Background:  Although the genetic diversity of HIV-1 has been extensively studied in structural proteins, integrase (IN) has not been well characterized. IN is an essential enzyme for HIV replication and a major target for drug therapy. It is not clear how long clinical benefit provided by therapy will last due to the genetic diversity of HIV and the emergence of multi-drug-resistant viral strains. The aim of this study was to document the IN genetic diversity of subtypes B (B”), F, and C samples obtained from drug-naive individuals, and identify the presence of natural IN mutations in multi-drug-resistant individuals, in order to verify if this genomic region is still an available target for treatment.

Methods:  HIV-1 DNA was extracted from 88 drug-naive patient samples, corresponding to the major prevalent subtypes in Brazil, previously typed and based on env sequences. Viral RNA was isolated from 38 multi-drug-resistant plasma samples from subtype-B-infected (pol) individuals. Samples were amplified by a nested polymerase chain reaction (PCR) and automatically sequenced. Specific programs were used for edition, alignment, translation, phylogenetic analysis (neighbor-joining), and definition of the consensus sequence.

Results:  Discordant IN and env or PR/RT subtypes were not found. However, intra-subtype IN recombinant genomes (1 B/F, 3 B/C) were identified among drug-naive individuals. Typical IN amino acid signatures could be identified for all subtypes and no differences were observed between subtype B and its B” variant. Regarding the IN inhibitor related mutations, V72I occurred as a typical signature (>85%) for subtype C and as a polymorphism for subtype B (45%); V165I and V201I occurred as a polymorphism for F (38.5%) and B (45.6%) samples, respectively. Moreover, V201I is a signature for subtypes C and F. V72/I (45.9%), V151I (10.8%), V165I (5.4%), and V201I (64.9%) were observed for multi-drug resistance. Minor differences were observed for the frequencies of these mutations when compared multi-drug-resistant and non-treated subtype B group. Moreover 35.1% of multi-drug-resistant patients presented V72I and V210I double mutations and 7.9% showed V151I and V210I.

Conclusions:  Some of the IN resistance mutations already described were identified as natural polymorphisms among Brazilian subtypes B, F, and C samples. Considering the development of IN inhibitors, our results highlight that more data should be generated concerning IN diversity, to verify the effect of such natural resistance mutations/polymorphisms in future HIV/AIDS treatment.