Repeated Intravaginal Inoculation with Cell‐Associated Simian Immunodeficiency Virus Results in Persistent Infection of Nonhuman Primates

Abstract

The goal of the present study was to develop a nonhuman primate model of intravaginal human immunodeficiency virus (HIV) transmission with cell-associated virus. Reproductively mature, cycling cynomolgus macaques with or without chemically induced, transient ulcers of the lower female reproductive tract repeatedly received challenge with a variable amount of in vitro simian immunodeficiency virus mac239-infected peripheral blood mononuclear cells. Persistent viremia was established with surprisingly few infectious lymphocytes containing physiologically relevant quantities of cell-associated virus. This model will be indispensable for the testing of vaccines and topical agents that are aimed toward the prevention of heterosexual transmission of HIV.

Genital Ulcers Facilitate Rapid Viral Entry and Dissemination following Intravaginal Inoculation with Cell-Associated Simian Immunodeficiency Virus SIVmac239

“…1B). This is consistent with our earlier observation that cell-associated virus, with less frequency, can establish a persistent infection in the apparent absence of visible ulceration (9). It is quite possible that transmission still occurs at sites of disruption of the mucosal barrier that were not detected visually or in the sections examined, as even in the section shown with an intact epithelium (Fig.…”

“…In this model, we apply 3% benzalkonium gel to the cervical and vaginal mucosa of macaques to induce epithelial disruption and acute inflammation. The irritation is visible by the second day of treatment (9,16) and lasts 7 to 9 days before resolving spontaneously. We have recently shown that intravaginal inoculation of surprisingly few SIV-infected cells established systemic infection with a high level of viremia (9).…”

“…Following our success in establishing the GUD-infection model, we hypothesized that genital ulceration could be used to define likely portals of entry for SIV, enabling us to dissect the earliest events in vaginal transmission. In the present study, we induced lower genital tract ulcers in female macaques and exposed the animals to cell-associated SIVmac239 as described previously (9). Subsequently, we investigated the cervix and vaginal mucosa for the presence of viral RNA (vRNA) and vRNA ϩ cells within the first 5 days of infection.…”

“…All procedures were performed according to an experimental protocol reviewed and approved by the Research Animal Resource Committee of the University of WisconsinMadison. Induction of transient lower female genital tract ulcers and intravaginal viral challenge were performed as described previously (9).…”

Characterization of the Influence of Semen-Derived Enhancer of Virus Infection on the Interaction of HIV-1 with Female Reproductive Tract Tissues

“…Using a unique method to identify distinct HIV-1 particles without the encumbrance of tissue autofluorescence, we demonstrated that HIV-1 can penetrate both the vaginal and ectocervical stratified squamous and endocervical simple columnar epithelia of the lower FRT (15). For a productive infection to occur, HIV-1 must efficiently traverse these epithelia to reach target cells (16)(17)(18) located in the intra-or subepithelial compartments (15,19). We took advantage of our ability to study the interaction of HIV-1 with mucosal sites to study the influence of SEVI on the diffusion of HIV-1 in FRT tissues.…”