Demographic Processes Affect HIV-1 Evolution in Primary Infection before the Onset of Selective Processes

Department of Microbiology, SC-42, University of Washington School of Medicine, Seattle, WA 98195-8070, USA.
Journal of Virology (Impact Factor: 4.44). 05/2011; 85(15):7523-34. DOI: 10.1128/JVI.02697-10
Source: PubMed


HIV-1 transmission and viral evolution in the first year of infection were studied in 11 individuals representing four transmitter-recipient pairs and three independent seroconverters. Nine of these individuals were enrolled during acute infection; all were men who have sex with men (MSM) infected with HIV-1 subtype B. A total of 475 nearly full-length HIV-1 genome sequences were generated, representing on average 10 genomes per specimen at 2 to 12 visits over the first year of infection. Single founding variants with nearly homogeneous viral populations were detected in eight of the nine individuals who were enrolled during acute HIV-1 infection. Restriction to a single founder variant was not due to a lack of diversity in the transmitter as homogeneous populations were found in recipients from transmitters with chronic infection. Mutational patterns indicative of rapid viral population growth dominated during the first 5 weeks of infection and included a slight contraction of viral genetic diversity over the first 20 to 40 days. Subsequently, selection dominated, most markedly in env and nef. Mutants were detected in the first week and became consensus as early as day 21 after the onset of symptoms of primary HIV infection. We found multiple indications of cytotoxic T lymphocyte (CTL) escape mutations while reversions appeared limited. Putative escape mutations were often rapidly replaced with mutually exclusive mutations nearby, indicating the existence of a maturational escape process, possibly in adaptation to viral fitness constraints or to immune responses against new variants. We showed that establishment of HIV-1 infection is likely due to a biological mechanism that restricts transmission rather than to early adaptive evolution during acute infection. Furthermore, the diversity of HIV strains coupled with complex and individual-specific patterns of CTL escape did not reveal shared sequence characteristics of acute infection that could be harnessed for vaccine design.

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    • "004-007 env exp exp 10 1 12 12 206-201 env exp exp 10 1 11 12 206-204 env exp exp 10 1 12 13 512-558 env exp exp 104 1 14 11 512-559 env exp exp 104 1 11 11 551-550 env exp exp 10 1 12 13 564-557 env exp exp 10 1 15 14 Continued on next page Table 1 – continued from previous page Dataset genomic region PS SS #days to first sam- pling #time points recipient # se- quences recipient # se- quences donor Herbeck et al. [14] 1 gag exp exp 36 15 304 20 1 env log log " 12 418 21 1 pol exp exp " 12 152 10 2 gag exp exp 13 1 18 10 2 env exp exp " " 18 10 2 pol exp exp " " 18 10 3 gag exp exp 30 1 93 10 3 env exp exp " " 93 10 3 pol exp exp " " 93 10 4 gag exp exp 20 1 30 38 4 env exp exp " " 30 38 4 pol exp exp " " 30 38 Lawson et al. [16] "
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    ABSTRACT: To determine how HIV-1 risk groups impact transmitted diversity and the tempo of viral evolution at a population scale. We investigated a set of previously described transmission chains (n = 70) using a population genetic approach, and tested whether the expected differences in proportions of multivariant transmissions are reflected by varying proportions of transmitted diversity between men having sex with men (MSM) and heterosexual (HET) subpopulations - the largest contributors to HIV spread. To assess evolutionary rate differences among the different risk groups, we compiled risk group datasets for subtypes A1, B and CRF01_AE, and directly compared the absolute substitution rate and its synonymous and non-synonymous components. There was sufficient demographic signal to inform the transmission model in Bayesian evolutionary analysis by sampling trees using env data to compare the transmission bottleneck size between the MSM and HET risk groups. We found no indications for a different proportion of transmitted genetic diversity at the population level between these groups. In the direct rate comparisons between the risk groups, however, we consistently recovered a higher evolutionary rate in the male-dominated risk group compared to the HET datasets. We find that the risk group composition affects the viral evolutionary rate and therefore potentially also the adaptation rate. In particular, risk group-specific sex ratios, and the variation in within-host evolutionary rates between men and women, impose evolutionary rate differences at the epidemic level, but we cannot exclude a role of varying transmission rates.
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    • "Lastly, we wished to identify adaptation-related features that discriminate protective from non-protective HLA alleles, defined here as their published hazard ratios for progression to AIDS [HR-AIDS] in natural history studies [36]. Although the timecourse of viral escape is influenced by complex factors including epitope immunodominance hierarchies, strength of selection, mutational/fitness constraints and transmitted virus characteristics [17,19,34,37-40], we reasoned that HLA alleles that restrict polymorphisms that are already highly prevalent in early infection (due to rapid escape and/or frequent transmission) would be generally unfavorable for HIV-1 control. Thus, for all HLA alleles for which ≥2 adapted polymorphisms were investigated in the present study (N = 17 alleles total), we computed their mean “percentage escaped” in early infection. "
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