Article

Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA

Peter Medawar Building, University of Oxford, Oxford OX13SY, UK.
Journal of Experimental Medicine (Impact Factor: 13.91). 04/2005; 201(6):891-902. DOI: 10.1084/jem.20041455
Source: PubMed

ABSTRACT Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of "negatively associated" or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.

3 Followers
 · 
137 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Fitness costs and slower disease progression are associated with a cytolytic T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains on the fitness costs due to the T242N mutation has not been well characterized. To better understand the extent of fitness costs of the T242N mutation and the repair of fitness loss through compensatory amino acids, we investigated its fitness impact in different transmitted/founder (T/F) viruses.ResultsThe T242N mutation resulted in various levels of fitness loss in four different T/F viruses. However, the fitness costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover, the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome resulted in significant fitness cost, suggesting the fitness loss caused by the T242N mutation had been fully repaired in the donor at transmission. Analysis of the global circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high prevalence of compensatory amino acids for the T242N mutation and other T cell escape mutations.Conclusions Our results show that the preexisting compensatory amino acids in the majority of circulating HIV-1 strains could significantly compromise the fitness loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.
    Retrovirology 11/2014; 11(1):101. DOI:10.1186/s12977-014-0101-0 · 4.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Proceedings of the National Academy of Sciences 12/2014; DOI:10.1073/pnas.1413339111 · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Author Summary HIV-1 is a relatively young virus, being introduced in the human population somewhere between 1884 and 1924. Yet, previous studies suggest that the virus has already evolved to be efficiently transmitted among humans. Efficient transmission occurs when the set-point virus load, the semi-stable number of virus particles in the blood during the asymptomatic phase, is intermediate (approximately particles/ml). At this virus load level, individuals remain asymptomatic for a long period (7.0 years on average), and still remain sufficiently infectious. In this study, we model the combined immunological and epidemiological dynamics of HIV-1 to explore whether population-level adaptation is feasible. We show that strong selective forces within the host are expected to dominate the much weaker population-level selection, unless the within-host dynamics of immune escape becomes exceedingly slow. Surprisingly, our analyses yield high levels of set-point virus load heritability, as observed in human populations. In the model, heritability of set-point virus load partially results from an immunological ‘footprint’ of the host-virus interaction in transmitting hosts, affecting the receiving hosts' virus load.
    PLoS Computational Biology 12/2014; 10(12):e1003899. DOI:10.1371/journal.pcbi.1003899 · 4.87 Impact Factor

Full-text (3 Sources)

Download
43 Downloads
Available from
May 16, 2014