Title: Subtype-associated determinants of HIV-1 drug resistance
Description: In recent years the use of highly active antiretroviral therapy (HAART) for the treatment of AIDS has become more widespread across Africa. It is therefore imperative to characterize the subtype-associated features of the drug targets in non-subtype B HIV-1 infection. In three studies using population-based sequencing, phylogenetics, molecular epidemiology, and bioinformatics, this dissertation characterizes HIV-1 viral diversity in Nigeria and examines its determinants and consequences with respect to response to antiretroviral therapy, drug resistance and mother-to-child transmission of HIV-1. The first study was carried out in drug-naive subjects. It details the subtype-associated molecular diversity patterns in the HIV-1 reverse transcriptase (RT) and protease genes. The subtype-associated codon usage and polymorphisms observed suggest involvement of differential pathways for drug resistance and host-driven viral evolution in HIV-1 CRF02_AG and subtype G, compared to subtype B. The second study characterized the viral diversity of HIV-1 viruses transmitted to Nigerian infants by mothers who received peripartum Nevirapine prophylaxis. The data suggests wide diversity for vertically transmitted HIV-1 viruses in Nigeria and highlights the potential significance of transmitting HIV-1 subtype G viruses harboring a rare Q207N mutation in RT.

The third study examined the relationship between antiretroviral therapy and gag p6 diversity in CRF02_AG and subtype G. p6 sequences from HAART-adherent individuals had a higher frequency of mutations than sequences from drug-naive individuals, suggesting that HAART influences gag p6 diversity. In addition a P5L/T mutation in subtype G p6 protein was associated with stavudine therapy, as well as with the loss of a phosphorylation site vital for viral budding. In general, the spectrum of drug resistance mutations in CRF02_AG and subtype G, was similar to that of subtype B. However, subtype-associated mutations occur at sites of potential evolutionary and functional significance. The patterns of drug resistance observed are influenced by differential codon usage by subtype, the potential for virus-host interactions, and compensatory mutations in non-drug targets.