Evidence of Genetic Variability of Human Immunodeficiency Virus Type 1 in Plasma and Cervicovaginal Lavage in Ethiopian Women Seeking Care for Sexually Transmitted Infections

Abstract

Most human immunodeficiency virus type 1 (HIV-1) transmission in developing countries occurs through heterosexual intercourse or during birth from mother to child. It is critical to characterize the virus of the genital tract variants as a target for the development of an HIV-1 vaccine and microbicidal therapies. We compared the C2V3 env domain genetic diversity of HIV-1 in female genital secretions and in plasma from Ethiopian women seeking care for sexually transmitted infections (STIs). Sequences within an individual differed between the plasma and cervicovaginal lavage (CLV) compartments with nucleotide and amino acid median difference values of 8.3 and 4.8%, respectively. Sequence diversity in CVL was greater than in plasma. And the V3 loop positive charge was often more elevated in CVL. These are markers of the differential evolution of the viruses in CVL and peripheral blood indicating that limited evolution at the site of contact is not the limiting factor determining the preferential transmission of macrophage tropic viruses.

Compartmentalization of HIV-1 within the Female Genital Tract Is Due to Monotypic and Low-Diversity Variants Not Distinct Viral Populations

“…Across the literature, compartmentalization of HIV-1 within the genital tract of women by statistical measures and detection of discordant patterns of drug-resistance has been interpreted as evolution of independent viral populations within the genital tract [7], [9], [11], [12], [13], [15], [17]. Often these data were from cross-sectional studies of cell-free viruses obtained from plasma and CVL from women with ongoing viral replication, which suggests that unique variants could predominant in the tissues for a period of time [8], [9], [11], [12], [13], [15], [16], [17], [48].…”

“…Distinct genetic populations of HIV-1 in the genital tract compared to blood have been reported in 170 men [1], [2], [3], [4], [5] and 57 women [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. Physical partitions, cellular membranes, inadequate penetration of antiretroviral drugs into the genital tract [19], [20] or localized inflammation [7], [8], [9] are hypothesized to facilitate replication in the genital tract independently from the blood, and allow evolution of HIV-1 genital tract variants that appear distinct from the blood [6], [7], [8].…”

“…While multiple reports suggest that HIV-1 appears compartmentalized between the genital tract and the blood of women [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [21], we hypothesized that the absence of strict physical barriers between the female genital tract and blood would allow viruses to mix between these two tissues.…”

“…Studies reporting compartmentalization of viruses within the female genital tract have often analyzed only cell-free viruses [8], [9], [11], [12], [13], [15], [16], [17], which, given the rapid turnover of HIV-1, are derived primarily from recent cycles of replication. We expand on these studies by analyzing both cell-free HIV-1 RNA and cell-associated HIV-1 DNA to sample both replicating and archived viruses, respectively, in the blood and genital tract.…”

HIV-1 Pathogenesis: The Virus

“…There is no obvious single tissue mass (equivalent to the prostate, for example) that could provide a source of localized virus production. Several studies have reported compartmentalization of viral sequences in the FMTwithin at least a subset of subjects (Poss et al 1998;Kemal et al 2003;Adal et al 2005;Andreoletti et al 2007). More recently, this compartmentalization was interpreted to be largely the result of clonal amplification (Bull et al 2009).…”