Willey, Samantha Jane; (2003) Cellular tropism of human immunodeficiency virus: Receptors and inhibitors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Highly active anti-retroviral therapy (HAART) has been very effective in reducing viral loads in HIV+ patients. However, current therapies carry detrimental side effects, require complex drug regimes for administration and are threatened by the emergence of resistant variants. The need for new effective therapies targeted to different stages in the HIV life cycle is urgent. The 7-transmembrane G protein-coupled chemokine receptors CCR5 and CXCR4 are the major coreceptors for HIV and SIV. The majority of transmitted viruses are R5-tropic, yet variants able to exploit CXCR4 (R5X4- or X4-tropic) emerge in the late stages of disease in up to 50% of individuals. As R5 strains remain present throughout disease, CCR5 is an ideal target for novel therapeutic intervention. At least a dozen other chemokine receptors or close relatives also support infection by particular HIV/SIV strains on CD4+ indicator cell lines in vitro. Despite the expression of many of these different receptors on primary CD4+ cells, their role during in vivo infection is currently thought to be insignificant. However, in the advent of CCR5 inhibitors, minority populations of variants able to use such coreceptors may become predominant and thus escape inhibition by CCR5-specific drugs. Here I have analysed the sensitivity of R5 and R5X4 strains of HIV and SIV to a series of six novel small molecule inhibitors of CCR5 on a diverse range of cell types, including lymphocytes and macrophages, the main cell types targeted by HIV-1 in vivo. In order to better evaluate the contribution of alternative coreceptors in vivo in the event of CCR5 being blocked, several primary untransformed cell cultures, including peripheral blood mononuclear cells (PBMCs), brain microvascular endothelial cells (BMVECs) and cells from immunoprivileged sites such as astrocytes and Leydig cells, were tested for expression of functional coreceptors able to support infection by HIV and SIV. A coreceptor of unknown identity has been discovered that is expressed on these primary cells and that supports infection by a subset of HIV and SIV isolates, including some from both subtypes B and C. The potential in vivo roles of CCR5 inhibitors and of alternative coreceptors will be discussed.

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