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Sequencing guide HIV- RT and Protease Sequencing for Drug Resistance Studies Reviews A Guide to HIV- Reverse Transcriptase and Protease Sequencing for Drug Resistance Studies Robert W Shafer Kathryn Dupnik Mark A Winters Susan H Eshleman Division of Infec

HIV- RT and Protease Sequencing for Drug Resistance Studies Reviews A Guide to HIV- Reverse Transcriptase and Protease Sequencing for Drug Resistance Studies Robert W Shafer Kathryn Dupnik Mark A Winters Susan H Eshleman Division of Infectious Diseases Stanford University Stanford CA Dept of Pathology The Johns Hopkins Medical Institutions Baltimore MD I HIV- Drug Resistance A Introduction HIV- RT and protease sequencing and drug susceptibility testing have been done in research settings for more than ten years to elucidate the genetic mechanisms of resistance to antiretroviral drugs Retrospective studies have shown that the presence of drug resistance before starting a new drug regimen is an independent predictor of virologic response to that regimen DeGruttola et al Hanna and D ? Aquila Haubrich and Demeter Prospective studies have shown that patients whose physicians have access to drug resistance data particularly genotypic resistance data respond better to therapy than control patients whose physicians do not have access to the same data Baxter et al Cohen et al De Luca et al Durant et al Melnick et al Meynard et al Tural et al The accumulation of retrospective and prospective data has led three expert panels to recommend the use of resistance testing in the treatment of HIV-infected patients EuroGuidelines Group for HIV Resistance Hirsch et al US Department of Health and Human Services Panel on Clinical Practices for Treatment of HIV Infection Table There have been several recent reviews on methods for assessing HIV- drug resistance Demeter and Haubrich Hanna and D ? Aquila Richman and on the mutations associated with drug resistance Deeks Hammond et al Loveday Miller Shafer et al b This review will detail the use of HIV- genotypic resistance testing in research settings where it is used to learn about the mechanisms and clinical signi ?cance of drug resistance and in clinical settings where it is used to help guide anti-HIV treatment B Evolution of HIV- drug resistance The evolution of HIV- drug resistance within an individual depends on the generation of genetic variation in the virus and on the selection of drug- resistant variants during therapy HIV- genetic variability is a result of the inability of HIV- RT to proofread nucleotide sequences during replication Mansky It is exacerbated by the high rate of HIV- replication in vivo the accumulation of proviral variants during the course of HIV- infection and genetic recombination when viruses with di ?erent sequences infect the same cell As a result innumerable genetically distinct variants quasispecies evolve in individuals in the months following primary infection Co ?n The HIV- quasispecies in an individual undergoes continuous genetic variation competition and selection Development of drug resistance depends on the size and heterogeneity of the HIV- population within an individual the extent to which virus replication continues during drug therapy the ease of acquisition of a particular mutation or set of mutations and the e ?ect of drug-resistance mutations on drug susceptibility and virus ?tness Some mutations selected during drug therapy confer measurable phenotypic resistance by