Characterising the Prevalence and Mode of CXCR4 Usage in HIV-1 Group M Subtype C

Abstract

Determination of CXCR4-usage patterns is essential in establishing suitability of CCR5 antagonist prescription in HIV-1 infected individuals to prevent treatment failure. Previous studies have suggested a switch to CXCR4-usage to be far less common in subtype C, yet recent studies have reported between 30 - 50% CXCR4-usage in this subtype. However, CXCR4-usage in subtype C is poorly characterised. Furthermore, the reliability of available genotypic algorithms is unknown for subtype C sequences. In this study, a comparative analysis of the predictive ability of several subtype B-modeled genotyping algorithms in subtype C tropism determination was undertaken. A total of 731 HIV-1 subtype C V3 sequences with phenotypically determined coreceptor tropism were collated from several sources. Datasets of 349 CCR5, 25 CXCR4 exclusive and 31 R5X4 (Dual) sequences were submitted to 11 various tropism prediction tools. The best performing tool was used to determine the tropism of 12,121 subtype C V3 sequences with unknown phenotypes, in order to characterise the prevalence and method of CXCR4 usage in HIV-1 subtype C. We determined that geno2pheno with a false positive rate of 5% is the best approach for predicting CXCR4-usage in subtype C sequences with an accuracy of 94% (89% sensitivity and 99% specificity). Contrary to what has been reported for subtype B, the optimal approaches for prediction of CXCR4-usage in sequence from viruses that use CXCR4 exclusively, also perform best at predicting CXCR4-use in dual-tropic viral variants. Furthermore, we find that a switch to CXCR4 usage is seen in subtype C for well over 20 years and has occurred consistently over time. At 5%, the frequency of CXCR4-usage in subtype C database records is lower than previous reports for both subtype C and B. The Geno2pheno coreceptor tool may be used as a reliable genotypic predictor in clinical settings to establish the viability of CCR5-antagonist therapies using drugs such as Maraviroc and provides a rapid and cost effective alternative to phenotypic testing in resource limited areas. A switch to CXCR4-usage in subtype C is constant but lower when compared to subtype B, a finding which may have broad implications for the design of intervention and treatment strategies for HIV-1 subtype C.