Lack of information on the immunologic mechanisms responsible for protection against HIV infection remains one of the major obstacles to the development of a safe and effective AIDS vaccine. Vaccination of macaques with attenuated SIV strains has consistently proven to be the most effective means to induce protection against pathogenic SIV challenge in macaques. Intensive study of macaques vaccinated with attenuated SIV strains therefore represents one of the best experimental models available for the determination of mechanisms of protective immunity against lentivirus infection. The overall goal of this Program Project application is to undertake a comprehensive, multidisciplinary effort to define mechanisms of immune protection mediated by live attenuated SIV strains. Complementary experiments conducted by three principal investigators with distinct areas of expertise will examine: 1. Mechanisms of mucosal protection induced by attenuated SIV. These experiments will undertake a detailed examination of the evolution of adaptive and innate immune responses induced by SIV?nef and correlate these responses with protection, examine the effect of prolonged B cell depletion on protective immunity, and study viral replication and immune responses in the female reproductive tract of SIV?nef-vaccinated animals after vaginal challenge. 2. The contribution of anti-envelope immune responses to protection mediated by live attenuated SIV. Specific questions include: Does a mismatch of envelope sequences in the challenge virus decrease the degree of protection? Does challenge with a closely-matched SIV strain that differs dramatically in coreceptor usage influence the degree of protection? Does variation in the strength of the anti-envelope antibody response induced using modified single-cycle SIV influence the degree of protection? 3. Mucosal immunity and heterologous protection induced by single-cycle SIV (scSIV). These experiments will examine if the site of immunization with scSIV determines the mucosal homing properties of T cell responses and resistance to an intrarectal challenge with SIVmac239;whether the site of priming influences the ability of virus-specific T cell responses to protect against a vaginal challenge with SIVmac239;and whether immunization with a mixture of antigenically diverse strains of scSIV can broaden virus-specific immune responses and enhance protection against a heterologous challenge with SIVmac239. Results from these studies should shed light on the nature of immune responses able to protect against HIV/SIV infection, which remains one of the outstanding unanswered questions of AIDS vaccine research, and thus will have important implications for the design of clinically applicable AIDS vaccines. PROJECT 1: Mechanisms of mucosal protection induced by attenuated SIV (Johnson, R. Paul) PROJECT 1 DESCRIPTION (provided by applicant): Lack of information on mechanisms of protection against HIV/SIV infection remains one of the leading obstacles to the development of a safe and effective AIDS vaccine. Vaccination of macaques with attenuated SIV strains has consistently proved to be the most effective means of inducing protection against pathogenic SIV challenge and offers the best available experimental model to define specific mechanisms responsible for protection. Previous studies from our group have provided evidence that SIV-specific CD8+ T cell and humoral responses both contribute to protective immunity induced by SIV?nef but have not been able to assess their relative importance or the potential contributions of novel adaptive (e.g. CD4+ T effector cells) or innate immune responses to protection. The goal of the current application is to utilize a number of novel techniques to carry out a comprehensive analysis of the role of adaptive and innate immune responses in mediating protection induced by SIV?nef against vaginal challenge, one of the most important modes of HIV transmission.
Specific aims i nclude: 1: To examine the evolution of adaptive and innate immune responses induced by SIV?nef and to correlate these responses with protection against homologous and heterologous challenge. 2: To examine the effect of prolonged B cell depletion on protective immunity induced by SIV?nef. 3: To examine viral replication, innate and adaptive immune responses in the female reproductive tract of SIV?nef-vaccinated animals after vaginal challenge.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI071306-05
Application #
8044819
Study Section
Special Emphasis Panel (ZAI1-MPM-A (J1))
Program Officer
Warren, Jon T
Project Start
2007-04-15
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2011
Total Cost
$3,233,225
Indirect Cost
Name
Harvard University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Shang, L; Smith, A J; Reilly, C S et al. (2018) Vaccine-modified NF-kB and GR signaling in cervicovaginal epithelium correlates with protection. Mucosal Immunol 11:512-522
Shang, L; Duan, L; Perkey, K E et al. (2017) Epithelium-innate immune cell axis in mucosal responses to SIV. Mucosal Immunol 10:508-519
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
Adnan, Sama; Colantonio, Arnaud D; Yu, Yi et al. (2015) CD8 T cell response maturation defined by anentropic specificity and repertoire depth correlates with SIV?nef-induced protection. PLoS Pathog 11:e1004633
George, Michael D; Hu, William; Billingsley, James M et al. (2014) Transcriptional profiling of peripheral CD8+T cell responses to SIV?nef and SIVmac251 challenge reveals a link between protective immunity and induction of systemic immunoregulatory mechanisms. Virology 468-470:581-91
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
Smith, Anthony J; Wietgrefe, Stephen W; Shang, Liang et al. (2014) Live simian immunodeficiency virus vaccine correlate of protection: immune complex-inhibitory Fc receptor interactions that reduce target cell availability. J Immunol 193:3126-33
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
Manrique, Julieta; Piatak, Michael; Lauer, William et al. (2013) Influence of mismatch of Env sequences on vaccine protection by live attenuated simian immunodeficiency virus. J Virol 87:7246-54
Rahmberg, Andrew R; Neidermyer Jr, William J; Breed, Matthew W et al. (2013) Tetherin upregulation in simian immunodeficiency virus-infected macaques. J Virol 87:13917-21

Showing the most recent 10 out of 31 publications