Background:  Subtype C is the most prevalent HIV-1 subtype worldwide. With increased treatment access, differences between B and C in the reverse transcriptase (RT) and protease genes may influence virus susceptibility, selection of mutations and genotypic interpretation of resistance. The impact of subtype on the evolution of drug resistance is not known.

Methods:  We analyzed RT and protease sequences from subtype-C-infected persons collected from 14 sites in 12 countries, and from the published literature. Subtypes were determined by boot-scanning. Mutations were defined as differences from consensus B. Subtype-C-treatment related mutations were defined as mutations significantly more prevalent in treated versus untreated subtype C sequences. Subtype-C-specific polymorphisms were defined as mutations significantly more prevalent in C versus B sequences without treatment. Data were analyzed by a logistic regression model with correction for multiple comparisons.

Results:   From 769 persons (345 treated, 424 naive) infected with subtype C, 708 RT and 601 protease sequences were compared with 2101 RT and 2082 protease sequences from 2646 persons (1898 treated, 748 naive) with subtype B. All 18 subtype B known NRTI-resistance mutations, With drug therapy, 19/22 known PI-resistance mutations and 14/15 known NNRTI-resistance mutations occurred in subtype C. Subtype-C-treatment-related mutations at positions not known to be related to treatment in subtype B included protease positions 13, 15, 23, 33, 37, 43, 62, 74, and 85; and RT positions 102, 123, 138, 173, 174, 203, 221, and 228. Subtype-C-specific polymorphisms included protease positions 12, 15, 16, 19, 20, 36, 41, 45, 60, 61, 63, 69, 74, 82, 89, and 93; and RT positions 35, 36, 39, 40, 43, 48, 53, 60, 62, 69, 104, 123, 158, 173, 174, 177, 200, 207, and 211. Selection of mutations was significantly greater in subtype C than subtype B at protease position 13 and RT positions 35, 98, 106, and 173; and was significantly lower in subtype C than in subtype B at protease positions 74 and 20 and RT positions 43, 60, 62, 69, and 104.

Conclusions:  Most resistance-associated mutations in RT and protease are present in subtypes B and C following therapy. However, subtype-specific changes under drug selective pressure and genotypic variation in untreated subjects may affect drug susceptibility, resistance evolution, and treatment response. Subtype-specific changes warrant continuous surveillance and characterization.

Keywords: non-B; subtype; drug resistance