The central hypothesis of the application is that specific inhibitors of HIV-i fusion with target cells, whenused in combination and when properly formulated and used appropriately, could prevent the vaginal orrectal transmission of HIV-i. In Research Project II, we will focus on the critical issue of microbicideformulation and delivery. We are conscious of recent experience from large-scale trials indicating thatcompliance is a very significant issue in microbicide research and development today. Specifically, thereare now serious concerns whether a microbicide intended for use immediately prior to sexual intercourseis a truly practical proposition; poor compliance in clinical trials may easily translate to the limited usageshould any product make it to licensure. Therefore, the aim of Research Project II is to develop longlasting,coitally-independent delivery methods for entry inhibitor-based microbicides, in the form ofsustained release semi-solid formulations that are applied once daily, and controlled release vaginal ringsthat can provide a continuous and constant supply of the active compound(s) in situ for a period ofweeks/months after application of a single device. These two very different formulation strategies aredeliberately being pursued within this project on account of the widely accepted consensus that a numberof microbicide products will be required to meet the differing social and cultural preferences of women.There are four specific objectives within Project II: i) To develop controlled-release matrix and reservoirtypevaginal ring devices containing each of the small molecule entry inhibitors CMPD 167, BMS-C andAMD3465. 2) To develop novel controlled release vaginal rings ('rod-insert' rings) containing the peptideentry inhibitor T-124Q. 3) To develop controlled release vaginal rings containing combination entryinhibitors. 4) To develop sustained-release semi-solid formulations of the small molecule entry inhibitorsCMPD 167, BMS-C, AMD34&5 and T-1249, both alone and in combination, for once-daily application.The Project Leader will be R. Karl Malcolm, Ph.D., with Mark Mitchnick, Ph.D. and A. David Woolfson,Ph.D. acting as co-investigators. The vaginal ring formulation component of the Project will be conductedat the School of Pharmacy, Queen's University Belfast, UK, while the semi-solid formulation componentwill be conducted at Particle Sciences Inc. PA, US. Both groups have considerable expertise in theirrespective formulation tasks.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-CCH-A (S1))
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Weill Medical College of Cornell University
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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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