ZIA BC 011062 (ZIA) | |||
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Title | Development of a Vaccine for HIV-AIDS: Cellular Immunity | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Robert-Guroff, Marjorie | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $708,554 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) |
Kaposi Sarcoma (33.0%) Non Hodgkins Lymphoma (34.0%) Sarcoma (33.0%) |
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Research Type | |||
Exogenous Factors in the Origin and Cause of Cancer Vaccines |
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Abstract | |||
We are pursuing an HIV vaccine approach based on replication-competent Adenovirus (Ad)-recombinants. The rationale for this strategy is based on the fact that live attenuated vaccines historically have been the most protective, eliciting essentially life-long immunity. Examples include vaccines for small pox, polio, measles, and yellow fever. We conduct pre-clinical vaccine studies in rhesus macaques and challenge with SIV or SHIV (a chimeric SIV virus containing an HIV envelope), viruses that model HIV-infection of humans. We use a prime-boost strategy, first immunizing with a replicating adenovirus (Ad) vector carrying an HIV/SIV gene(s) followed by a boosting with HIV/SIV envelope protein. Ad replicates in epithelial cells that line mucosal inductive sites, and therefore elicits strong, persistent cellular immunity at mucosal effector sites as well as in the blood. In studying vaccine-induced cellular immunity, we have recently focused on several specific cell types. Natural killer (NK) cells are a key population which have a rapid response potential, can kill target cells directly, and also mediate antibody-dependent effector functions such as antibody-dependent cellular cytotoxicity (ADCC) which has been shown to contribute to protective efficacy. They also have recently been shown to persist for long periods of time in vivo and to have the capacity to establish immunologic memory. We have studied the phenotype and function of circulatory and tissue-resident NK cells in a unique cohort of SIV controlling rhesus macaques that maintained low to undetectable levels of viremia during the chronic phase of infection. We compared the NK responses of these macaques with those observed in SIV non-controlling and uninfected macaques, aiming to identify markers and activities of NK subpopulations associated with disease control. Most of the differences among the NK cells of the three groups of macaques were seen in tissue-resident cells. While SIV infection resulted in NK cell dysfunction, double negative NK cells (CD56-CD16-), and those expressing CXCR3, NKG2D, and IL-18Ralpha were associated with viremia control, as was antibody-dependent cytotoxic function. Double-negative NK cells have been reported to have potent cytotoxic activity and IFN-gamma production. The results of this study suggested several novel targets for therapeutic intervention. Currently we are studying the effect of vaccination on NK cells, particularly those in mucosal tissues, and investigating whether subsets of mucosal NK cells are associated with protective efficacy of our vaccine regimen. In HIV infection, CD8+ T cells play a critical role in controlling viremia. B cell follicles have been thought to be immune privileged sites of HIV infection. However, follicular CD8+ T cells (fCD8 cells) that reside within B cell follicles were recently described. We have observed comparable levels of fCD8 cells between chronically SIV infected rhesus macaques with low viral loads (LVL) and high viral loads (HVL), raising the question concerning their contribution to viremia control. We investigated the role of SIV-specific fCD8 cells in lymph nodes (LNs) over the course of SIV infection in rhesus macaques. fCD8, T follicular helper (Tfh), and T follicular regulatory (Tfreg) cells were all elevated in chronic SIV infection. fCD8 cells of LVL animals tended to express more Gag-specific granzyme B and exhibited significantly greater killing than HVL animals, and their cell frequencies negatively correlated with viremia, suggesting a role in viremia control. Env- and Gag-specific IL-21+Tfh of LVL but not HVL macaques negatively correlated with viral load, suggesting better provision of T cell help to fCD8 cells. Tfreg positively correlated with fCD8 cells in LVL animals and negatively correlated with viremia, suggesting a potential benefit of Tfregs via suppression of chronic inflammation. In contrast, in HVL macaques, Tfreg and fCD8 cell frequencies tended to negatively c |