Growth of the HIV pandemic that is largely transmitted through sex, gives a compelling need to develop strategies to limit its explosive spread. It is clear that there is not yet a single strategy that will accomplish this. Thus it is vital to continue research at multiple levels and disciplines to develop potentially useful prevention strategies that may provide attenuation of HIV transmission. We have assembled an outstanding team who propose three interlocking projects that will provide new information critical to the development of microbicide strategies in general, to strategies targeting CCR5 and to developing a better understanding of the human and non-human primate female genital tract. We have been developing RANTES analogues that block OCRS and inhibit HIV replication at subnanomolar concentrations. Our first lead, PSC-RANTES has protected all 10 of 10 rhesus macaques challenged with SHIV 162P3 thus providing the most potent protection against SHIV of any agent reported to date. Limitations to this strategy include an incomplete understanding of the fundamental mechanisms whereby different RANTES analogues block HIV access to CCR5, their potential agonist activity that may result in inflammation, a limited durability of protection, the costs of synthesis and finally an incomplete understanding of the similarities and differences between the human and rhesus female genital tracts that may limit generalization of findings in the one to application in the other. Here, we propose to address each of these issues, with three projects: Project 1: Defining inhibitory Mechanisms of Novel CCRS-targeted Microbicide Candidates - As we have developed several classes of RANTES analogues with discreetly different effects on CCR5 localization and signaling, these studies are designed to explore the cellular and molecular interactions that underlie the activities of these analogues. Project 2: Comparative gynecologic studies in humans and rhesus macaques - This will focus on defining the similarities and differences between the cervicovaginal epithelium of humans and non-human primates to establish the degree to which findings in these animals can be transposed to projections of activity in humans. Thus, the results of this work will be critical both to the development of RANTES analogues as well as to all other strategies for topical prevention of HIV transmission. Project 3: Developing RANTES analogues as topical strategies to prevent HIV transmission: will explore agonist activities of different analogues to identify inhibitory pathways of potential inflammatory effects, will examine synergistic activities of HIV inhibitor combinations and novel hydrogel formulations to enhance the durability of protection and will develop methods for large scale GMP synthesis of fully recombinant agents that will permit affordable application of this strategy. An experienced Administrative Core provides infrastructural support for these projects as well as statistical expertise for analyses of their results. PROJECT 1: Defining Inhibitory Mechanisms of Novel CCRS-targeted Microbicide Candidates, Mosier, D. PROJECT 1 DESCRIPTION (provided by applicant): The goal of Project 1 is to define the mechanism of action of three new chemokine analogues with potent activity in blocking HIV-1 entry via CCR5. These fully recombinant molecules display three distinct activity profiles: (group I) CCR5 blockade without signaling activity or receptor internalization;(group II), CCR5 rapid internalization with signaling activity;and (group III), moderate CCR5 internalization and blockade without signaling activity. These new molecules have significant potential advantages in terms of safety and cost of production over current inhibitors such as PSC-RANTES, but further improvements on these candidate microbicides requires more detailed knowledge of their mechanisms of action. We will define the route to intracellular sequestration for group II molecules, and compare with that of the group III molecules. We will examine a number of hypotheses to explain prolonged antiviral activity in the absence of intracellular receptor sequestration (group I) or with moderate internalization (group III), including changes in CCR5 dimer formation, altered receptor localization in the membrane, allosteric effects, and receptor internalization independent of G-protein-linked signaling. We will also examine the impact of CCR5, CCL5, and CCL3L1 genetic polymorphisms on CCR5 protein synthesis and turnover rate. These studies are designed to investigate variability in the susceptibility of primary target cells from normal human donors to each of the new inhibitors. We will also use a panel of mutant CCR5 molecules to examine structural correlates of activity. We will use this information on mechanism and target cell variability to develop new molecules with even better activity profiles, and we will perform coordinated experiments with other projects in this Program to relate our findings in cell-based models to the effects of current and new CCR5 inhibitors in tissue explant and whole animal models. This approach will generate better and safer CCR5 inhibitors that can be produced on a scale suitable for stopping the spread of HIV/AIDS in the most-impacted areas.

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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Turpin, Jim A
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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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