Heterosexual Transmission of Subtype C HIV-1 Selects Consensus-Like Variants without Increased Replicative Capacity or Interferon-α Resistance

Abstract

Heterosexual transmission of HIV-1 is characterized by a genetic bottleneck that selects a single viral variant, the transmitted/founder (TF), during most transmission events. To assess viral characteristics influencing HIV-1 transmission, we sequenced 167 near full-length viral genomes and generated 40 infectious molecular clones (IMC) including TF variants and multiple non-transmitted (NT) HIV-1 subtype C variants from six linked heterosexual transmission pairs near the time of transmission. Consensus-like genomes sensitive to donor antibodies were selected for during transmission in these six transmission pairs. However, TF variants did not demonstrate increased viral fitness in terms of particle infectivity or viral replicative capacity in activated peripheral blood mononuclear cells (PBMC) and monocyte-derived dendritic cells (MDDC). In addition, resistance of the TF variant to the antiviral effects of interferon-α (IFN-α) was not significantly different from that of non-transmitted variants from the same transmission pair. Thus neither in vitro viral replicative capacity nor IFN-α resistance discriminated the transmission potential of viruses in the quasispecies of these chronically infected individuals. However, our findings support the hypothesis that within-host evolution of HIV-1 in response to adaptive immune responses reduces viral transmission potential.

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

“…The replicative capacity of viruses can influence their reproductive ratio (R 0 ) and thus their ability to expand an initial infection (51). Comparing IMCs from unrelated subjects, we previously failed to detect differences in the growth potential of TF and chronic HIV-1 strains (26), and similar results were reported for donor and recipient viruses from transmission pairs (27,28). Here, we compared the replicative capacity of limiting dilution-derived isolates in normal donor CD4 + T cells.…”

“…We previously reported that TF viruses were 2-fold more infectious than chronic viruses from unrelated subjects (26), but two subsequent studies failed to identify virus infectivity as a determinant of transmission fitness (27,28). Here, we used TZM-bl cells, which express luciferase under the control of an HIV-1 promoter (48,49), to determine the per-particle infectivity of CD4 + T-cellderived viral stocks.…”

“…However, a potential confounder of these studies was the fact that TF and CC viruses were not derived from epidemiologically linked transmission pairs. To compare transmitted and nontransmitted viruses close to the time of transmission, two recent studies characterized the phenotype of viruses from matched donor and recipient pairs (27,28). Examining various biological properties, including the sensitivity of donor and recipient viruses to IFNα2, both studies failed to identify viral traits that were indicative of enhanced transmission fitness (27,28).…”

Cervicovaginal Inflammation Facilitates Acquisition of Less Infectious HIV Variants

“…In contrast, Deymier et al [4] did not observe selection for higher infectivity in a study of 6 transmission pairs, although this could be due to the use of DEAE-dextran in their infectivity assay and/or the presence of subclinical inflammation. The Figure 1.…”

“…This transmitted founder virus is rarely the dominant variant, suggesting that transmission is not entirely stochastic but favors certain viral phenotypes [3][4][5]. The most likely determinants of this bottleneck are the physical and immunological properties of the healthy genital mucosa, which constitutes an efficient barrier to HIV acquisition and is able to block most unprotected sexual exposures [6].…”