title: Functional conservation of HIV-1 Gag: implications for rational drug design.
abstract: BACKGROUND
  HIV-1 replication can be successfully blocked by targeting gag gene products, offering a promising strategy for new drug classes that complement current HIV-1 treatment options. However, naturally occurring polymorphisms at drug binding sites can severely compromise HIV-1 susceptibility to gag inhibitors in clinical and experimental studies. Therefore, a comprehensive understanding of gag natural diversity is needed.
  
  
  RESULTS
  We analyzed the degree of functional conservation in 10862 full-length gag sequences across 8 major HIV-1 subtypes and identified the impact of natural variation on known drug binding positions targeted by more than 20 gag inhibitors published to date. Complete conservation across all subtypes was detected in 147 (29%) out of 500 gag positions, with the highest level of conservation observed in capsid protein. Almost half (41%) of the 136 known drug binding positions were completely conserved, but all inhibitors were confronted with naturally occurring polymorphisms in their binding sites, some of which correlated with HIV-1 subtype. Integration of sequence and structural information revealed one drug binding pocket with minimal genetic variability, which is situated at the N-terminal domain of the capsid protein.
  
  
  CONCLUSIONS
  This first large-scale analysis of full-length HIV-1 gag provided a detailed mapping of natural diversity across major subtypes and highlighted the considerable variation in current drug binding sites. Our results contribute to the optimization of gag inhibitors in rational drug design, given that drug binding sites should ideally be conserved across all HIV-1 subtypes.
authors.affiliation: Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium. Kristof.Theys@rega.kuleuven.be.
authors.forename: Guangdi
authors.initials: G
authors.lastname: Li
authors.forename: Jens
authors.initials: J
authors.lastname: Verheyen
authors.forename: Soo-Yon
authors.initials: SY
authors.lastname: Rhee
authors.forename: Arnout
authors.initials: A
authors.lastname: Voet
authors.forename: Anne-Mieke
authors.initials: AM
authors.lastname: Vandamme
authors.forename: Kristof
authors.initials: K
authors.lastname: Theys
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000302:isolation & purification / Q000494:pharmacology; D015195:Drug Design; D014644:Genetic Variation; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D020125:Mutation, Missense; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D054301:gag Gene Products, Human Immunodeficiency Virus