Structural mechanisms of HIV drug resistance.
Antiviral therapy for AIDS has focused on the discovery and design of inhibitors for two main enzyme targets of the human immunodeficiency virus type 1 (HIV)--reverse transcriptase (RT) and protease (PR). Despite several classes of promising new anti-HIV agents, the clinical emergence of drug-resistant variants of HIV has severely limited the long-term effectiveness of these drugs. Genetic analysis of resistant virus has identified a number of critical mutations in the RT and PR genes. Structural analysis of inhibitor-enzyme complexes and mutational modeling studies are leading to a better understanding of how these drug-resistance mutations exert their effects at a structural level. These insights have implications of the design of new drugs and therapeutic strategies to combat drug resistance to AIDS.
Erickson
J W
JW
Structural Biochemistry Program, Frederick Biomedical Supercomputing Center, SAIC-Frederick, NCI-Frederick Cancer Research and Development Center, Maryland 21702, USA.
Burt
S K
SK
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004352:Drug Resistance, Microbial / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D016333:HIV Protease