Genotypic and phenotypic characterization of HIV-1 from cerebrospinal fluid and blood compartments in patients with cryptococcal meningitis.

Doctor of Philosophy in the School in Virology. University of KwaZulu-Natal. Durban, 2017.The combination of HIV and cryptococcal meningitis (CM) is a major cause of morbidity and mortality in sub-Saharan Africa. The phylogenetic relatedness of HIV-1 subtype C (HIV-1C) variants in peripheral blood and the central nervous system (CNS) compartments of individuals with CM is unknown. Additionally, the major and alternative coreceptor usage of HIV-1C in those compartments are not clear and these have implications for the pathogenesis of the virus, and the use of coreceptor blocking therapies. For genotypic studies, 16 antiretroviral therapy naïve individuals with CM were randomly selected. We conducted single-genome, or bulk PCR amplification and sequencing of full-length HIV-1 env genes from plasma and/or cerebrospinal fluid (CSF) of the participants. Additionally, we estimated the prevalence of CXCR4-using variants in our cohort using coreceptor usage prediction algorithms (CPAs). Next, we evaluated the usage of CCR3, CCR5 and CXCR4 expressed on NP2/U87-CD4 cells by HIV-1C Envs derived from the plasma and/or CSF of 14 of the 16 participants. CCR3 alone, or in combination with the other receptors. Overall, our results have improved the understanding of HIV-1C pathogenesis in the peripheral blood and CNS compartments of individuals with end-stage infection and CM, and provides clinically relevant information for therapies including coreceptor antagonists in this setting