The earliest events following mucosal HIV-1 exposure represent a critical window of opportunity for vaccine-elicited immune responses to impact the acquisition and propagation of HIV-1 infection. However, very little is known about the biology of the eclipse phase of HIV-1 infection in humans, particularly the immunologic and virologic events that occur at the mucosal site of transmission. Given the difficulties in studying the earliest mucosal events of HIV-1 infection in humans, modeling these events in nonhuman primates is required. Such studies will provide insight into the early events of virus transmission and the capacity of immune responses to block or to attenuate these events. In this Project, we hypothesize that SIV-specific immune responses elicited by adenovirus and poxvirus vaccine vectors will substantially impact the early events following intravaginal (IVAG) SIV infection of rhesus monkeys. In particular, we hypothesize that vaccine-elicited mucosal immune responses at the site of inoculation will limit the initial local amplification of virus at the mucosal portal of entry during the eclipse phase of infection prior to systemic virus dissemination. The goal is to define precisely when and where innate and adaptive immune responses intercept the virus following IVAG SIV infection of both .naive and vaccinated animals. To evaluate these hypotheses, we propose the following Specific Aims: 1. To define the early virologic, immunologic, and pathologic events following IVAG SIV infection of naive, unvaccinated rhesus monkeys; 2. To evaluate the capacity of adenovirus vector-based vaccines to impact the early events following IVAG SIV infection of rhesus monkeys;and 3. To assess the capacity of poxvirus vector-based vaccines to impact the early events following IVAG SIV infection of rhesus monkeys.
The earliest events of mucosal HIV-1 infection in humans remain largely undefined, given the short duration and asymptomatic nature of the eclipse phase of HIV-1 infection. An improved understanding of the earliest events following IVAG SIV infection of rhesus monkeys will yield insights into critical viral vulnerabilities during the transmission process that can be exploited by vaccine-elicited immune responses. Such knowledge will lead to the development of improved next generation HIV-1 vaccine strategies.
|Aid, Malika; Abbink, Peter; Larocca, Rafael A et al. (2017) Zika Virus Persistence in the Central Nervous System and Lymph Nodes of Rhesus Monkeys. Cell 169:610-620.e14|
|Barouch, Dan H; Thomas, Stephen J; Michael, Nelson L (2017) Prospects for a Zika Virus Vaccine. Immunity 46:176-182|
|Abbink, Peter; Larocca, Rafael A; Visitsunthorn, Kittipos et al. (2017) Durability and correlates of vaccine protection against Zika virus in rhesus monkeys. Sci Transl Med 9:|
|Ackerman, Margaret E; Barouch, Dan H; Alter, Galit (2017) Systems serology for evaluation of HIV vaccine trials. Immunol Rev 275:262-270|
|McMichael, Andrew J; Picker, Louis J (2017) Unusual antigen presentation offers new insight into HIV vaccine design. Curr Opin Immunol 46:75-81|
|Keele, Brandon F; Li, Wenjun; Borducchi, Erica N et al. (2017) Adenovirus prime, Env protein boost vaccine protects against neutralization-resistant SIVsmE660 variants in rhesus monkeys. Nat Commun 8:15740|
|Zeng, Ming; Smith, Anthony J; Shang, Liang et al. (2016) Mucosal Humoral Immune Response to SIVmac239?nef Vaccination and Vaginal Challenge. J Immunol 196:2809-18|
|Liu, Jinyan; Ghneim, Khader; Sok, Devin et al. (2016) Antibody-mediated protection against SHIV challenge includes systemic clearance of distal virus. Science 353:1045-1049|
|Martinez-Navio, José M; Fuchs, Sebastian P; Pedreño-López, Sònia et al. (2016) Host Anti-antibody Responses Following Adeno-associated Virus-mediated Delivery of Antibodies Against HIV and SIV in Rhesus Monkeys. Mol Ther 24:76-86|
|Stephenson, Kathryn E; Neubauer, George H; Bricault, Christine A et al. (2016) Antibody Responses After Analytic Treatment Interruption in Human Immunodeficiency Virus-1-Infected Individuals on Early Initiated Antiretroviral Therapy. Open Forum Infect Dis 3:ofw100|
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