title: Molecular and structural aspects of clinically relevant mutations related to the approved non-nucleoside inhibitors of HIV-1 reverse transcriptase.
abstract: In recent years relevant progress has been made in the treatment of HIV-1 with a consequent decrease in mortality. The availability of potent antiretroviral drugs and the ability of viral load assays that accurately evaluate the true level of viral replication, have led to a better understanding of pathogenesis of the disease and how to obtain improved therapeutic profiles. The highly active antiretroviral therapy (HAART), based on a combination of three or more antiretroviral drugs, has radically changed the clinical outcome of HIV. In particular, reverse transcriptase non-nucleoside inhibitors (NNRTIs) play an essential role in most protocols and are often used in first line treatment. The high specificity of these inhibitors towards HIV-1 has increased the number of structural and molecular modeling studies of enzyme complexes and that have led to chemical syntheses of more selective second and third-generation NNRTIs. However, a considerable percentage of new HIV-1 infections are caused by the emergence of drug-resistant mutant viruses that complicate treatment strategies. In this review we discuss relevant clinical and structural aspects for the management of antiretroviral drug resistance, with detailed explanations of mechanisms and mutation patterns useful to better understand the relation between drug resistance and therapy failure.
authors.affiliation: Laboratorio di Chimica Farmaceutica Computazionale, Dipartimento di Scienze Farmacobiologiche Università"Magna Græcia" di Catanzaro, Campus Universitario, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.forename: Claudia
authors.initials: C
authors.lastname: Alteri
authors.forename: Anna
authors.initials: A
authors.lastname: Artese
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: Giosuè
authors.initials: G
authors.lastname: Costa
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.forename: Lucia
authors.initials: L
authors.lastname: Parrotta
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
mesh_terms: D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009705:Nucleosides / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase