Assessment of Gamma/Delta T Cell Functionality Following Pathogenic HIV/SIV and Non-Pathogenic SIV Infections




Kosub, David Alan

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Pathogenic HIV/SIV infection induces high viral loads, aberrant immune activation, and dysfunction in numerous immunologic cells (including gamma/delta (gamma delta ) T cells) leading to opportunistic infections. gamma delta T cells bridge the innate and adaptive immune responses primarily via cytokines produced in response to microbial phosphoantigens. gamma delta T cells have also been implicated in the control of an SIV challenge infection as evidenced by increased numbers and beta -chemokine expression at mucosal sites in vaccinated macaques. The goal of Aim 1 of this thesis was to assess the impact of an acute SIV infection on the levels of gamma delta T cells at mucosal and lymphoid sites in macaques utilizing quantitative PCR. At two days post-infection, a decrease in gamma delta T cell levels was observed at mucosa sites whereas increased levels were present at regional lymph nodes. Also, an increase in lymphoid homing molecules was observed at these lymph nodes, indicating a mechanism whereby gamma delta T cells migrate away from mucosal sites towards secondary lymphoid tissues following an acute SIV infection. The redistribution of gamma delta T cells may be important for the initiation of an anti-viral immune response and control of rapid viral spread. The goal of Aims 2 and 3 was to assess the ability of gamma delta T cells in HIV-infected patients to express cytokines and compare these results to analysis of the non-pathogenic SIV infection of sooty mangabeys. Following stimulation with the non-specific activators PMA/Ionomycin or the gamma delta TCR specific ligand isopentenyl pyrophosphate, a decrease in the percentages of gamma delta T cells expressing Th1 pro-inflammatory cytokines including TNF-alpha and IFN-gamma was observed in the HIV+ patients (regardless of CD4+ T cell levels). Highly active anti-retroviral therapy (HAART) partially restored the ability of gamma delta T cells from HIV+ patients to express Th1 cytokines. SIV infection of mangabeys results in high viral replication, low levels of immune activation, and generally no signs of progression to AIDS. Evidence for preserved or increased functionality of gamma delta T cells from SIV+ mangabeys (regardless of CD4+ T cell levels) was demonstrated by maintained percentages of gamma delta T cells that expressed Th1 cytokines following ex vivo stimulation. These data suggest that in the absence of aberrant immune activation, controlled Th1 responses by gamma delta T cells from mangabeys may assist in suppressing damage due to the SIV infection as well as inhibiting the onset of opportunistic infections. These data provide rationale for therapies aimed at increasing gamma delta T cell functionality in humans, particularly with regard to Th1 cytokine responses to augment protection against opportunistic infections and HIV disease progression.

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