Mucosal HIV exposures are responsible for the vast majority of HIV-1 infections worldwide. Specifically, vaginal intercourse is the most common form of HIV transmission. Therefore, prevention of sexual transmission is urgently needed. Despite the highly encouraging results from the CAPRISA 004 trial it is clear that the level of protection observed is suboptimal and that there is significant room for further improvement. In addition, Tenofovir, the chemo-prophylactive agent being used (alone or in combination) in ongoing randomized clinical trials of pre-exposure prophylaxis (PrEP) is also being widely used as front line therapy for HIV infection. In this proposal we combine the strengths of four outstanding investigators at Merck and UNC with highly complementary skills to address, using highly innovative approaches, issues of fundamental importance to the development of the next generation of PrEP agents. Specifically, 1) a novel second generation integrase inhibitor (MK-2048) developed by Daria Hazuda at Merck that has not been used for treatment or for PrEP and that has a resistance profile that is different from other integrase inhibitors;2) at UNC, a highly innovative in vivo model of mucosal HIV transmission developed by J. Victor Garcia that will for the first time utilize cell free and cell associated primary transmitted/founder (F/T) viruses for challenge in the presence of semen;3) state-of-the-art analytical methods developed by Angela Kashuba at UNC to determine the PD/PK of vaginally applied MK-2048 to establish correlates of in vivo protection;and 4) mucoadhesive gel formulations and intravaginal rings developed by Russ Mumper at UNC for the optimized release of MK-2048 capable of penetrating the tissues of the female reproductive tract to establish an effective pharmacological barrier. In order to attain these goals we propose the following specific aims:
Specific Aim 1) To develop the basic and preclinical framework for the development and in vivo testing of new generations of PrEP agents.
Specific Aim 2) To develop aqueous-based mucoadhesive gel formulations of the integrase inhibitor MK- 2048 for vaginal administration.
Specific Aim 3) To conduct proof-of-concept safety and efficacy studies of MK-2048 in humanized BLT mice.
Specific Aim 4) To generate pharmacokinetic-pharmacodynamic (PK-PD) models to assess the protective effect of MK-2048 in the female reproductive tract of humanized BLT mice.

Public Health Relevance

Despite the use of antivirals for the treatment of HIV/AIDS the epidemic continues to spread. Recent results from the CAPRISA 004 trial demonstrating partial protection from HIV acquisition demonstrated that this approach could serve to prevent or slow down the spread of the epidemic. In this application we propose to develop the infrastructure needed to discover, develop and test the next generation of Pre-Exposure Prophylactic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI096138-03
Application #
8484345
Study Section
Special Emphasis Panel (ZAI1-RB-A (M1))
Program Officer
Veronese, Fulvia D
Project Start
2011-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$1,053,496
Indirect Cost
$341,674
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Garcia, J Victor (2016) In vivo platforms for analysis of HIV persistence and eradication. J Clin Invest 126:424-31
Kovarova, Martina; Swanson, Michael D; Sanchez, Rosa I et al. (2016) A long-acting formulation of the integrase inhibitor raltegravir protects humanized BLT mice from repeated high-dose vaginal HIV challenges. J Antimicrob Chemother 71:1586-96
Victor Garcia, J (2016) Humanized mice for HIV and AIDS research. Curr Opin Virol 19:56-64
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Dumond, Julie B; Yang, Kuo H; Kendrick, Racheal et al. (2015) Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells. Antimicrob Agents Chemother 59:6395-401
Kovarova, Martina; Council, Olivia D; Date, Abhijit A et al. (2015) Nanoformulations of Rilpivirine for Topical Pericoital and Systemic Coitus-Independent Administration Efficiently Prevent HIV Transmission. PLoS Pathog 11:e1005075
Salgado, Maria; Swanson, Michael D; Pohlmeyer, Christopher W et al. (2014) HLA-B*57 elite suppressor and chronic progressor HIV-1 isolates replicate vigorously and cause CD4+ T cell depletion in humanized BLT mice. J Virol 88:3340-52
Wahl, Angela; Victor Garcia, J (2014) The use of BLT humanized mice to investigate the immune reconstitution of the gastrointestinal tract. J Immunol Methods 410:28-33

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