Our long term-goal is to investigate novel approaches to prevent HIV transmission by the use of topical microbicides. For this purpose we have developed and implemented a small animal model where human stem cells are used to reconstitute the hematopoietic system of immunodeficient mice (47). In these humanized mice (designated BIT to represent the fact they are generated from a bone marrow transplant of mice previously implanted with a piece of autologous human fetal liver and thymic tissue) there is systemic reconstitution with human hematopoietic cells in all hematopoietic and non-hematopoietic tissues tested. Like non-human primates, these humanized mice are susceptible to infection with X4- or R5-tropic HIV-1 administered either intrarectally or intravaginally (13, 65). Infection results in plasma antigenemia, development of anti-HIV specific human antibodies, and progressive depletion of human CD4+ cells from the peripheral blood. Furthermore, infection can be efficiently prevented by pre-exposure prophylaxis with antivirals (13). In this grant we will use this system to test the hypothesis that topical administration of microbicides can effectively prevent rectal HIV-1 transmission.
Specific Aim 1) To determine the potential protective effect of UC781 to prevent rectal HIV-1 infection.
Specific Aim 2) To determine the efficacy of topically administered tenofovir (TFV) to prevent rectal HIV-1 transmission.
Specific Aim 3) To determine the protective effect of a combination of TFV and UC781 to prevent rectal HIV- 1 transmission
With almost 5 million people becoming infected during the past year, the global HIV-1 pandemic continues to spread rapidly. Anal intercourse is practiced by both heterosexuals and homosexuals and HIV-1 transmission has been shown to be more efficient through anal intercourse than through vaginal intercourse. Rectal microbicides have the potential to slow the spread of HIV-1.
|Hiruy, Hiwot; Fuchs, Edward J; Marzinke, Mark A et al. (2015) A Phase 1 Randomized, Blinded Comparison of the Pharmacokinetics and Colonic Distribution of Three Candidate Rectal Microbicide Formulations of Tenofovir 1% Gel with Simulated Unprotected Sex (CHARM-02). AIDS Res Hum Retroviruses 31:1098-108|
|Mcgowan, Ian; Cranston, Ross D; Duffill, Kathryn et al. (2015) A Phase 1 Randomized, Open Label, Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Three Formulations of Tenofovir 1% Gel (the CHARM-01 Study). PLoS One 10:e0125363|
|Hladik, Florian; Burgener, Adam; Ballweber, Lamar et al. (2015) Mucosal effects of tenofovir 1% gel. Elife 4:|
|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|
|McGowan, Ian (2014) The development of rectal microbicides for HIV prevention. Expert Opin Drug Deliv 11:69-82|
|Dezzutti, Charlene S; Russo, Julie; Wang, Lin et al. (2014) Development of HIV-1 rectal-specific microbicides and colonic tissue evaluation. PLoS One 9:e102585|
|McGowan, Ian; Dezzutti, Charlene (2014) Rectal microbicide development. Curr Top Microbiol Immunol 383:117-36|
|Rohan, Lisa C; Yang, Haitao; Wang, Lin (2013) Rectal pre-exposure prophylaxis (PrEP). Antiviral Res 100 Suppl:S17-24|
|Chateau, Morgan L; Denton, Paul W; Swanson, Michael D et al. (2013) Rectal transmission of transmitted/founder HIV-1 is efficiently prevented by topical 1% tenofovir in BLT humanized mice. PLoS One 8:e60024|
|Chateau, Morgan; Swanson, Michael D; Garcia, J Victor (2013) Inefficient vaginal transmission of tenofovir-resistant HIV-1. J Virol 87:1274-7|
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