During the first funding period of this grant our goal was to develop the humanized BLT mouse system as a highly innovative model for the evaluation of different topical microbicides and systemic drugs for HIV prevention. We succeeded in this endeavor in ways that go beyond our initial proposal, published 11 papers and the BLT mouse model in now recognized as an excellent model for the pre-clinical evaluation of virtually all types of HIV prevention approaches. However, also during the tenure of this grant results from several large clinical trials of HIV prevention have brought to the forefront significant problems concerning compliance with both topical microbicides and systemic drug therapy. Indeed, the results from human clinical trials show that drugs like tenofovir when used by high-risk individuals are highly effective at preventing HIV transmission, but lack of compliance has been correlated with lack of protection. Therefore the focus of the prevention field has now shifted to alternatives that can improve compliance and thus reduce HIV transmission. One approach has recently gained significant attention: long-acting (LA) injectable formulations. Having completed the development and initial testing of the BLT model for the evaluation HIV preventive strategies and in an effort to continue to be avant-garde, in thi competitive renewal application we are addressing the critical issue of compliance by proposing the in vivo evaluation of a LA injectable formulation of Rilpivirine as a proof-of- concept for thi approach. LA antiretroviral preparations that stably release drugs over many weeks as nano-formulations are a novel approach to pre-exposure prophylaxis. This approach offers major benefits including: (a) the ability to mitigate poor patient compliance with daily systemic PrEP dosing;(b) the potential for a reduced reliance on frequently used HIV therapeutic drugs;and (c) their ability to be utilized discreetly without requiring a partner's knowledge or consent. To date no long-acting drug formulations have been evaluated for HIV prevention efficacy as systemic PrEP, which leads to the fundamental question of this proposal: Can long- acting PrEP provide durable protection from HIV transmission? Several drugs are being formulated for sustained release including Rilpivirine (RPV;TMC278), a recently approved non-nucleoside reverse transcriptase inhibitor (NNRTI). RPV was identified as an excellent antiretroviral candidate for LA formulation because it interferes early in the HIV life cycle, is effective against a broad rang of wild type and mutant viruses with reduced susceptibility to commonly prescribed agents, and has low cross-resistance to other NNRTIs. In addition, it has a better tolerability profile than other similar drugs and has fewer neuropsychiatric and metabolic side effects than efavirenz. This depot formulation of Rilpivirine, RPV-LA kindly provided to us by Janssen R&D, has several characteristics that make it a quality candidate for long-acting systemic PrEP. Intramuscular injection of RPV-LA in humans was found to be safe, had no side effects and resulted in sustained plasma and cervical-vaginal fluid drug concentrations for at least 12 weeks. In addition, there were no changes in QT interval. The ability of RPV-LA to prevent vaginal HIV transmission will be systematically tested in the state-of-the-art bone marrow, liver, thymus (or BLT) humanized mouse model that has become widely utilized in human immunology and infectious disease research. For this purpose we will utilize highly relevant transmitted/founder viruses from a variety of HIV subtypes responsible for a significant portion of the AIDS epidemic.
Specific Aim 1) To perform pharmacokinetic analyses of RPV-LA in mice to determine RPV concentrations and biodistribution over time with a focus on the duration of drug exposure plasma and in the female reproductive tract (FRT).
Specific Aim 2) To perform pharmacokinetic-pharmacodynamic (PK-PD) analyses directly relating RPV concentrations with the efficacy of RPV-LA for preventing vaginal HIV transmission in BLT mice.
Specific Aim 3) To evaluate the protective effect of systemic PrEP with RPV-LA from acquisition of naturally occurring, highly relevant transmitted/founder HIV isolates.

Public Health Relevance

Despite highly successful therapeutic interventions the HIV/AIDS epidemic continues to spread. The long-term goal of our research is to obtain fundamental knowledge regarding HIV transmission and its prevention. In this application we propose to evaluate a novel approach at HIV prevention using long-acting antiretrovirals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI073146-06A1
Application #
8609291
Study Section
Special Emphasis Panel (ZRG1-AARR-K (04))
Program Officer
Turpin, Jim A
Project Start
2007-05-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
6
Fiscal Year
2013
Total Cost
$595,276
Indirect Cost
$203,647
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
Victor Garcia, J (2016) Humanized mice for HIV and AIDS research. Curr Opin Virol 19:56-64
Garcia, J Victor (2016) In vivo platforms for analysis of HIV persistence and eradication. J Clin Invest 126:424-31
Olesen, Rikke; Swanson, Michael D; Kovarova, Martina et al. (2016) ART influences HIV persistence in the female reproductive tract and cervicovaginal secretions. J Clin Invest 126:892-904
Council, Olivia D; Swanson, Michael D; Spagnuolo, Rae Ann et al. (2015) Role of Semen on Vaginal HIV-1 Transmission and Maraviroc Protection. Antimicrob Agents Chemother 59:7847-51
Swanson, Michael D; Boudreaux, Daniel M; Salmon, Loïc et al. (2015) Engineering a therapeutic lectin by uncoupling mitogenicity from antiviral activity. Cell 163:746-58
Wahl, Angela; Baker, Caroline; Spagnuolo, Rae Ann et al. (2015) Breast Milk of HIV-Positive Mothers Has Potent and Species-Specific In Vivo HIV-Inhibitory Activity. J Virol 89:10868-78
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
Martinez-Torres, Francisco; Nochi, Tomonori; Wahl, Angela et al. (2014) Hypogammaglobulinemia in BLT humanized mice--an animal model of primary antibody deficiency. PLoS One 9:e108663
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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