Central nervous system compartmentalisation and drug resistance in HIV-1 sub-type C infection (360G-Wellcome-206440_Z_17_Z)

My research proposes to study HIV compartment shifts from the CNS to the peripheral blood, the evolution of drug resistance in the CNS and the relationship between CNS co-infection with other neurotropic organisms and CNS compartmentalisation in HIV-1 subtype C. Within a longitudinal cohort I will conduct a proof-of-principle study with the aim of testing the hypothesis that the CNS is a reservoir for HIV, where independent replication with the possibility of developing drug resistant mutations that may seed into plasma on treatment interruption. I will track the dynamics of compartment shifts and the evolution of drug resistance in paired plasma and CSF before and during the course of ART over 2 years. I will follow-up patients in this cohort initiating first-line therapy, and go on to repeat paired sampling of plasma and CSF in those with low level viraemia (LLV), where I expect 20% to have CNS compartmentalised HIV. Finally, I will capitalize on collaboration with an ongoing therapeutic clinical trial of cryptococcal meningitis (CM) (the ACTA trial) to examine HIV CNS compartmentalisation and the emergence of ART resistance in the brain in patients with CM. I will benefit from having access to stored samples of paired CSF and plasma from 680 patients in this multi-centre trial in Africa. Phenotypic drug susceptibility using pseudotyped viruses with patients’ derived gag-pol in a single cycle infection assay system and genotypic assessments of compartmentalised viruses will be performed, using next generation sequencing and single genome amplification. The project builds upon the continuing close collaboration between Dr Ravi Gupta’s group at UCL and Professor Deenan Pillay at the Africa Health Health Research Institute in KZN, South Africa. The proposal complements and extends the research programs in both centres. I will have access to superb experimental science facilities in Durban where there is a major focus on HIV drug resistance and with clinical and population based research excellence at the epicentre of the HIV epidemic. The Gupta laboratory at UCL specializes in HIV drug resistance, HIV reservoirs, particularly within macrophages, with complementary skills and interests in Durban.