Session 82Poster Presentations Microbicides Session Day and Time: Tuesday 1:30 - 3:30 pm Room: Hall A
676 Protection of Macaques from SHIV Infection by Vaginal Application of Anti-gp120 Monoclonal Antibody b12 R. S. Veazey*1, R. J. Shattock2, M. Pope3, P. J. Klasse4, J. C. Kirijan1, J. Jones3, P. A. Marx1, D. R. Burton5, J. P. Moore6 1Tulane Natl Primate Res Ctr, Tulane Univ Hlth Sci Ctr, Covington, LA; 2St George's Hosp Med Sch, London, UK; 3Ctr for BioMed Res, The Population Council, NY; 4Jefferiss Res Trust Labs, Wright-Fleming Inst, Imperial Coll, London, UK; 5Scripps Res Inst, La Jolla, CA; and 6Weill Med Coll of Cornell Univ, New York, NY
Background: The development of a microbicide that could be applied to the vagina and prevent the transmission of HIV-1 could save lives. Unfortunately, compounds that destroy HIV-1 are also likely to damage mucosal tissues. Alternatively, fusion inhibitors that attach to viral or host cell receptors may provide a safe and effective mechanism to prevent HIV-1 infection. Here we describe how vaginal administration of the broadly neutralizing monoclonal antibody (MAb) b12 can protect macaques from SHIV infection by the vaginal route of transmission.
Methods: In multiple experiments designed to assess the efficacy, the dose, and the effect of carriers on preventing SHIV162P4 vaginal transmission by a microbicide, a total of 30 progestin-treated rhesus macaques were used. Macaques were vaginally inoculated with 5 ml of either placebo (saline, irrelevant antibody, or hydroxymethylcellulose gel (HMC)) or 1 mg/ml of b12 in either saline or HMC. An additional 4 macaques were similarly treated with lower doses (40-200 ug/ml) of b12. In most experiments, macaques were vaginally inoculated 15 min later with 300 TCID50 of SHIV162P4. In 3 animals, viral challenge was delayed 1, 2, or 6 h after vaginal b12 treatment to assess duration of protection. All animals were monitored weekly by quantitative viral load analysis.
Results: Of control animals treated with HMC, saline, or irrelevant antibody, 12 of 13 were infected. In contrast, only 3/12 animals receiving 5 mg of b12 vaginally in either saline or HMC within 2 h of b12 treatment became infected. The level of protection by b12 was highly significant (p = 0.00087). One (1) of 2 macaques receiving a lower dose (200 ug/ml) of b12 became infected, while both animals treated with 40 ug/ml were infected. The macaque challenged 6 h after b12 treatment was also infected, whereas animals challenged 1 and 2 h after treatment were protected. Hence, protection by b12 was dose dependent and of finite duration.
Conclusions: This study demonstrates that vaginal delivery of the human anti-gp120 MAb, b12, can protect rhesus macaques against vaginal transmission of SHIV-162P4. The challenge virus is derived from a subtype B primary HIV-1 isolate and utilizes the CCR5 co-receptor, which is highly relevant to the biology of HIV-1 transmission. Our results serve as proof-of-concept for the development of specific entry inhibitors as topical microbicides for the prevention of vaginal transmission of HIV-1 in humans.
