Subtype-associated determinants of HIV-1 drug resistance
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First published: 2007
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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.
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.