Vaccination of macaques with attenuated SIV strains has consistently provided the most effective protection against pathogenic SIV challenge and offers the best available experimental model to define specific mechanisms responsible for protection. Recent studies from our group have demonstrated that a significant maturation of protective immunity against vaginal challenge occurs between 5 and 20 weeks after vaccination with SIVAnef, which is associated with evolution of both cellular and humoral immune responses. Furthermore, SIVAnef-vaccinated animals do not manifest the recently described mobilization of pDCs and recruitment of CD4+ T cells that occurs early after vaginal challenge of naive animals. Based on these observations, we hypothesize that SIVAnef is able to block critical stages of SIV replication and spread in the first 7 days after vaginal challenge. Since our previous studies have largely focused on later time points (>7 days after challenge) and examination of immune responses in the peripheral blood, these emerging data dictate a new and comprehensive analysis of the early events in tissues following vaginal challenge of SIVAnef-vaccinated animals. The goal of this proposal is to apply a panel of innovative techniques to serial necropsies of SIVAnef-vaccinated animals before and after challenge to elucidate the roles of adaptive and innate immune responses in mediating protection induced by SIVAnef and to identify the sites of containment of viral replication within the female reproductive tract.
Specific aims i nclude: 1: To examine the evolution of adaptive and innate immune responses in the female reproductive tract induced by SIVAnef;2. To identify sites of viral containment and characterize local immune responses following vaginal challenge of SIVAnef-vaccinated animals;and 3. To examine the effect of B cell depletion on protective immunity against vaginal challenge induced by SIVAnef. These studies will provide novel insights into mechanisms of protective immunity induced by SIVAnef, offer a direct comparison of both immunologic and virologic analyses for animals vaccinated with alternative vectors, and ultimately guide the identification of mechanisms of protection against mucosal infection with lentiviruses.

Public Health Relevance

Lack of information on mechanisms of protective immunity against HIV remains one of the leading barriers to the development of a safe and effective AIDS vaccine. These studies will use a live attenuated SIV vaccine, which has provided the most consistent protection in monkey studies so far, to help identify the types of immune responses that should be induced by clinically applicable AIDS vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI095985-03
Application #
8495245
Study Section
Special Emphasis Panel (ZAI1-LR-A)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$527,864
Indirect Cost
$48,129
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Stephenson, Kathryn E; Neubauer, George H; Reimer, Ulf et al. (2015) Quantification of the epitope diversity of HIV-1-specific binding antibodies by peptide microarrays for global HIV-1 vaccine development. J Immunol Methods 416:105-23
Barouch, Dan H; Picker, Louis J (2014) Novel vaccine vectors for HIV-1. Nat Rev Microbiol 12:765-71
Dugast, Anne-Sophie; Chan, Ying; Hoffner, Michelle et al. (2014) Lack of protection following passive transfer of polyclonal highly functional low-dose non-neutralizing antibodies. PLoS One 9:e97229
Balandya, Emmanuel; Miller, Andrew D; Beck, Matthew et al. (2014) Adenovirus serotype 26 and 35 vectors induce simian immunodeficiency virus-specific T lymphocyte responses in foreskin in rhesus monkeys. J Virol 88:3756-65
Barouch, Dan H; Michael, Nelson L (2014) Accelerating HIV-1 Vaccine Efficacy Trials. Cell 159:969-72
Li, Qingsheng; Zeng, Ming; Duan, Lijie et al. (2014) Live simian immunodeficiency virus vaccine correlate of protection: local antibody production and concentration on the path of virus entry. J Immunol 193:3113-25
Whitney, James B; Hill, Alison L; Sanisetty, Srisowmya et al. (2014) Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature 512:74-7
Teigler, Jeffrey E; Phogat, Sanjay; Franchini, Genoveffa et al. (2014) The canarypox virus vector ALVAC induces distinct cytokine responses compared to the vaccinia virus-based vectors MVA and NYVAC in rhesus monkeys. J Virol 88:1809-14
Shang, Liang; Smith, Anthony J; Duan, Lijie et al. (2014) NK cell responses to simian immunodeficiency virus vaginal exposure in naive and vaccinated rhesus macaques. J Immunol 193:277-84
Barouch, Dan H; Deeks, Steven G (2014) Immunologic strategies for HIV-1 remission and eradication. Science 345:169-74

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