Multiple Vaginal Exposures to Low Doses of R5 Simian‐Human Immunodeficiency Virus: Strategy to Study HIV Preclinical Interventions in Nonhuman Primates

Abstract

A nonhuman-primate model of human immunodeficiency virus type 1 (HIV-1) infection that more closely emulates human heterosexual transmission by use of multiple exposures to low doses of virus is critical to better evaluate intervention strategies that include microbicides or vaccines. In this report, we describe such a system that uses female pig-tailed macaques exposed vaginally to a CCR5-using simian-human immunodeficiency virus (SHIV(SF162P3)) at weekly intervals. Results of dose-titration experiments indicated that 3 once-weekly exposures to 10 tissue culture infectious doses of SHIV(SF162P3) resulted in consistent transmission of virus and establishment of systemic infection. The efficacy of cellulose acetate phthalate (CAP) as a vaginal microbicide was evaluated by applying it to the vaginal vault of macaques (n = 4) 15 min before each weekly exposure to SHIV(SF162P3). One conclusion that can be drawn from the data derived from multiple exposures to virus is that CAP prevented infection in 12 of 13 possible chances for infection, over the course of 39 total exposures. Our findings provide a basis to refine monkey models for transmission of HIV-1, which may be relevant to preclinical evaluation for therapeutic interventions.

Cyclic changes in the vaginal epithelium of normal rhesus macaques

“…To avoid using excessive amounts of virus, some propose using low doses of virus applied weekly to the vagina of macaques in an attempt to more closely mimic the 'natural' exposure of women to HIV-infected semen (Regoes et al 2005). In these models, animals are repeatedly challenged weekly with low doses of virus until all control animals become infected (Otten et al 2005, Regoes et al 2005. However, multiple low-dose challenge models rely on the assumption that each exposure is identical, which may not be accurate.…”

Susceptibility to Repeated, Low-Dose, Rectal SHIVSF162P3 Challenge Is Independent of TRIM5 Genotype in Rhesus Macaques

“…There are many advantages to this approach as a model for HIV transmission, namely the similarity in inoculum and multiplicity in virus exposure before systemic infection to humans. 1 The use of higher physiological doses has been thought to dilute the effects of microbicide or vaccine-induced immunity, thereby underestimating the potential of candidate biomedical preventions. In the RLD model, it is possible to measure susceptibility as the number of challenges required to infect with the assumption that each animal is vulnerable to infection with each challenge.…”

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS

“…A physiologically relevant viral dose to what is seen in humans during exposure to seminal fluid is used, and repeated exposures mimic multiple sexual transmission events. Unlike the models which use a single high viral inoculum exposure, the repeat low-dose model [79,[151][152][153] allows the investigator to assess the efficacy of anti-HIV regimens in a repeated fashion that is closer to human use patterns.…”

“…A low-dose titration in pig-tailed macaques showed that systemic infection can be achieved with 3 once-weekly intravaginal exposures to 10TCID50 of SHIV162P3 [152]. It was reported recently that the susceptibility to infection in normally cycling female pigtail macaques is substantially greater in the luteal phase when the challenge regimen used is the repeat low dose model [78].…”