Impact of HIV-1 Subtype and Antiretroviral Therapy on Protease and Reverse Transcriptase Genotype: Results of a Global Collaboration

Abstract

BackgroundThe genetic differences among HIV-1 subtypes may be critical to clinical management and drug resistance surveillance as antiretroviral treatment is expanded to regions of the world where diverse non-subtype-B viruses predominate.Methods and FindingsTo assess the impact of HIV-1 subtype and antiretroviral treatment on the distribution of mutations in protease and reverse transcriptase, a binomial response model using subtype and treatment as explanatory variables was used to analyze a large compiled dataset of non-subtype-B HIV-1 sequences. Non-subtype-B sequences from 3,686 persons with well characterized antiretroviral treatment histories were analyzed in comparison to subtype B sequences from 4,769 persons. The non-subtype-B sequences included 461 with subtype A, 1,185 with C, 331 with D, 245 with F, 293 with G, 513 with CRF01_AE, and 618 with CRF02_AG. Each of the 55 known subtype B drug-resistance mutations occurred in at least one non-B isolate, and 44 (80%) of these mutations were significantly associated with antiretroviral treatment in at least one non-B subtype. Conversely, of 67 mutations found to be associated with antiretroviral therapy in at least one non-B subtype, 61 were also associated with antiretroviral therapy in subtype B isolates.ConclusionGlobal surveillance and genotypic assessment of drug resistance should focus primarily on the known subtype B drug-resistance mutations.

A previously unrecognized sixth genotype of GB virus C revealed by analysis of 5′‐untranslated region sequences

“…As reported recently [Kantor et al, 2005], HIV-1 subtypes differ from one another by 10%-12% in nucleotide sequence and only 5%-6% in amino acid sequence in protease and reverse transcriptase genes. Furthermore, some observations suggest that HIV-1 non-B subtypes respond differently to certain antiretroviral drugs (see references 27-35 in [Kantor et al, 2005]). Hence, high sequence conservation does not necessarily indicate low (i.e., predictable) biological variability.…”

The Challenge of HIV-1 Subtype Diversity

“…81,82 Overall, it appears that most antiretroviral resistance in non-B subtypes is accounted for within the current resistance databases. 83 Further studies of treated cohorts infected with non-B HIV-1 are needed to determine whether other subtype-specific pathways to resistance exist (Table 3).…”

Impact of HIV Type 1 Subtype on Drug Resistance Mutations in Nigerian Patients Failing First-Line Therapy

“…49 A 2005 meta-analysis of 3686 persons with non-B subtypes and 4769 with B subtypes found that 55 known treatmentassociated mutations that were observed in subtype B were also found in non-B subtypes, and the converse was true for 61/67 mutations observed in non-B subtypes. 50 In contrast, a study by Palma et al in 2009 found that genetic background played a role in different treatment-associated mutations that developed in subtypes B and G in Portuguese patients. 51 In a study of patients from Rio Grande do Sul, Brazil, in a population infected by subtypes B and C, a lower rate of accumulation of mutations was found in subtype C than subtype B.…”