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Extensive host immune adaptation in a concentrated North American HIV epidemic.

ABSTRACT: OBJECTIVE:HIV incidence in the Canadian province of Saskatchewan, where Indigenous persons make up 80% of those infected, are among the highest on the continent. Reports of accelerated HIV progression, associated with carriage of certain human leukocyte antigen (HLA) alleles (including the typically protective HLA-B*51) have also emerged from the region. Given that acquisition of HIV preadapted to host HLA negatively impacts clinical outcome, we hypothesized that HIV-host adaptation may be elevated in Saskatchewan. DESIGN:Comparative analysis of population-level HIV sequence datasets from Saskatchewan and elsewhere in Canada/USA. METHODS:We analyzed 1144 HIV subtype B Pol sequences collected in Saskatchewan between 2000 and 2016, comprising ?65% of cumulative provincial HIV cases, for the presence of 70 HLA-associated Pol mutations. Sequences from British Columbia (N?=?6525) and elsewhere in Canada/USA (N?=?6517) were used for comparison. HIV adaptation levels to 34 HLA alleles were also computed. Putative HIV transmission clusters were identified, and the prevalence of HLA-associated adaptations within and outside these clusters was investigated. RESULTS:Analyses confirmed significantly elevated and temporally increasing levels of HIV adaptation to commonly expressed HLA alleles, in particular B*51. Notably, HLA-adapted HIV strains were significantly enriched among phylogenetic clusters in Saskatchewan. CONCLUSION:Extensive circulating HIV adaptation to HLA in Saskatchewan provides a plausible explanation for accelerated progression, while enrichment of adapted variants in phylogenetic clusters suggests they are being widely transmitted. Results highlight the utility of Pol sequences, routinely collected for drug resistance monitoring, for surveillance of HIV-host adaptation, and underscore the urgent need to expand HIV prevention and treatment programmes in Saskatchewan.

SUBMITTER: Brumme ZL

PROVIDER: S-EPMC6125742 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Extensive host immune adaptation in a concentrated North American HIV epidemic.

Brumme Zabrina L ZL Kinloch Natalie N NN Sanche Stephen S Wong Alexander A Martin Eric E Cobarrubias Kyle D KD Sandstrom Paul P Levett Paul N PN Harrigan P Richard PR Joy Jeffrey B JB

AIDS (London, England) 20180901 14

<h4>Objective</h4>HIV incidence in the Canadian province of Saskatchewan, where Indigenous persons make up 80% of those infected, are among the highest on the continent. Reports of accelerated HIV progression, associated with carriage of certain human leukocyte antigen (HLA) alleles (including the typically protective HLA-B*51) have also emerged from the region. Given that acquisition of HIV preadapted to host HLA negatively impacts clinical outcome, we hypothesized that HIV-host adaptation may ...[more]

PMID: 30048246

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Project description:UnlabelledHuman 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.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.

Project description:HLA-restricted immune escape mutations that persist following HIV transmission could gradually spread through the viral population, thereby compromising host antiviral immunity as the epidemic progresses. To assess the extent and phenotypic impact of this phenomenon in an immunogenetically diverse population, we genotypically and functionally compared linked HLA and HIV (Gag/Nef) sequences from 358 historic (1979-1989) and 382 modern (2000-2011) specimens from four key cities in the North American epidemic (New York, Boston, San Francisco, Vancouver). Inferred HIV phylogenies were star-like, with approximately two-fold greater mean pairwise distances in modern versus historic sequences. The reconstructed epidemic ancestral (founder) HIV sequence was essentially identical to the North American subtype B consensus. Consistent with gradual diversification of a "consensus-like" founder virus, the median "background" frequencies of individual HLA-associated polymorphisms in HIV (in individuals lacking the restricting HLA[s]) were ∼ 2-fold higher in modern versus historic HIV sequences, though these remained notably low overall (e.g. in Gag, medians were 3.7% in the 2000s versus 2.0% in the 1980s). HIV polymorphisms exhibiting the greatest relative spread were those restricted by protective HLAs. Despite these increases, when HIV sequences were analyzed as a whole, their total average burden of polymorphisms that were "pre-adapted" to the average host HLA profile was only ∼ 2% greater in modern versus historic eras. Furthermore, HLA-associated polymorphisms identified in historic HIV sequences were consistent with those detectable today, with none identified that could explain the few HIV codons where the inferred epidemic ancestor differed from the modern consensus. Results are therefore consistent with slow HIV adaptation to HLA, but at a rate unlikely to yield imminent negative implications for cellular immunity, at least in North America. Intriguingly, temporal changes in protein activity of patient-derived Nef (though not Gag) sequences were observed, suggesting functional implications of population-level HIV evolution on certain viral proteins.

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Extensive host immune adaptation in a concentrated North American HIV epidemic.

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Extensive host immune adaptation in a concentrated North American HIV epidemic.

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