Abstract
BackgroundIn human immunodeficiency virus type 1 (HIV-1) infection, transmitted viruses generally use the CCR5 chemokine receptor as a coreceptor for host cell entry. In more than 50% of subtype B infections, a switch in coreceptor tropism from CCR5- to CXCR4-use occurs during disease progression. Phenotypic or genotypic approaches can be used to test for the presence of CXCR4-using viral variants in an individual’s viral population that would result in resistance to treatment with CCR5-antagonists. While genotyping approaches for coreceptor-tropism prediction in subtype B are well established and verified, they are less so for subtype C.MethodsHere, using a dataset comprising V3 loop sequences from 349 CCR5-using and 56 CXCR4-using HIV-1 subtype C viruses we perform a comparative analysis of the predictive ability of 11 genotypic algorithms in their prediction of coreceptor tropism in subtype C. We calculate the sensitivity and specificity of each of the approaches as well as determining their overall accuracy. By separating the CXCR4-using viruses into CXCR4-exclusive (25 sequences) and dual-tropic (31 sequences) we evaluate the effect of the possible conflicting signal from dual-tropic viruses on the ability of a of the approaches to correctly predict coreceptor phenotype.ResultsWe 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.ConclusionsThe accuracy of genotyping approaches at correctly predicting the coreceptor usage of V3 sequences from subtype C viruses is very high. We suggest that genotyping approaches can be used to test for coreceptor tropism in HIV-1 group M subtype C with a high degree of confidence that they will identify CXCR4-usage in both CXCR4-exclusive and dual tropic variants.
Highlights
In human immunodeficiency virus type 1 (HIV-1) infection, transmitted viruses generally use the C-C chemokine receptor type 5 (CCR5) chemokine receptor as a coreceptor for host cell entry
While many amino acid positions throughout gp120 have been suggested to influence coreceptor affinity and tropism [29,30,31,32,33,34,35], the V3 loop appears to be the strongest determinant of coreceptor tropism with amino acid mutations affecting V3 net charge, charge at positions 11, 24 and 25 and glycan binding patterns all implicated in causing a switch from CCR5- to C-X-C chemokine receptor type 4 (CXCR4)-usage [36,37,38,39,40,41]
In total 731 HIV-1 group M subtype C V3 sequences with experimentally verified coreceptor tropism were retrieved
Summary
Study data A dataset consisting of 731 HIV-1 subtype C V3 nucleotide sequences with phenotypically determined coreceptor tropism was sourced. Genotypic algorithms The coreceptor tropism of each V3 sequence was predicted using a number of genotyping methods These comprised PSSMX4R5 and PSSMSINSI [42] as well as the subtype C PSSM tool [43], geno2pheno [44] and four variants (C4.5, C4.5 with p8-p12, PART and SVM) of the wetcat package [45]. If a tested genotyping approach was not designed to account for ambiguous nucleotide positions, all possible combinations of amino acid sequences were output and a worst-case scenario approach was employed whereby if one of these translated sequences was predicted as CXCR4-using, the genotyping call for the original sequence was taken as X4. For each calculation we normalized the TP and FN values relative to the TN and FP values to account for the disproportionate number of sequences representing the positive (CXCR4-using or CXCR4-exclusive) and negative (CCR5) datasets (see Additional file 1: Table S1 for the uncorrected values).
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