Distinct HIV-1 Escape Patterns Selected by Cytotoxic T Cells with Identical Epitope Specificity

Self Cite

Associations between HIV-1 cytotoxic T lymphocyte (CTL) escape mutations and their restricting human leukocyte antigen (HLA) alleles imply that HIV could adapt to divergent HLA repertoires of human populations globally. Using publicly available databases, we examine the relationship between the frequencies of 19 experimentally validated CTL escape mutations in HIV-1 reverse transcriptase and their restricting HLA alleles in 59 countries. From these extensive data, we find evidence of differential HIV adaptations to human populations at only a limited number of the studied epitope sites.T he cytotoxic T lymphocyte (CTL) response is a major driving force of host-specific HIV-1 adaptation (1). As a result, HIV polymorphisms in CTL epitopes that "escape" this immune response tend to correlate with human leukocyte antigen (HLA) variations among individuals (2), an observation that has been subsequently refined and corroborated (3,4). Under the control of this mechanism, it is conceivable that HIV populations are differentially adapting to the HLA allele repertoires of each human population (5). Such adaptation would pose a challenge for HIV vaccine development, because the compositions of CTL epitopes in transmitted HIV variants would differ among regions. In an analysis of cohorts from 8 countries, Kawashima and colleagues (5) reported significant positive correlations between protective HLA alleles, such as B*51, and their respective CTL epitope variants among HIV-1 sequences circulating in these populations. In the present study, we analyzed large public databases to evaluate associations between HLA and HIV genotypes from up to 59 countries using an ecological approach to reassess this hypothesis.HIV-1 reverse transcriptase (RT) nucleotide sequence data were obtained from the Stanford University HIV Drug Resistance Database (6). Sequences were restricted to those from therapynaive subjects and filtered to one sequence per patient, leaving 44,934 sequences in total. A total of 132 countries were represented by these data. The median number of sequences per country was 123 (interquartile range [IQR] ϭ 19 to 279), with the greatest number of sequences collected in the United States (n ϭ 4,616). Countries with fewer than 100 sequences were excluded from further analyses. Pairwise alignment of the translated sequences against the HXB2 reference amino acid sequence (GenBank accession number K03455) was performed using HyPhy (7); sequence insertions relative to this reference were excluded. Although the sequence data set comprised many HIV subtypes, CTL epitopes are defined with respect to HXB2. Nonsynonymous mixtures were assumed to contribute equally to all possible amino acid resolutions of the respective codons. We selected 19 HIV RT amino acid polymorphisms within 9 optimally described CTL epitopes restricted by 8 HLA alleles (A*02, A*03, A*11, A*68, B*40, B*51, B*52, and B*57). These polymorphisms have been experimentally validated to confer diminished CTL responses in vitro (8).HLA frequencies were retrieved from...

supporting

confidence: 49%

Global Database-Driven Assessment of HIV-1 Adaptation to the Immune Repertoires of Human Populations

Karakas

Brumme

Poon

2015

Self Cite

“…Second, we hypothesize that polymorphisms are spreading differentially across global regions due to differential HLA-driven selection pressures in these populations. In Japan, for example, HLA-B*52, a relatively common allele in the population, also selects I135X (72), thereby contributing to its maintenance in circulation. Another possibility is that the Japanese HIV-1 epidemic was founded by an I135X-containing variant (73), which would also explain its persistent high prevalence.…”

Section: Discussionmentioning

confidence: 99%

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

Kinloch

MacMillan

et al. 2016

Self Cite

HumanHIV-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 ϳ2.5-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. IMPORTANCEHLA 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.

“…C1R cells expressing HLA-B*52:01 or HLA-C*12:02 and 721.221 cells expressing CD4 molecules as well as HLA-B*52:01 or HLA-C*12:02 were previously generated (36,38,39) and maintained in RPMI medium with 10% fetal calf serum (FCS) and 0.15 mg/ml hygromycin B.…”

Section: Methodsmentioning

confidence: 99%

Accumulation of Pol Mutations Selected by HLA-B52:01-C12:02 Protective Haplotype-Restricted Cytotoxic T Lymphocytes Causes Low Plasma Viral Load Due to Low Viral Fitness of Mutant Viruses

Murakoshi

Koyanagi

Chikata

et al. 2017

Self Cite

HLA-B*52:01-C*12:02, which is the most abundant haplotype in Japan, has a protective effect on disease progression in HIV-1-infected Japanese individuals, whereas HLA-B*57 and -B*27 protective alleles are very rare in Japan. A previous study on HLA-associated polymorphisms demonstrated that the number of HLA-B*52:01-associated mutations at four Pol positions was inversely correlated with plasma viral load (pVL) in HLA-B*52:01-negative individuals, suggesting that the transmission of HIV-1 with these mutations could modulate the pVL in the population. However, it remains unknown whether these mutations were selected by HLA-B*52:01-restricted CTLs and also reduced viral fitness. In this study, we identified two HLA-B*52:01-restricted and one HLA-C*12:02-restricted novel cytotoxic T-lymphocyte (CTL) epitopes in Pol. Analysis using CTLs specific for these three epitopes demonstrated that these CTLs failed to recognize mutant epitopes or more weakly recognized cells infected with mutant viruses than wild-type virus, supporting the idea that these mutations were selected by the HLA-B*52:01- or HLA-C*12:02-restricted T cells. We further showed that these mutations reduced viral fitness, although the effect of each mutation was weak. The present study demonstrated that the accumulation of these Pol mutations selected by HLA-B*52:01- or HLA-C*12:02-restricted CTLs impaired viral replication capacity and thus reduced the pVL. The fitness cost imposed by the mutations partially accounted for the effect of the HLA-B*52:01-C*12:02 haplotype on clinical outcome, together with the effect of HLA-B*52:01-restricted CTLs on viral replication, which had been previously demonstrated. IMPORTANCE Numerous population-based studies identified HLA-associated HIV-1 mutations to predict HIV-1 escape mutations from cytotoxic T lymphocytes (CTLs). However, the majority of these HLA-associated mutations have not been identified as CTL escape mutations. Our previous population-based study showed that five HLA-B*52:01-associated mutations at four Pol positions were inversely correlated with the plasma viral load in HLA-B*52:01-negative Japanese individuals. In the present study, we demonstrated that these mutations were indeed selected by CTLs specific for novel B*52:01- and C*12:02-restricted epitopes and that the accumulation of these mutations reduced the viral fitness in vitro. This study elucidated the mechanism by which the accumulation of these CTL escape mutations contributed to the protective effect of the HLA-B*52:01-HLA-C*12:02 haplotype on disease progression in HIV-1-infected Japanese individuals.