Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Jean D. Boyer

Abstract

With the advancement in anti-retroviral therapy (ART) regimens there has been a significant improvement in the quality of life and survival of those individuals infected with HIV-1. Even with the benefits to CD4+ cell counts, decrease in viremia and inflammatory biomarkers, HIV-1 infected individuals continue to exhibit functional issues in their T-cell immune responses to recall antigens and vaccines. Additionally, researchers believe that T-cell mediated responses will be important to elicit in a therapeutic vaccination setting. These T-cell functionality issues can leave individuals infected with HIV-1 at risk from opportunistic infections and co-morbidities. Furthermore, a therapeutic HIV-1 vaccine is needed that can elicit responses to help infected subjects better control HIV infection so as to potentially reduce the need for long-term therapy. However, basic research on HIV is still needed to solidify potential immune correlates against HIV and other pathogens affecting HIV-1 infected subjects. Likewise, investigation of therapeutic targets that can aid in enhancing T-cell immune responses in these individuals is of importance.

In this thesis, we examined whether a therapeutic HIV-1 DNA vaccine delivered with in vivo electroporation to HIV-1 infected subjects on ART could elicit potent cellular immune responses previously suggested to be important in the control of HIV. This vaccine strategy demonstrated an enhancement in cell-mediated IFN-γ production and cytotoxic immune responses to HIV-1. However, until a vaccine or therapy for HIV-1 is developed, these individuals also continue to be at risk for other opportunistic infections, such as influenza infection. Supported by previous studies that focus on influenza vaccination, we found that a standard dose of the H1N1 vaccine (15μg; Novartis) did not elicit sero-protection in all individuals. Importantly, the ability of these individuals to respond to vaccination was associated with the frequency of naïve CD4+ T-cells prior to vaccination, thereby reinforcing the importance of CD4+ T-cell help and the need for better CD4+ T-cell reconstitution. In addition, HIV-1 infected subjects, despite ART, have an altered cytokine/chemokine environment. Thereby it is important to explore whether targeting the cytokine milieu can lead to improvements in responses to vaccination in these individuals. We specifically found that the pro-inflammatory chemokine IP-10 was elevated in the sera of those infected with HIV-1 while on ART. Additionally, elevated levels of IP-10 were associated with decreased cellular immune responses, which could be improved by neutralizing IP-10 prior to antigen stimulation. Therefore, the studies herein support the need for better understanding of the basic science of HIV-1 infection to uncover and comprehend what potential immune correlates are needed for therapeutic treatment of these individuals.

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