Background:  HIV are classified into subtypes based on their genetic diversity. Interactions between antiretroviral drugs and their HIV target is dependent on the viral genetic sequence. Differences in genetic sequence may influence these interactions; therefore HIV subtype variability has the potential to effect drug resistance. The magnitude of this effect and its clinical relevance for each drug and subtype may differ. Although a minority of patients worldwide are infected with subtype B, it has been the primary target for drug development and traditionally the majority of research. Data on the effect of different subtypes on HIV drug resistance has been increasing in recent years. Refinements of resistance diagnostic tools to optimize results in non-B subtypes have been performed and research continues to identify remaining gaps. Studies have identified a number of subtype-related effects on drug resistance. Resistance-associated mutations, rarely or never identified in wild type subtype B, can be found more frequently in other subtypes. These have the potential to modify viral susceptibility to specific drugs and affect the evolutionary pathway to resistance. Diversity may be at the amino acid or nucleotide level. Subtype-specific codon use can favor selection of unique resistance mutations not commonly seen in subtype B. Therefore individual subtypes may differ in their susceptibility to specific drugs, frequency of resistance pathways usage, selection of unique (non-B-related) mutations, as well as influence of specific resistance patterns. The clinical effect of these findings remain to be precisely determined. The large number of subtypes and drugs makes the challenge exceptionally complex and difficult. Although for specific subtypes and drugs relevant interactions have been identified, evidence clearly indicates that the majority of antiretroviral agents are effective in different subtypes with excellent clinical results. Interpretation of resistance assays may also be complicated by our lack of understanding of subtle subtype related differences. Here too, the effect currently appears to be minimal.

Conclusions:  Pooling data in large collaborative efforts will facilitate further progress. In addition, continued investigation into the complex relationships between genetic diversity, specific drug susceptibility and viral replication will provide important insight.