cohort of 42 individuals with primary HIV-1 subtype C infection using single-genome amplification/sequencing. In HLA-B*57/5801-negative subjects infected with 242N escape variant, reversion to Asn appeared at median (IQR) 103 days (97-213 days) post-seroconversion (p/s) and became dominant at 193 days (170-215 days) p/s. In subjects expressing HLA-B*57/5801 and infected with the wild-type virus, the T242N escape appeared at 203 days (196-231) p/s, reached dominance at 277 days (265-315 days) p/s, and became complete at 323 days (289-373 days) p/s. HLA-B*57/5801-negative subjects infected with 242N escape variant did not show reduced viral load or increased CD4 count. The study highlights the differential selection of T242N escape by HLA-B*57 and B*5801 and suggests that the presence of HLA-B*57/5801-mediated immune pressure is able to control replication of the wild-type virus encoding Thr at Gag residue 242 but fails to suppress the T242N escape variant.
    Full-text · Article · Jul 2010 · Virology
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