Role of donor genital tract HIV-1 diversity in the transmission bottleneck

Abstract

The predominant mode of HIV-1 infection is heterosexual transmission, where a genetic bottleneck is imposed on the virus quasispecies. To probe whether limited genetic diversity in the genital tract (GT) of the transmitting partner drives this bottleneck, viral envelope sequences from the blood and genital fluids of eight transmission pairs from Rwanda and Zambia were analyzed. The chronically infected transmitting partner's virus population was heterogeneous with distinct genital subpopulations, and the virus populations within the GT of two of four women sampled longitudinally exhibited evidence of stability over time intervals on the order of weeks to months. Surprisingly, the transmitted founder variant was not derived from the predominant GT subpopulations. Rather, in each case, the transmitting variant was phylogenetically distinct from the sampled locally replicating population. Although the exact distribution of the virus population present in the GT at the time of transmission cannot be unambiguously defined in these human studies, it is unlikely, based on these data, that the transmission bottleneck is driven in every case by limited viral diversity in the donor GT or that HIV transmission is solely a stochastic event.

Cumulative Impact of Host and Viral Factors on HIV-1 Viral-Load Control during Early Infection

“…While the fact that HIV-1-infected females present lower VLs than their male counterparts may in part act as a confounder in the VL correlation between TSPs and SCs, it seems unlikely that this completely explains the difference. The other possible difference between these studies is that in the studies of heterosexual transmission pairs, the transmitting partner was already identified as HIV positive prior to inclusion of the couple in discordant couple prevention studies, and in most linked transmission pairs we have studied phylogenetically, the diversity of the TSP virus population is consistent with chronic infection (42)(43)(44). In a study by Hecht et al (21), the majority of TSPs were identified posttransmission, and 9 of the 24 TSPs represented individuals with recent infection.…”

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

“…The VH2000 env gene sequences exhibited a maximum pairwise distance of 2% (Fig. S1), which is lower in diversity than what is generally present in an HIV-1-infected transmitting partner (24)(25)(26). Fig.…”

“…T/F virus variant in the vast majority of individuals (24)(25)(26). In each case of breakthrough, an env gene amplicon representative of the T/F sequence, or the predominant env gene sequence in the case of RJn11, was cloned to assess neutralization sensitivity.…”

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

“…This inefficiency is exemplified by a stringent population bottleneck, in which only one or a limited number of variants from the diverse quasispecies of the transmitting donor establish the new infection (9). Transmitted viruses are not usually the most abundant strains in the genital secretions of infected donors (10), and analyses of viral sequences from 137 matched donor and recipient pairs indicated that viruses with a more ancestral genotype are preferentially transmitted (11). These data suggested that mucosal transmission selects for variants with enhanced transmission fitness (11).…”