Abstract
BackgroundCompartmentalization of HIV-1 between the genital tract and blood was noted in half of 57 women included in 12 studies primarily using cell-free virus. To further understand differences between genital tract and blood viruses of women with chronic HIV-1 infection cell-free and cell-associated virus populations were sequenced from these tissues, reasoning that integrated viral DNA includes variants archived from earlier in infection, and provides a greater array of genotypes for comparisons.Methodology/Principal FindingsMultiple sequences from single-genome-amplification of HIV-1 RNA and DNA from the genital tract and blood of each woman were compared in a cross-sectional study. Maximum likelihood phylogenies were evaluated for evidence of compartmentalization using four statistical tests. Genital tract and blood HIV-1 appears compartmentalized in 7/13 women by ≥2 statistical analyses. These subjects' phylograms were characterized by low diversity genital-specific viral clades interspersed between clades containing both genital and blood sequences. Many of the genital-specific clades contained monotypic HIV-1 sequences. In 2/7 women, HIV-1 populations were significantly compartmentalized across all four statistical tests; both had low diversity genital tract-only clades. Collapsing monotypic variants into a single sequence diminished the prevalence and extent of compartmentalization. Viral sequences did not demonstrate tissue-specific signature amino acid residues, differential immune selection, or co-receptor usage.Conclusions/SignificanceIn women with chronic HIV-1 infection multiple identical sequences suggest proliferation of HIV-1-infected cells, and low diversity tissue-specific phylogenetic clades are consistent with bursts of viral replication. These monotypic and tissue-specific viruses provide statistical support for compartmentalization of HIV-1 between the female genital tract and blood. However, the intermingling of these clades with clades comprised of both genital and blood sequences and the absence of tissue-specific genetic features suggests compartmentalization between blood and genital tract may be due to viral replication and proliferation of infected cells, and questions whether HIV-1 in the female genital tract is distinct from blood.
Highlights
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]
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
To explore whether recent replication or proliferation biased the statistical tests towards compartmentalization, identical sequences were collapsed to a single sequence and reanalyzed for compartmentalization
Summary
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]. 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 HIV1, are derived primarily from recent cycles of replication. Compartmentalization of HIV-1 between the genital tract and blood was noted in half of 57 women included in 12 studies primarily using cell-free virus. To further understand differences between genital tract and blood viruses of women with chronic HIV-1 infection cell-free and cell-associated virus populations were sequenced from these tissues, reasoning that integrated viral DNA includes variants archived from earlier in infection, and provides a greater array of genotypes for comparisons
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