HLA class I sequence-based typing using DNA recovered from frozen plasma

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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.

Section: Methodsmentioning

confidence: 99%

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

Kinloch

MacMillan

et al. 2016

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“…These steps ensured that each Nef clone encoded an intact open reading frame and was free of gross genetic defects (e.g., large deletions) and that clones chosen for functional analysis were representative of each individual's circulating viral quasispecies. HLA class I typing was performed using genomic DNA extracted from PBMC or plasma using sequence-based methods (50).…”

Section: Methodsmentioning

confidence: 99%

Impaired Nef Function Is Associated with Early Control of HIV-1 Viremia

Kuang

Anmole

et al. 2014

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Host and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in HIV-1 controllers during the chronic phase, but the kinetics and mechanisms of Nef attenuation in such individuals remain unclear. We examined plasma RNA-derived Nef clones from 10 recently infected individuals who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) and 50 recently infected individuals who did not control viremia (acute progressors). Nef clones from acute controllers displayed a lesser ability to downregulate CD4 and HLA class I from the cell surface and a reduced ability to enhance virion infectivity compared to those from acute progressors (all P < 0.01). HLA class I downregulation activity correlated inversely with days postinfection (Spearman's R ‫؍‬ ؊0.

“…HLA class I typing for the HOMER cohort was performed at the BCCfE using an in-house sequence-based typing protocol and interpretation algorithm (19,20,32), yielding a mixture of intermediate-and high (subtype-level)-resolution data. High-resolution HLA class I typing for the WAHCS and ACTG 5142/5128 cohorts was performed at the CCIBS as previously described (20,60).…”

Section: Ihac the International Hiv Adaptation Collaborative (Ihac)mentioning

confidence: 99%

Correlates of Protective Cellular Immunity Revealed by Analysis of Population-Level Immune Escape Pathways in HIV-1

Carlson

Brumme

Martin

et al. 2012

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102

266

i HLA class I-associated polymorphisms identified at the population level mark viral sites under immune pressure by individual HLA alleles. As such, analysis of their distribution, frequency, location, statistical strength, sequence conservation, and other properties offers a unique perspective from which to identify correlates of protective cellular immunity. We analyzed HLA-associated HIV-1 subtype B polymorphisms in 1,888 treatment-naïve, chronically infected individuals using phylogenetically informed methods and identified characteristics of HLA-associated immune pressures that differentiate protective and nonprotective alleles. Over 2,100 HLA-associated HIV-1 polymorphisms were identified, approximately one-third of which occurred inside or within 3 residues of an optimally defined cytotoxic T-lymphocyte (CTL) epitope. Differential CTL escape patterns between closely related HLA alleles were common and increased with greater evolutionary distance between allele group members. Among 9-mer epitopes, mutations at HLA-specific anchor residues represented the most frequently detected escape type: these occurred nearly 2-fold more frequently than expected by chance and were computationally predicted to reduce peptide-HLA binding nearly 10-fold on average. Characteristics associated with protective HLA alleles (defined using hazard ratios for progression to AIDS from natural history cohorts) included the potential to mount broad immune selection pressures across all HIV-1 proteins except Nef, the tendency to drive multisite and/or anchor residue escape mutations within known CTL epitopes, and the ability to strongly select mutations in conserved regions within HIV's structural and functional proteins. Thus, the factors defining protective cellular immune responses may be more complex than simply targeting conserved viral regions. The results provide new information to guide vaccine design and immunogenicity studies. HIV-1 is notorious for its genetic diversity and its ability to adapt to selection pressures (44,87,116). Despite this, within-host HIV-1 evolution in response to antiretroviral (61, 72), host cellular immune (15,50,71,94,95), antibody (46), and vaccine-induced (103) selection pressures occurs along generally predictable mutational pathways (3, 84). Studying these evolutionary pathways can offer insight into the immunopathogenesis of HIV-1 and may help inform the design of immune-based interventions and vaccines.Substantial progress has been made in our understanding of HIV-1's ability to evade human leukocyte antigen (HLA) class I-restricted CD8 ϩ cytotoxic T-lymphocytes (CTL). In particular, application of novel statistical methods (13,25,84) to large population-based data sets of linked host and viral genetic information has facilitated the systematic identification of HLA-associated immune escape and covarying mutations in 20,60,81,99,104), revealing important insights into HIV-1 adaptation to its host. We now appreciate that immune selection represents a major force shaping HIV-1 diversity (3,80,...