title: A reliable phenotype predictor for human immunodeficiency virus type 1 subtype C based on envelope V3 sequences.
abstract: In human immunodeficiency virus type 1 (HIV-1) subtype B infections, the emergence of viruses able to use CXCR4 as a coreceptor is well documented and associated with accelerated CD4 decline and disease progression. However, in HIV-1 subtype C infections, responsible for more than 50% of global infections, CXCR4 usage is less common, even in individuals with advanced disease. A reliable phenotype prediction method based on genetic sequence analysis could provide a rapid and less expensive approach to identify possible CXCR4 variants and thus increase our understanding of subtype C coreceptor usage. For subtype B V3 loop sequences, genotypic predictors have been developed based on position-specific scoring matrices (PSSM). In this study, we apply this methodology to a training set of 279 subtype C sequences of known phenotypes (228 non-syncytium-inducing [NSI] CCR5(+) and 51 SI CXCR4(+) sequences) to derive a C-PSSM predictor. Specificity and sensitivity distributions were estimated by combining data set bootstrapping with leave-one-out cross-validation, with random sampling of single sequences from individuals on each bootstrap iteration. The C-PSSM had an estimated specificity of 94% (confidence interval [CI], 92% to 96%) and a sensitivity of 75% (CI, 68% to 82%), which is significantly more sensitive than predictions based on other methods, including a commonly used method based on the presence of positively charged residues (sensitivity, 47.8%). A specificity of 83% and a sensitivity of 83% were achieved with a validation set of 24 SI and 47 NSI unique subtype C sequences. The C-PSSM performs as well on subtype C V3 loops as existing subtype B-specific methods do on subtype B V3 loops. We present bioinformatic evidence that particular sites may influence coreceptor usage differently, depending on the subtype.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA, USA. mark.jensen@emory.edu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jensen
authors.forename: Mia
authors.initials: M
authors.lastname: Coetzer
authors.forename: Angélique B
authors.initials: AB
authors.lastname: van 't Wout
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
mesh_terms: D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000145:classification* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA
chemical_list: D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments