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Session 30 Oral Abstracts
Preventive Microbicide Strategies
Wednesday, 11:45 am - 12:30 pm
Presentation Time: 12:15 pm
Room 2008


159
Cellulose Acetate Phthalate Protects Macaques from Multiple, Low-dose Vaginal Exposures with an SHIV Virus: New Strategy to Study HIV Pre-clinical Interventions in Non-human Primates
R A Otten*1, D R Adams1, C N Kim1, E Jackson1, J K Pullium2, K Lee1, L Grohskopf1, M Monsour1, N Jivani3, E Serbinova3, S T Butera1, and T M Folks1
1CDC, Atlanta, GA, USA; 2Emory Univ., Atlanta, GA, USA; and 3Dow Pharm. Sci., Petaluma, CA, USA

Background:  A nonhuman primate model for HIV-1 infection that more closely mimics sexual transmission by repeated low-dose exposure is critical to better understand and design intervention strategies using microbicides or vaccines. 

Methods:  Here we describe such an in vivo system using female pig-tailed macaques infected by multiple, low-dose SHIVSF162P3 inoculations given at  weekly intervals via the intravaginal route.  Macaques given 10 tissue culture infectious doses (TCID) were systemically infected after 3 exposures.  Those given 2 TCID were infected after 4 to 8 exposures. No overt infection was observed using 0.2 TCID after 12 exposures.  We have applied this low-dose exposure strategy using the 10-TCID dose to evaluate cellulose acetate phthalate (CAP, 13% formulation) as a topical microbicide for vaginal use. 

Results:  CAP safety was demonstrated by colposcopy of the cervicovaginal region of macaques (n = 2) after applying 2 mL of product daily for 4 consecutive days.  Efficacy was evaluated by applying 2 mL of CAP to the cervicovaginal region of macaques (n = 4) 15 minutes before each virus exposure.  Systemic infection, defined by detectable virus in the peripheral blood leading to seroconversion, was observed in mock-treated control macaques (n = 3/3) following 3 virus exposures.  Mean peak plasma vRNA levels reached ~106 copies/mL and vRNA was also detected in cervicovaginal lavage specimens (~ 105 copies per lavage). Interestingly, 3 of the 4 macaques (75%) treated with CAP have remained virus-free through 8 virus exposures to date and we intend to give a total of 12 exposures overall. Similar to the results with the controls, 1 of 4 CAP-treated macaques (25%) was infected after only 3 virus exposures. The peak plasma vRNA level in this breakthrough macaque was ~2-log10 lower than that of control macaques, suggesting a blunted peak of plasma viremia. 

Conclusions:  Our findings provide a basis to further refine nonhuman primate mucosal challenge models to mimic more closely natural human HIV exposures.  This unique study provides data highly relevant to the design of preclinical trials to investigate the efficacy of therapeutic interventions, including microbicides and vaccines.

Keywords: Microbicides; Macaque; Intervention