Repetitive exposures with simian/human immunodeficiency viruses: strategy to study HIV pre-clinical interventions in non-human primates.

BACKGROUND: Non-human primate models for human immunodeficiency virus (HIV) infection represent a valuable pre-clinical tool to evaluate interventions (e.g., topical microbicides, vaccines, and chemoprophylaxis) designed to prevent transmission or slow disease progression after infection. Standard transmission models use a single-dose exposure with high, non-physiologic levels of virus to approach 100% infection rates of control animals. These single-exposure models do not represent the circumstances of mucosal HIV transmission in humans and may result in misleading data with regard to intervention efficacy. Therefore, we have developed a repetitive mucosal exposure model using doses of virus that better reflects human exposures. METHODS: The virus used for these evaluations was simian-human immunodeficiency virus [SHIVSF162P3 (R5-using, subtype B HIV-1 envelope)] and the virus dose used (approximately 10(5)-10(6) viral particle equivalents or approximately 10 tissue culture infectious doses per exposure) approximates viral loads observed in the semen during acute HIV-1 infection. Using the repeated mucosal exposure approach, we have evaluated a candidate vaginal microbicide (cellulose acetate phthalate, CAP) given 15 minutes prior to each weekly virus exposure. Pig-tailed macaques were exposed weekly by vaginal inoculations with and without microbicide until systemic viral RNA was detected. RESULTS: Groups of naïve control monkeys were infected after an average of three to four exposures for the vaginal route of inoculation. Data from the first application of this monkey model to evaluate the topical microbicide CAP suggested that protection from SHIV infection was possible with three of four CAP-treated monkeys remaining uninfected after 12 exposures (P = 0.015). CAP efficacy was markedly improved from 66% in a previous single-dose virus exposure study to 92% in this repeated exposure system. CONCLUSIONS: Our experience with using repetitive virus exposures to study topical microbicides and the findings to date from this study provides a basis to refine monkey models to more closely resemble human exposure during HIV transmission. This model may be highly relevant to pre-clinical evaluation for a variety of therapeutic interventions which is discussed here.

Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges.

We examined the efficacy of tenofovir disoproxil fumarate (TDF) in blocking simian human immunodeficiency virus (SHIV) infection in Chinese rhesus macaques. Once weekly for 14 weeks or until a macaque became infected, 12 male macaques were inoculated intrarectally with amounts of SHIV(SF162P3) (10 median tissue culture infective doses; 3.8 x 10(5) virus particles) that were approximately 5-fold higher than the human immunodeficiency virus type 1 RNA levels noted in human semen during an acute infection. Of the 12 macaques, 4 received oral TDF daily, 4 received oral TDF once weekly, and 4 (control animals) received no TDF. The control animals became infected after receiving a median of 1.5 virus inoculations; macaques receiving TDF daily (1 macaque remained uninfected after 14 inoculations) and those receiving TDF weekly became infected after a median duration of 6.0 and 7.0 weeks, respectively. Although infection was delayed in treated macaques, compared with control macaques, the differences were not statistically significant (P=.315); however, the study was limited by the small numbers of animals evaluated and the variability in blood levels of TDF that resulted from oral dosing. These data demonstrate that treatment with oral TDF provided partial protection against SHIV infection but ultimately did not protect all TDF treated animals against multiple virus challenges.