Passive sexual transmission of human immunodeficiency virus type 1 variants and adaptation in new hosts

Abstract

Human immunodeficiency virus type 1 (HIV-1) genetic diversity is a major obstacle for the design of a successful vaccine. Certain viral polymorphisms encode human leukocyte antigen (HLA)-associated immune escape, potentially overcoming limited vaccine protection. Although transmission of immune escape variants has been reported, the overall extent to which this phenomenon occurs in populations and the degree to which it contributes to HIV-1 viral evolution are unknown. Selection on the HIV-1 env gene at transmission favors neutralization-sensitive variants, but it is not known to what degree selection acts on the internal HIV-1 proteins to restrict or enhance the transmission of immune escape variants. Studies have suggested that HLA class I may determine susceptibility to HIV-1 infection, but a definitive role for HLA at transmission remains unproven. Comparing populations of acute seroconverters and chronically infected patients, we found no evidence of selection acting to restrict transmission of HIV-1 variants. We found that statistical associations previously reported in chronic infection between viral polymorphisms and HLA class I alleles are not present in acute infection, suggesting that the majority of viral polymorphisms in these patients are the result of transmission rather than de novo adaptation. Using four episodes of HIV-1 transmission in which the donors and recipients were both sampled very close to the time of infection we found that, despite a transmission bottleneck, genetic variants of HIV-1 infection are transmitted in a frequency-dependent manner. As HIV-1 infections are seeded by unique donor-adapted viral variants, each episode is a highly individual antigenic challenge. Host-specific, idiosyncratic HIV-1 antigenic diversity will seriously tax the efficacy of immunization based on consensus sequences.

FIG. 1.

Population-level distribution of amino acid variation in RT in two patient cohorts. Variant frequency in the HIV-1 RT gene (amino acids 1 to 250) across a population of 62 drug-naïve chronically infected patients with subtype B HIV-1 recruited at St. Mary's Hospital, London (a) and a population of 101 individuals sampled shortly after infection recruited at St. Mary's Hospital, London (b). (c) Differences in polymorphism frequencies for the HIV-1 RT gene in acute and chronic patients. *, site at which the difference in proportions is statistically significant.

FIG. 2.

Analyses of variant frequencies in acute versus chronic patients using Spearman's nonparametric correlation coefficient for all polymorphic sites in RT (a) or only sites at which variation is associated with the presence of the restricting HLA class I allele (b). Correlations are shown between acute seroconverters from St. Mary's Hospital and chronically infected patients from St. Mary's Hospital.

FIG. 3.

HLA class I-independent variation in acutely infected patients. For each site known to adapt to the class I-restricted CTL response (see Table S1 in the supplemental material), the number of times a variant was observed in association with an HLA allele known to direct variation at that site was counted. The observed score for the seroconverter cohort was 46. Patient sequences were then randomly assigned to different HLA class I alleles expressed in the seroconverter cohort. Repetition of this process generated the null distribution of scores expected if the amino acid variants expressed by an infecting virus were unrelated to the HLA type of the patient. The mean for the null distribution was 42.4. The expected score for a cohort of previously described chronically infected patients (calculated using published odds ratios) (21) is 82.7, which is significantly different from the null distribution (P < 0.0001).

FIG. 4.

(a) Neighbor-joining phylogenetic tree of gag p24 nucleotide sequences from donor-recipient pairs, assuming the HKY85 model of nucleotide substitution. Sequences were 843 bp long. The number of sequences for each patient was as follows: D₁, 48; R₁, 43; D₂, 19; R₂, 14; D₃, 29; R₃, 25; D₄, 38; R₄, 27. Subtype A and B reference sequences were obtained from the HIV Sequence Database (www.hiv.lanl.gov). Horizontal branch lengths are drawn to scale. Divergence is the number of substitutions per site, expressed as a percentage. (b) Retention of HIV-1 amino acid variants during sexual transmission. gag p24 from four donor-recipient pairs is shown. The variant frequency (proportion of amino acids at a particular site that differ from the subtype consensus sequence) is plotted on the vertical axis. Different-colored bars represent different amino acids at a given site. The horizontal axis represents the linear amino acid sequence from position 1 to 278. Regions of gag p24 restricted by the HLA alleles expressed in the infected patient are marked by red bars.

FIG. 5.

Frequency-dependent transmission of HLA class I antigenic variants, as shown by donor frequencies of transmission of all intraepitope, polymorphic sites. The median frequencies for the transmitted and nontransmitted variants are shown and were found to be significantly different (P < 0.0001, two-tailed Mann-Whitney test).