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

Abstract

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.

Modeling the immunological pre-adaptation of HIV-1

“…These results are roughly comparable with real data: On the one hand, the effect of being infected with a pre-adapted virus can be quite large [63]. However, the fraction of infections with highly pre-adapted viruses currently remains low [47]. A warning from this study would be that the level of pre-adaptation is expected to increase during the next century.…”

“…The spread of CTL-escape mutations through the population can have a significant impact on virulence, in a way that is dependent on the HLA genotype of the patient [13,19,47,71]. Having full knowledge of the transmitter-founder virus, the exact genetic makeup of the virus that seeded the epidemic (the wild type), and all possible responses that a host is able to mount, it is possible to quantify the impact of pre-adaptation on progression to AIDS in our model.…”

“…Pre-adaptation can lead to the apparent loss of HLA associations, if the statistical model does not properly correct for this pre-adaptation [13]. Furthermore, evidence is accumulating that HLA pre-adaptation is a major determinant of disease progression [63], although currently the population-level health effects appear to be relatively small [47].…”

Extensive host immune adaptation in a concentrated North American HIV epidemic

“…Our results also identify Saskatchewan as the first documented example of a North American HIV epidemic characterized by significant circulating viral adaptation to HLA [6,8]. As no licensed preventive or therapeutic vaccine exists to boost anti-HIV immunity against strains harbouring transmitted (or de novo selected) immune escape mutations, our observation of extensive HIV adaptation to host HLA in Saskatchewan, combined with regional reports of rapid HIV progression [18], add even greater urgency to addressing this epidemic in which infection burden is already concentrated among the most marginalized persons [14,15].…”

“…1c), a remarkable observation given Pol's relative conservation and the long-term stability of the North American [8] and global (http://www.hiv.lanl.gov/) subtype B Pol consensus sequences. For all but RT-272 [where Proline and Alanine occur at comparable (47% vs. 45%) frequencies in subtype B globally], the magnitude of these differences was also striking.…”