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Abstract:
HIV infects target cells by binding of its envelope gp120 protein to CD4 and a
coreceptor on the cell surface. In vivo, the different HIV-strains use either
CCR5 or CXCR4 as coreceptor. CCR5-using strains are named R5 viruses, while
CXCR4-using strains are named X4. X4 viruses usually occur in the later stages.
Coreceptor usage is a marker for disease progression. Additionally interest on
coreceptors continually raises as a consequence of the development of a new
class of antiretroviral drugs, namely the coreceptor antagonists or blockers.
These specific drugs block the CCR5 or the CXCR4 coreceptors. So far, the CXCR4
blockers are not allowed to be used in the clinical practice due to their
severe side effects. On the other hand, CCR5 blockers are currently in clinical
practice, although they can only be administered after a baseline determination
of the coreceptor usage of the predominant viral strain. Most of the coreceptor
analyses in clinical cohorts have been performed with commercially available
phenotypic assays. As for resistance testing of NRTIs, NNRTIs and PIs, efforts
have also been made to predict the coreceptor usage from the genotype of the
viruses. Different rules have been published based on the amino acid sequence
of the Env-V3 region of HIV-gp120, which is known to be the major determinant
of coreceptor usage. Among these, the most widely used is the 11/25 rule.
Recently, bioinformatics driven prediction systems have been developed. Three
of the interpretation systems are freely available via internet: WetCat,
WebPSSM, geno2pheno[coreceptor]. All three systems focus on the Env-V3 region
and take the amino acid sequence only into account. They learn from phenotypic
and corresponding genotypic data. So far, two cohorts have been analyzed with
such a genotypic approach and provided frequencies of R5 virus strains that are
within the range of those reported with phenotypic assays. For one of the
systems, geno2pheno[coreceptor], additional clinical data (e.g. CD4+T-cell
counts) or structural information can be used to improve the prediction. Such
genotypic systems provide the possibility for rapid screening of patients who
may be administered with CCR5 blockers like the recently licensed Maraviroc.
