A reliable phenotype predictor for human immunodeficiency virus type 1 subtype C based on envelope V3 sequences.
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Date
Authors
Jensen, Mark A.
Coetzer, Mia.
Van 't Wout, Angelique B.
Morris, Lynn.
Mullins, James I.
Journal Title
Journal ISSN
Volume Title
Publisher
American Society for Microbiology.
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.
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Citation
Jensen, M.A., et al. 2006. A reliable phenotype predictor for human immunodeficiency virus type 1 subtype C based on envelope V3 sequences. J. Virol. 80(10) pp. 4698-4704.