Project 2 Worldwide, over 80% of HIV infections occur as a result of vaginal transmission. There is a desperate need for a safe and effective microbicide than can prevent the transmission of HIV to women. However, methods for screening potential microbicide candidates vary and include cell and tissue culture experiments to assess efficacy and nonhuman primate models for assessing efficacy and safety. However, methods vary between different laboratories regarding the types of cells and organ cultures used, various laboratories use different species of nonhuman primates. To date, no comparative studies have beejn. performed between/'normal''human, .female reproductive tissues and nonhuman primates, Thus,-it4s.not known-whether-microbicide studies-in nonhuman primates will be predictive of efficacy and safety in women. Furthermore, most vaginal explant studies of women used for assessing baseline levels of immune cells in the vagina, testing microbicide candidates, and studies of HIV transmission in vitro have invariably involved the use of tissues derived from hysterectomies, which are invariably diseased. Thus, inflammation, hyperplasia, ulcerations or other abnormalities may exist in such tissues that could affect the results of microbicide studies. The goal of Research Project 2 is to perform comparative studies of normal and hysterectomy-derived vaginal and cervical tissues of women to those of two species of macaques (rhesus and pigtails) to compare the anatomy and immunophenotype of immune cells and responses between female reproductive tissues of these species so that better informed decisions for microbicide testing can be made. We will also investigate the mechanisms of action of CCR5 inhibitors (RANTES analogs) in explant models using photoactivateable virions and labeled RANTES analogs to determine where blocking of these microbicide candidates takes place.
The specific aims are to:
Specific Aim 1 : Compare the anatomy, immunology, and physiology of normal macaque and human female reproductive tissues using identical methodology;
Specific Aim 2 : Compare the immune responses of cervical explants of women, rhesus, and pig-tailed macaques to mitogens, potential microbicide candidates (RANTES analogs), and HIV/SIV using identical methodology, and;
Specific Aim 3 : Assess the depth of penetration and mechanisms of action of synthetic RANTES derivatives, and other CCR5 inhibitor microbicide candidates in human and macaque vaginal tissues.
|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|
|Xu, Huanbin; Wang, Xiaolei; Malam, Naomi et al. (2016) Persistent Simian Immunodeficiency Virus Infection Drives Differentiation, Aberrant Accumulation, and Latent Infection of Germinal Center Follicular T Helper Cells. J Virol 90:1578-87|
|Veazey, R S; Pilch-Cooper, H A; Hope, T J et al. (2016) Prevention of SHIV transmission by topical IFN-? treatment. Mucosal Immunol 9:1528-1536|
|Xu, Huanbin; Wang, Xiaolei; Malam, Naomi et al. (2015) Persistent Simian Immunodeficiency Virus Infection Causes Ultimate Depletion of Follicular Th Cells in AIDS. J Immunol 195:4351-7|
|Hadzic, Sarah V; Wang, Xiaolei; Dufour, Jason et al. (2014) Comparison of the vaginal environment of Macaca mulatta and Macaca nemestrina throughout the menstrual cycle. Am J Reprod Immunol 71:322-9|
|Wang, Nick X; Sieg, Scott F; Lederman, Michael M et al. (2013) Using glycosaminoglycan/chemokine interactions for the long-term delivery of 5P12-RANTES in HIV prevention. Mol Pharm 10:3564-73|
|Ahsan, Muhammad H; Gill, Amy F; Alvarez, Xavier et al. (2013) Kinetics of liver macrophages (Kupffer cells) in SIV-infected macaques. Virology 446:77-85|
|Xu, Huanbin; Wang, Xiaolei; Lackner, Andrew A et al. (2013) CD8 down-regulation and functional impairment of SIV-specific cytotoxic T lymphocytes in lymphoid and mucosal tissues during SIV infection. J Leukoc Biol 93:943-50|
|Veazey, Ronald S (2013) Animal models for microbicide safety and efficacy testing. Curr Opin HIV AIDS 8:295-303|
|Dinh, Minh H; Okocha, Eneniziaogochukwu A; Koons, Ann et al. (2012) Expression of structural proteins in human female and male genital epithelia and implications for sexually transmitted infections. Biol Reprod 86:32|
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