Our understanding of early anti-viral mechanisms in the cervico-vaginal compartment that may reduce HIV-1 or SIV infectivity in the absence IgG-mediated or CD8 T-cell responses remains incomplete and is the basis for this proposal. Evidence for resistance to infection in highly HIV-exposed women that remain seronegative (exposed sero-negative, ESN) in presence of anti-HIV responses is also supported by non-human primate (NHP) models where repeated low-dose cervico-vaginal challenges in Rhesus macaques can result in a refractory state that can only be overcome by increased infectious doses or by-pass of the mucosal micro- environment (e.g. intravenous viral challenge). Our preliminary data now shows for the first time that repeated cervico-vaginal exposures to SIV in the NHP can result in an increase in innate effector cell infiltrates including (1) plasmacytoid dendritic cells expressing IFN-a as a potential inductive factor associated with the local increase in tissue APOBEC 3G expression, and (2) CD68 macrophages infiltrates among Fc-receptor bearing cells. We will test the hypothesis that uninfectious viral exposures in the female cervico-vaginal compartment can induce an innate/IgA mechanism mediating a state of reduced mucosal infectivity. Specifically, we will: 1. Determine the presence of local cellular cervical tissue infiltrate, IFN-mediated gene expression, and mucosal anti-HIV IgA antibody responses in 3 well-defined groups of women with differential exposure risk based on sexual activity/partners. 2. Determine if repeated cervico-vaginal exposures to non-infectious SIV E660 exposures induce a persistent innate cellular infiltrate (plasmacytoid DCs, NK, macrophages) that in combination with mucosal SIV-specific IgA antibody levels decreases mucosal infectivity SIV mac251. This proposal represents a collaborative effort between The University of Puerto Rico, Nebraska University, University of Minnesota, Duke University, University of Massachusetts, Tulane University, National Cancer Institute, and The Wistar Institute.
(provided by applicant): There is a need to develop new strategies to prevent HIV-1 transmission in women. Our application seeks to understand correlates of lack of infection in women expected to be highly exposed to HIV-1 by their behavior and to determine if a particular immune response (specific innate immunity and IgA responses) is over- represented in them. We also will test directly the impact of targeting the selective activation of candidate innate and antibody response in non-human primates to obtain direct data as to whether these responses can decrease viral transmission.
|Rivera, L E; Kraiselburd, E; MelÃ©ndez, L M (2016) Cystatin B and HIV regulate the STAT-1 signaling circuit in HIV-infected and INF-Î²-treated human macrophages. J Neurovirol 22:666-673|
|Abdulhaqq, S A; Zorrilla, C; Kang, G et al. (2016) HIV-1-negative female sex workers sustain high cervical IFNÉ›, low immune activation, and low expression of HIV-1-required host genes. Mucosal Immunol 9:1027-38|
|Demers, Andrew; Kang, Guobin; Ma, Fungrui et al. (2014) The mucosal expression pattern of interferon-Îµ in rhesus macaques. J Leukoc Biol 96:1101-7|
|Abdulhaqq, Shaheed A; Martinez, Melween I; Kang, Guobin et al. (2014) Serial cervicovaginal exposures with replication-deficient SIVsm induce higher dendritic cell (pDC) and CD4+ T-cell infiltrates not associated with prevention but a more severe SIVmac251 infection of rhesus macaques. J Acquir Immune Defic Syndr 65:405-13|
|Zorrilla, Carmen D; Rabionet, Silvia E; Mosquera, Ana M et al. (2012) Biomedical HIV prevention strategies: state of the art and implications for public health policy in the Caribbean. P R Health Sci J 31:170-9|
|Tomescu, C; Abdulhaqq, S; Montaner, L J (2011) Evidence for the innate immune response as a correlate of protection in human immunodeficiency virus (HIV)-1 highly exposed seronegative subjects (HESN). Clin Exp Immunol 164:158-69|