WebPSSM Description:

WebPSSM is a bioinformatic tool for predicting HIV-1 coreceptor usage from the amino acid sequence of the third variable loop (V3) of the envelope gene. A description and comprehensive analysis of the method is located here.

No user sequences are stored. If you would like to "donate" sequences that have known associated phenotypes, for the improvement of this method and the development of multiple subtype matrices, please contact Mark Jensen.

Use:

You may enter as many as 100 V3 sequences in FASTA format. Scores and prediction data are returned in the same window after submission. The user can obtain results in tab-delimited format for use in Excel or other programs.

Alignment feature:

The typical V3 in subtype B is 35 amino acids long, but length differences are frequent. The matrix in the current implementation is designed to score a 35 aa fragment. To obtain a correct score for length variants, it is important that homologous residues be in the correct position. Before sequences are scored, they are aligned against a HIV-1 subtype B consensus sequence using Needleman-Wunsch algorithm and a amino acid distance matrix. Gaps and insertions relative to the consensus are ignored in the scoring (this does not affect the predictions much, in general; see Jensen et al. 2003). If multiple best alignments are calculated, all these alignments are scored, and the actual scored sequences are displayed in the output.

Sequences which align poorly to the V3 consensus are flagged in the output. These sequences may not be actual V3 loops, or may be from a highly divergent subtype.

Matrices:

Two matrices are available for determining scores in subtype B: X4R5, calculated using sequences of known coreceptor phenotype, as assayed on indicator cells expressing exogenous CD4 and either CCR5 or CXCR4; and SINSI, calculated using sequences of known synctyium-inducing phenotype on the MT2 cell line. We have found that these matrices can give different phenotype predictions depending on sequence (see Jensen et al., 2003), and that correlations with disease progression (in preparation) and prognosis on HAART (Brumme et al., 2004) are better using SINSI scores. The reason for these differences appears to be that there are significant amino acid differences between X4 sequences and SI sequences, according to preliminary bioinformatic analyses. For subtype C only a SINSI matrix is available. Questions regarding matrices can be sent to Mark Jensen.

Citations:

• Jensen, M. A., F.-S. Li, A. B. van 't Wout, D. C. Nickle, D. Shriner, H.-X. He, S. McLaughlin, R. Shankarappa, J. B. Margolick, and J. I. Mullins. 2003. Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of HIV-1 env V3 loop sequences. Journal of Virology 77: 13376-13388.
• Brumme, Z. L., W. W. Dong, B. Yip, B. Wynhoven, N. G. Hoffman, R. Swanstrom, M. A. Jensen, J. I. Mullins, R. S. Hogg, J. S. Montaner, and P. R. Harrigan. 2004. Clinical and immunological impact of HIV envelope V3 sequence variation after starting initial triple antiretroviral therapy. AIDS 18: F1-F9.
• Jensen, M. A., M. Coetzer, A. B. van 't Wout, L. Morris, and J. I. Mullins. 2006. A reliable phenotype predictor for human immunodeficiency virus type 1 subtype C based on Envelope V3 sequences. Journal of Virology 80: 4698-4704.

Caveats:

The current implementation uses matrices derived using either subtype B or C sequences only, and have been tested only on phenotyped subtype B or C sequences respectively. Predictions for other subtypes should be treated with extreme skepticism. Matrices are planned for subtypes A and D. Contributions of V3 sequences with associated known phenotypes in these or any subtype would be greatly appreciated: please contact Mark Jensen