Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Robert W. Doms

Abstract

Sexual transmission of HIV-1 is often established by one genetic variant, the transmitted/founder (T/F) virus. T/F HIV-1 may have specific phenotypic properties that are selected for during transmission. To date, the most consistent phenotypic property associated with T/F viruses is use of the chemokine receptor CCR5 as a coreceptor for entry. Small molecule CCR5 antagonists, such as Maraviroc (MVC), inhibit HIV-1 entry by functioning as allosteric inhibitors. These molecules bind within the transmembrane helices of CCR5, inducing a conformational change that prevents the HIV-CCR5 interaction. As with most drugs, HIV-1 has developed strategies to overcome this inhibition. Some viruses develop mutations in the envelope (Env) glycoprotein that enable the use of antagonist-bound CCR5. In Chapter Two, we evaluate 87 CCR5-using viruses to address differences between T/F viruses and viruses isolated from chronically infected individuals (chronic controls-CC) in their ability to mediate entry via varying amounts of CCR5 in the presence of MVC. We demonstrate that CC viruses exhibit partial resistance (PR) to MVC more frequently than T/F viruses, suggesting that T/F and CC HIV-1 differentially utilize CCR5 in a manner that may be biologically important in the context of transmission. Following the discovery of the chemokine receptors CXCR4 and CCR5 as cofactors for HIV-1 entry, it was revealed that their cognate chemokine ligands could inhibit HIV-1 infection in vitro. Multiple cell types have been implicated in secreting chemokines that function to modulate HIV-1 infection. Recently the platelet-derived chemokine PF4 was shown to inhibit HIV-1. However, despite plasma and local concentrations of PF4 being within the range used in these studies, HIV-1 is still able to propagate in vivo. In Chapter Four, we sought to understand the mechanism of action of PF4 and determine it’s in vivo relevance. I confirmed and extended previous studies showing that PF4 inhibits infection by HIV-1 and other viruses. However, the inhibitory capacity of PF4 is limited to a defined concentration range, after which inhibition wanes and viral infection is ultimately enhanced at higher chemokine concentrations that are commonly found in vivo. Thus, rather than being a potential anti-viral agent as previously suggested, PF4 may contribute to the hematologic abnormalities commonly seen in HIV-infected individuals by enhancing virus infection in the bone marrow.

Included in

Virology Commons

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