Introduction Human immunodeficiency virus (HIV) infects immune system cells by binding cell-surface CD4 and one of two coreceptors, CCR5 or CXCR4. Maraviroc (MVC) is an anti-HIV drug that binds to CCR5 and blocks HIV entry. Because MVC is ineffective against CXCR4-using viruses, it is only prescribed to patients shown to exclusively harbour CCR5-using viruses. The major obstacles to MVC being more widely used in anti-HIV therapies are (i) traditional pre-treatment prognostic “tropism tests” to determine CCR5- or CXCR4-usage are expensive and time consuming, and (ii) cheaper and rapid genotypic tropism tests have been developed only for subtype B viruses, which account for only 10% of infections worldwide. We developed PhenoSeq, a suite of reliable genotypic tropism tests for the major HIV subtypes; A, B, C, D and circulating recombinant forms of AE (CRF01_AE) and AG (CRF02_AG), which together account for 95% of infections worldwide.
Methods Development of genotypic tropism tests was informed by analysis of all previously published HIV genetic sequences with corresponding coreceptor usage and subtype data (n = 2257; 630 CXCR4-using and 1637 CCR5-using), to elucidate statistically significant mutations that distinguish CXCR4- from CCR5-using viruses. The accuracy of PhenoSeq was validated against independent HIV sequences from patients previously enrolled in phase III MVC clinical trials (A4001064 and MERIT), relative to phenotypic tropism tests results.
Results PhenoSeq genotypic algorithms exhibited more favourable sensitivity and specificity profiles for establishing CCR5- or CXCR4-usage of HIV subtypes A, B, C, D, CRF01_AE and CRF02_AG than alternative algorithms, including in-use algorithms geno2pheno and WebPSSM (two tailed t-test, p ≤ 0.05 considered significant).
Conclusion As the only platform of algorithms that reliably infer tropism of all major global HIV subtypes, PhenoSeq may inform the use of MVC and future CCR5 blocking drugs, in particular for regions burdened most by the HIV pandemic, where non-B HIV predominates.
Disclosure of interest statement JFD and FD are employees of ViiV Healthcare. PRG is a former member of the ViiV Australia scientific advisory board and has received honoraria. KC and PRG have received funding from ViiV Healthcare Australia for conference travel. KC and PRG presently receive research funding from ViiV Healthcare to further develop PhenoSeq algorithms. PRH is supported by CIHR/GSK Research Chair in Clinical Virology and has consulted and/or received grant funding from a variety pharmaceutical diagnostic companies and has received grants from, served as an ad hoc advisor to, or spoke at various events sponsored by: Pfizer, Glaxo-Smith Kline, Abbott, Merck, Selah, Tobira, Virco and Quest Diagnostics.
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