Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Ronald G. Collman

Abstract

Natural host sooty mangabeys infected with simian immunodeficiency viruses (SIV) exhibit high plasma viral loads without widespread CD4+ T cell loss. By contrast, non-natural host rhesus macaques experimentally infected with related SIV exhibit high viral loads but display subsequent CD4+ T cell loss and progression to AIDS, analogous to the effects of HIV-1 infection in humans. Several mechanisms have been proposed to explain these discrepant outcomes, including infection of distinct target cells in vivo. Cell targeting is substantially determined at the level of viral entry. Prior work demonstrated that sooty mangabey infection occurs in the absence of functional coreceptor CCR5, implicating alternative SIV entry pathways in this natural host. In this thesis, I identified host-dependent patterns of SIV coreceptor use that distinguish viral entry in sooty mangabeys from viral entry in rhesus macaques. I cloned and characterized a panel of putative sooty mangabey coreceptors. Transfected target cells expressing species-specific CD4 and coreceptors identified sooty mangabey CCR5, CXCR6, and GPR15 as functional coreceptors of SIV in vitro. While rhesus macaque CCR5 and GPR15 also supported robust SIV infection in vitro, rhesus macaque CXCR6 was a remarkably poor coreceptor of SIV. Using CCR5 antagonist Maraviroc to block CCR5-mediated infection in primary peripheral blood mononuclear cells (PBMCs), I determined that SIV were highly CCR5-dependent in rhesus macaque PBMCs, whereas SIV were partially CCR5-independent in sooty mangabey PBMCs, implicating alternative coreceptors in infection of the natural host primary cells. A chemokine ligand of CXCR6, CXCL16, partially attenuated SIV infection of sooty mangabey PBMCs, indicating that sooty mangabey CXCR6 was indeed an alternative coreceptor of some SIV in primary sooty mangabey cells. Collectively, these data define coreceptor use as a host determinant distinguishing sooty mangabey SIV infection from rhesus macaque SIV infection in primary cells. Because CD4+ T cells from sooty mangabeys express exceedingly low levels of CCR5 relative to CD4+ T cells from rhesus macaques, the expression patterns of CXCR6 and other alterative coreceptor(s) in sooty mangabey CD4+ cell subsets may classify host target cells that maintain high levels of SIV replication without leading to loss of CD4+ T cell homeostasis.

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