Abstract
In the majority of cases, human immunodeficiency virus type 1 (HIV-1) infection is transmitted through sexual intercourse. A single founder virus in the blood of the newly infected donor emerges from a genetic bottleneck, while in rarer instances multiple viruses are responsible for systemic infection. We sought to characterize the sequence diversity at early infection, between two distinct anatomical sites; the female reproductive tract vs. systemic compartment. We recruited 72 women from Uganda and Zimbabwe within seven months of HIV-1 infection. Using next generation deep sequencing, we analyzed the total genetic diversity within the C2-V3-C3 envelope region of HIV-1 isolated from the female genital tract at early infection and compared this to the diversity of HIV-1 in plasma. We then compared intra-patient viral diversity in matched cervical and blood samples with three or seven months post infection. Genetic analysis of the C2-V3-C3 region of HIV-1 env revealed that early HIV-1 isolates within blood displayed a more homogeneous genotype (mean 1.67 clones, range 1–5 clones) than clones in the female genital tract (mean 5.7 clones, range 3–10 clones) (p<0.0001). The higher env diversity observed within the genital tract compared to plasma was independent of HIV-1 subtype (A, C and D). Our analysis of early mucosal infections in women revealed high HIV-1 diversity in the vaginal tract but few transmitted clones in the blood. These novel in vivo finding suggest a possible mucosal sieve effect, leading to the establishment of a homogenous systemic infection.
Highlights
The sexual transmission of human immunodeficiency virus type 1 (HIV-1) establishes initial infection with high viral loads which is eventually resolved but followed by a slow progression to acquired immunodeficiency syndrome (AIDS)
During chronic HIV-1 infection, high viral diversity can be found in the blood and semen of donors
Our findings provide novel in vivo evidence for the existence of an intra-patient genetic bottleneck restricting the HIV-1 from the vaginal tract to the blood during early heterosexual HIV-1 transmission
Summary
The sexual transmission of HIV-1 establishes initial infection with high viral loads which is eventually resolved but followed by a slow progression to acquired immunodeficiency syndrome (AIDS). Male-to-female heterosexual transmission of HIV-1 requires the inoculating virus from the semen to penetrate the vaginal mucosa, the epithelial layer, and infect and/or bind to susceptible Langerhans or dendritic cells in the lamina propria of the vaginal/cervical lining [4, 5]. Each of these steps is poorly understood, e.g. penetration and infection of the various vaginal layers and dissemination into blood and lymphoid tissue could involve genetic bottlenecks. Certain viral characteristics such as glycosylation [8], receptor tropism [1], increased infinity for α4β7 integrin and general fitness [9] might favor selection of specific transmitted founder variants from the donor inoculum
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