Population-level Immune-mediated Adaptation in HIV-1 Polymerase during the North American Epidemic.

2015 | J Virol

Program(s): Laboratory |

Abstract:

Human 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 (1979-1989, N=338) and modern (2001-2011, N= 278) eras from across North America (Vancouver, Boston, New York, and San Francisco). 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 near-identical to the modern North American subtype B consensus. Nevertheless, modern HIV-1 Pol sequences exhibited roughly 2-fold higher patristic (tip-to-tip) genetic distances compared to historic ones, with HLA pressures likely driving ongoing diversification. Moreover, the frequency of published HLA-associated polymorphisms in individuals lacking the selecting HLA class I allele was on average ∼2.5-fold higher in modern compared to historic eras, 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. Overall however, despite evidence of polymorphism spread, North American hosts generally remain at relatively low risk of acquiring an HIV-1 Polymerase sequence substantially pre-adapted to their HLA profile, even in the present era.

IMPORTANCE:

HLA class I-restricted 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 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 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 pre-adapted to one's HLA profile remains relatively low in North America, even in the present era.

Text or Node

Kinloch NN

BC Centre for Excellence in HIV/AIDS

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Population-level Immune-mediated Adaptation in HIV-1 Polymerase during the North American Epidemic.

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