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.
Kim
Caryn N
CN
Laboratory Branch, Division of HIV/AIDS Prevention, National Center for HIV, STD, TB Prevention, CCID, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
Adams
Debra R
DR
Bashirian
Sheila
S
Butera
Sal
S
Folks
Thomas M
TM
Otten
Ron A
RA
D000282:Administration, Intravaginal; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage*; D000914:Antibodies, Viral / Q000097:blood; D002482:Cellulose / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D005260:Female; D008254:Macaca nemestrina; D016016:Proportional Hazards Models; D012367:RNA, Viral / Q000097:blood; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000276:immunology / Q000517:prevention & control* / Q000635:transmission*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
D000891:Anti-Infective Agents, Local; D000914:Antibodies, Viral; D012367:RNA, Viral; D002482:Cellulose; C011708:cellulose acetate phthalate