Abstract
The majority of new HIV infections occur in women as a result of heterosexual intercourse, overcoming multiple innate barriers to infection within the mucosa. However, the avenues through which infection is established, and the nature of bottlenecks to transmission, have been the source of considerable investigation and contention. Using a high dose of a single round non-replicating SIV-based vector containing a novel dual reporter system, we determined the sites of infection by the inoculum using the rhesus macaque vaginal transmission model. Here we show that the entire female reproductive tract (FRT), including the vagina, ecto- and endocervix, along with ovaries and local draining lymph nodes can contain transduced cells only 48 hours after inoculation. The distribution of infection shows that virions quickly disseminate after exposure and can access target cells throughout the FRT, with an apparent preference for infection in squamous vaginal and ectocervical mucosa. JRFL enveloped virions infect diverse CD4 expressing cell types, with T cells resident throughout the FRT representing the primary target. These findings establish a new perspective that the entire FRT is susceptible and virus can reach as far as the ovary and local draining lymph nodes. Based on these findings, it is essential that protective mechanisms for prevention of HIV acquisition must be present at protective levels throughout the entire FRT to provide complete protection.
Highlights
The majority of new female human immunodeficiency virus (HIV) infections are the direct result of vaginal intercourse with an infected male partner [1,2,3]
Luminescence is used as macroscopic guide for detection of tissue sites where individual infected cells can be subsequently identified with fluorescence microscopy of cryosections
We examined the cellular phenotype of the JRFL pseudotyped reporter transduced cells by staining for CD4 (HIV-1 receptor), CD3 (T cell specific) or CD68
Summary
The majority of new female human immunodeficiency virus (HIV) infections are the direct result of vaginal intercourse with an infected male partner [1,2,3]. Multiple studies examining viral acquisition after vaginal exposure in macaque models have concluded that the endocervix and it’s less robust single cell columnar epithelial barrier is a primary portal of entry for virions in the FRT [7,8] They have suggested that the transformation zone, where the columnar epithelium of the endocervix merges with the more robust squamous epithelial barriers of the vaginal vault is especially susceptible because of inefficient barrier function where the two different types of epithelium come together. Breaks in the vaginal epithelium due to abrasion or ulcerative STIs, or exposure of the more permissive simple columnar epithelium in the ectocervix due to cervical ectopy, can facilitate viral ingress [3] These cervix-centric studies have led to the field focusing on this as a principle site of transmission and excluding much of the FRT as important to protect [7,8]. Another implication of this work is that the primary bottleneck for Author Summary
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