Worldwide, over 80% of HIV infections occur as a result of vaginal transmission. There is a desperateneed for a safe and effective microbicide than can prevent the transmission of HIV to women. The goal ofResearch Project 3 is to identify the optimal combination and formulation of fusion inhibitors thatdemonstrates the greatest level of safety, efficacy, and duration of protection against vaginal HIVtransmission using the nonhuman primate model of vaginal transmission. Over the last several years, wehave demonstrated that several fusion inhibitors can completely protect against vaginal transmission ofmultiple simian/immunodeficiency virus (SHIV) strains that are highly relevant to HIV-1 transmission. Wenow propose to determine optimal combinations of these inhibitors that provide the greatest level ofefficacy against multiple strains and repeated challenge with divergent strains of virus. We will also testsustained delivery systems (vaginal rings) designed to confer extended protection in mucosal tissuesafter a single application. Finally, we will rigorously assess the safety of these inhibitors and deliverysystems to determine how long these may be applied without inducing inflammation or adverse effects.Our experiments are thus designed to test the efficacy and safety of fusion inhibitors, alone, incombination, and particularly in sustained release formulations to identify the optimal combination offusion inhibitors that can be safely and economically used as a microbicide to slow the spread of HIVinfection, particularly in areas where the epidemic is spreading the fastest.
The specific aims ofResearch Project 3 are to:
Specific Aim 1. Determine the most effective combination of fusion inhibitors that provides optimalprotection against mucosal transmission of diverse strains of SIV/SHIV in macaques;
Specific Aim 2. Compare the efficacy and duration of protection of fusion inhibitors administered insustained delivery devices in vivo, and;
Specific Aim 3. Assess the safety of multiple dosing and sustained release formulations of fusioninhibitors in both the vaginal and rectal mucosa.The ultimate goal of this project is to identify a combination of HIV fusion inhibitors that can be safelyapplied in a sustained release formulation that will consistently protect women against repeated exposureto highly divergent strains of HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI076982-01
Application #
7418091
Study Section
Special Emphasis Panel (ZAI1-CCH-A (S1))
Project Start
2008-06-23
Project End
2012-05-31
Budget Start
2008-06-23
Budget End
2009-05-31
Support Year
1
Fiscal Year
2008
Total Cost
$1,017,895
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Veazey, Ronald S; Ling, Binhua (2017) Short Communication: Comparative Susceptibility of Rhesus Macaques of Indian and Chinese Origin to Vaginal Simian-Human Immunodeficiency Virus Transmission as Models for HIV Prevention Research. AIDS Res Hum Retroviruses 33:1199-1201
Fletcher, Patricia; Herrera, Carolina; Armanasco, Naomi et al. (2016) Short Communication: Limited Anti-HIV-1 Activity of Maraviroc in Mucosal Tissues. AIDS Res Hum Retroviruses 32:334-8
Malcolm, R Karl; Lowry, Deborah; Boyd, Peter et al. (2014) Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application. J Antimicrob Chemother 69:1325-9
Forbes, Claire J; McCoy, Clare F; Murphy, Diarmaid J et al. (2014) Modified silicone elastomer vaginal gels for sustained release of antiretroviral HIV microbicides. J Pharm Sci 103:1422-32
Fetherston, Susan M; Geer, Leslie; Veazey, Ronald S et al. (2013) Partial protection against multiple RT-SHIV162P3 vaginal challenge of rhesus macaques by a silicone elastomer vaginal ring releasing the NNRTI MC1220. J Antimicrob Chemother 68:394-403
Veazey, Ronald S (2013) Animal models for microbicide safety and efficacy testing. Curr Opin HIV AIDS 8:295-303
Malcolm, R Karl; Forbes, Claire J; Geer, Leslie et al. (2013) Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques. J Antimicrob Chemother 68:678-83
Barouch, Dan H; Klasse, Per Johan; Dufour, Jason et al. (2012) Macaque studies of vaccine and microbicide combinations for preventing HIV-1 sexual transmission. Proc Natl Acad Sci U S A 109:8694-8
Malcolm, R Karl; Veazey, Ronald S; Geer, Leslie et al. (2012) Sustained release of the CCR5 inhibitors CMPD167 and maraviroc from vaginal rings in rhesus macaques. Antimicrob Agents Chemother 56:2251-8
Dufour, Jason P; Phillippi-Falkenstein, Kathrine; Bohm, Rudolf P et al. (2012) Excision of femoral head and neck for treatment of coxofemoral degenerative joint disease in a rhesus macaque (Macaca mulatta). Comp Med 62:539-42

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