The Kinetics of Myeloid Derived Suppressor Cell Frequency and Function in Chronic Retroviral Infections

Thesis (Ph.D.)--University of Washington, 2016-06During chronic retroviral infection, poor clinical outcomes correlate both with systemic inflammation and poor proliferative ability of HIV-specific T cells, however the connection between the two is not clear. Myeloid derived suppressor cells (MDSC), suppressive cells of myeloid origin that accumulate during states of elevated circulating inflammatory cytokines, may link the systemic inflammation and poor T cell function characteristic of retroviral infections. MDSC have been partially characterized in retroviral infections, and questions remain regarding their phenotype, persistence, activity and clinical significance in HIV and SIV infection. We enrolled HIV+ individuals on combination antiretroviral therapy (cART) across a spectrum of ages and found significantly elevated frequencies of MDSC of granulocytic (gMDSC) and not monocytic (mMDSC) origin in HIV+ individuals over the age of 50 compared to age-matched HIV-individuals. These gMDSC suppressed ex vivo HIV-specific T cell responses. We then followed rhesus macaques (Macaca mulatta) over the course of SIV infection. We observed low frequencies of MDSCs pre-SIV infection and elevated gMDSC at all stages of SIV infection that increased most markedly at 20 weeks post-cART. These cells exert suppressive effects on T cell responses to polyclonal and SIV peptide stimuli. In both models MDSC frequency correlated with levels of circulating inflammatory cytokines. In the animal model the cytokines independently correlating with MDSC were characteristic of microbial translocation. While MDSC have been previously described in HIV and SIV infection, novel findings of this work are the two distinct times of elevated inflammation in chronic retroviral infection leading to accumulation of MDSC. MDSC are elevated during aging even in a cART-suppressed host, and MDSC are markedly elevated during treatment interruption in a previously cART-suppressed host. This work highlights a potential risk of non-adherence, or treatment interruption, in cART-suppressed HIV+ individuals. This is important because the US Department of Health and Human Services recommend all HIV+ individuals initiate antiretroviral therapy regardless of CD4 count. Future work exploring therapies to abrogate microbial translocation or disable MDSC suppression at these times in retroviral infection may be warranted