Official websites use. Share sensitive information only on official, secure websites. Address correspondence to Miguel E. With 29 individual antiretroviral drugs available from six classes that are approved for the treatment of HIV-1 infection, a combination of different phenotypic and genotypic tests is currently needed to monitor HIV-infected individuals.
This comprehensive test, the first of its class, will be instrumental in the development of new antiretroviral drugs and, more importantly, will aid in the treatment and management of HIV-infected individuals. Not only has this broader access to antiretroviral drugs led to considerable reductions in morbidity and mortality 2 , 3 , but unfortunately, it has increased the risk of virologic failure due to the emergence 3 , 4 and potential transmission 5 of drug-resistant viruses.
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Therefore, detecting and quantifying drug resistance, and in the case of CCR5 receptor antagonists, determining HIV-1 coreceptor tropism, have become the standard of care prior to designing new antiretroviral regimens 3 , 6 — 8. To date, 29 individual antiretroviral drugs from six drug classes have been approved by the U. HIV-1 resistance to PI, NRTI, NNRTI, and INI can be determined using i indirect methods based on the detection of specific amino acid substitutions due to underlying nucleotide mutations in the respective coding regions previously associated with resistance to specific antiretroviral drugs i.
Similarly, since treatment with CCR5 antagonists requires prior knowledge of the HIV-1 coreceptor tropism in the patient, i. Phenotypic assays to determine HIV-1 drug resistance or tropism usually involve the generation of patient-derived pol 11 — 13 or env recombinant 18 — 20 viruses, respectively, to quantify their ability to infect susceptible cell lines expressing the appropriate HIV-1 receptors and coreceptors; in the case of HIV-1 tropism, these measures may also be based on the quantification of cell-to-cell fusion events 21 — Conversely, genotypic HIV-1 tropism tests 8 , 15 , 16 , 24 — 26 take advantage of the properties of specific regions in the env gene as determinants of CCR5 or CXCR4 tropism, mainly the V3 region of gp, and their interpretations are based on a series of bioinformatics methods to infer the ability of HIV-1 to use either or both coreceptors to enter host cells 27 — As expected, phenotypic experimental and genotypic computational approaches to determining HIV-1 drug resistance or HIV-1 coreceptor tropism have some disadvantages, including the longer turnaround times and higher cost of the phenotypic assays or the intrinsic predictive nature of the genotypic tests.
Particular emphasis has been made on the limited sensitivities of genotypic HIV-1 tropism assays to detect minor non-R5 variants 16 , 31 , and to a lesser extent on the ability of genotypic HIV-1 drug resistance tests to detect minority drug-resistant variants 32 — In the case of HIV-1 drug resistance, the vast amount of information accumulated during the last 2 decades by correlating mutations with phenotypic data has led to the almost exclusive use of genotypic antiretroviral testing based on population Sanger sequencing to manage patients infected with HIV-1 2 , In contrast, although several studies have shown significant concordance and similar predictive values 36 — 40 , genotypic HIV-1 tropism assays based on population sequencing seem to be less sensitive and specific than phenotypic assays 8 , 16 , 17 , Thus, a cell-based assay Trofile; Monogram Biosciences 19 , 42 is currently the standard method in the United States for determining HIV-1 coreceptor tropism, while genotypic HIV-1 tropism tests are largely used in Europe 16 , However, and although this is still uncertain, drug-resistant HIV-1 minority variants i.
