HIV-2 integrase variation in integrase inhibitor-naïve adults in Senegal, West Africa

Abstract

Background: Antiretroviral therapy for HIV-2 infection is hampered by intrinsic resistance to many of the drugs used to treat HIV-1. Limited studies suggest that the integrase inhibitors (INIs) raltegravir and elvitegravir have potent activity against HIV-2 in culture and in infected patients. There is a paucity of data on genotypic variation in HIV-2 integrase that might confer intrinsic or transmitted INI resistance.

Methods: We PCR amplified and analyzed 122 HIV-2 integrase consensus sequences from 39 HIV-2-infected, INI-naive adults in Senegal, West Africa. We assessed genetic variation and canonical mutations known to confer INI-resistance in HIV-1.

Results: No amino acid-altering mutations were detected at sites known to be pivotal for INI resistance in HIV-1 (integrase positions 143, 148 and 155). Polymorphisms at several other HIV-1 INI resistance-associated sites were detected at positions 72, 95, 125, 154, 165, 201, 203, and 263 of the HIV-2 integrase protein.

Conclusion: Emerging genotypic and phenotypic data suggest that HIV-2 is susceptible to the new class of HIV integrase inhibitors. We hypothesize that intrinsic HIV-2 integrase variation at "secondary" HIV-1 INI-resistance sites may affect the genetic barrier to HIV-2 INI resistance. Further studies will be needed to assess INI efficacy as part of combination antiretroviral therapy in HIV-2-infected patients.

Figure 1. Phylogenetic tree of HIV-2 integrase nucleotide sequences (N = 122, black taxa) from 39 INI-naïve Senegalese adults and HIV-2 reference sequences (gray taxa) from the Los Alamos HIV Database (

http://www.hiv.lanl.gov ). HIV-2 Group A (N = 37 subjects) and Group B (N = 2 subjects) clades are shown.

Figure 2. HIV-2 integrase variation at sites implicated in INI resistance.

(Top) Amino acid substitutions that appear in HIV-1 sequences from patients treated with raltegravir, elvitegravir, or other INIs, or that emerge in HIV-1 in response to INI selection in culture. This list was compiled from sources listed under Methods. The consensus HIV-1 sequence (http://www.hiv.lanl.gov) is shown for comparison. Gray boxes indicate the locations of primary INI resistance mutations in HIV-1. Amino acid changes that are associated with >5-fold resistance to raltegravir or elvitegravir in HIV-1 (http://hivdb.stanford.edu) are shown in red. (Bottom) Consensus sequences for group A and group B HIV-2 isolates were derived from previously-published data (http://www.hiv.lanl.gov); positions that contain two or more residues are polymorphic in HIV-2. Patient-derived HIV-2 integrase sequences (n = 122) were obtained from 39 INI-naïve individuals in the Senegal cohort. HIV-2 integrase residues that correspond to INI resistance-associated mutations in HIV-1 are highlighted in yellow boxes. Values below the boxes indicate the number of HIV-2 patient sequences containing the each resistance-associated residue (RAR, in parentheses) and the number of patients in which these amino acids were present.