Defining effective anti-HIV immune responses is a major unsolved problem in HIV vaccine development. We have previously shown that immunization with virulence-attenuated SHPV89.6 protects 60% of rhesus macaques against vaginal challenge with pathogenic SIVmac239. Thus, the SHIV89.6 vaccine/SIVmac239 challenge system provides us with the opportunity to define immune correlates of protection by comparing immune responses in vaccinated-protected and vaccinated-unprotected animals. As live attenuated viruses persistently replicate in the host, and it is conceivable that the more robust protection observed with this compared to other vaccine strategies is the result of both attenuated lentivirus-induced innate antiviral immune responses and anamnestic T and B cell responses. Importantly, innate effector cells are present at mucosal surfaces, the primary entry site for HIV/SIV, they can directly inhibit virus replication, and they are critical for the induction of adaptive antiviral responses. Despite evidence that innate effector mechanisms contribute to attenuated-lentivirus vaccine-mediated protection and contribute to the control of HIV-1 replication in long-term non-progressor patients, there are no studies examining the complex interaction between innate and adaptive antiviral immune responses in HTV/SIV infection and vaccine-mediated protection. Thus, the goal of Aim 1 is to define differences in host immune responses in vaccinated-protected and vaccined-unprotected animals and to determine which host immune responses are associated with SHIV89.6-mediated protection. The results of this study will form the basis for Aims 2-6 in this application as we will then confirm and define the relative contribution of multiple effector mechanisms identified in Aim 1 to vaccine-mediated anti-SIV immunity by either depleting distinct effector cell populations (Aims 3 and 4) or by using pharmacological interventions (Aims 2, 5, and 6) to interfere with distinct immune mechanisms. Further, by selectively manipulating innate or adaptive effector responses, the interplay and dependence of both mechanisms on each other can be demonstrated. If we can identify innate immune mechanisms important in attenuated-lentivirus induced vaccine-mediated protection against vaginal SIV challenge, we can then try to exploit and stimulate these responses in """"""""conventional"""""""" vaccine strategies through the use of adjuvants or immunomodulatory therapies to increase overall vaccine efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI066314-02
Application #
7310356
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$405,641
Indirect Cost
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Ciupe, Stanca M; Miller, Christopher J; Forde, Jonathan E (2018) A Bistable Switch in Virus Dynamics Can Explain the Differences in Disease Outcome Following SIV Infections in Rhesus Macaques. Front Microbiol 9:1216
Fieni, Francis; Stone, Mars; Ma, Zhong-Min et al. (2013) Viral RNA levels and env variants in semen and tissues of mature male rhesus macaques infected with SIV by penile inoculation. PLoS One 8:e76367
McChesney, Michael B; Miller, Christopher J (2013) New directions for HIV vaccine development from animal models. Curr Opin HIV AIDS 8:376-81
Rothaeusler, Kristina; Ma, Zhong-Min; Qureshi, Huma et al. (2012) Antiviral antibodies and T cells are present in the foreskin of simian immunodeficiency virus-infected rhesus macaques. J Virol 86:7098-106
Genescà, Meritxell; Ma, Zhong-Min; Wang, Yichuan et al. (2012) Live-attenuated lentivirus immunization modulates innate immunity and inflammation while protecting rhesus macaques from vaginal simian immunodeficiency virus challenge. J Virol 86:9188-200
Genescà, Meritxell; McChesney, Michael B; Miller, Christopher J (2010) Depo-provera treatment does not abrogate protection from intravenous SIV challenge in female macaques immunized with an attenuated AIDS virus. PLoS One 5:e9814
Stone, Mars; Keele, Brandon F; Ma, Zhong-Min et al. (2010) A limited number of simian immunodeficiency virus (SIV) env variants are transmitted to rhesus macaques vaginally inoculated with SIVmac251. J Virol 84:7083-95
Vaidya, Naveen K; Ribeiro, Ruy M; Miller, Christopher J et al. (2010) Viral dynamics during primary simian immunodeficiency virus infection: effect of time-dependent virus infectivity. J Virol 84:4302-10
Lozano Reina, José-Manuel; Favre, David; Kasakow, Zeljka et al. (2009) Gag p27-specific B- and T-cell responses in Simian immunodeficiency virus SIVagm-infected African green monkeys. J Virol 83:2770-7
Genescà, M; McChesney, M B; Miller, C J (2009) Antiviral CD8+ T cells in the genital tract control viral replication and delay progression to AIDS after vaginal SIV challenge in rhesus macaques immunized with virulence attenuated SHIV 89.6. J Intern Med 265:67-77

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