title: Protease polymorphisms in HIV-1 subtype CRF01_AE represent selection by antiretroviral therapy and host immune pressure.
abstract: BACKGROUND
  Most of our knowledge about how antiretrovirals and host immune responses influence the HIV-1 protease gene is derived from studies of subtype B virus. We investigated the effect of protease resistance-associated mutations (PRAMs) and population-based HLA haplotype frequencies on polymorphisms found in CRF01_AE pro.
  
  
  METHODS
  We used all CRF01_AE protease sequences retrieved from the LANL database and obtained regional HLA frequencies from the dbMHC database. Polymorphisms and major PRAMs in the sequences were identified using the Stanford Resistance Database, and we performed phylogenetic and selection analyses using HyPhy. HLA binding affinities were estimated using the Immune Epitope Database and Analysis.
  
  
  RESULTS
  Overall, 99% of CRF01_AE sequences had at least 1 polymorphism and 10% had at least 1 major PRAM. Three polymorphisms (L10 V, K20RMI and I62 V) were associated with the presence of a major PRAM (P < 0.05). Compared to the subtype B consensus, six additional polymorphisms (I13 V, E35D, M36I, R41K, H69K, L89M) were identified in the CRF01_AE consensus; all but L89M were located within epitopes recognized by HLA class I alleles. Of the predominant HLA haplotypes in the Asian regions of CRF01_AE origin, 80% were positively associated with the observed polymorphisms, and estimated HLA binding affinity was estimated to decrease 19-40 fold with the observed polymorphisms at positions 35, 36 and 41.
  
  
  CONCLUSIONS
  Polymorphisms in CRF01_AE protease gene were common, and polymorphisms at residues 10, 20 and 62 most likely represent selection by use of protease inhibitors, whereas R41K and H69K were more likely attributable to recognition of epitopes by the HLA haplotypes of the host population.
authors.affiliation: University of California San Diego, La Jolla, California, USA. drweerawat@hotmail.com
authors.forename: Weerawat
authors.initials: W
authors.lastname: Manosuthi
authors.forename: David M
authors.initials: DM
authors.lastname: Butler
authors.forename: Josué
authors.initials: J
authors.lastname: Pérez-Santiago
authors.forename: Art Fy
authors.initials: AF
authors.lastname: Poon
authors.forename: Satish K
authors.initials: SK
authors.lastname: Pillai
authors.forename: Sanjay R
authors.initials: SR
authors.lastname: Mehta
authors.forename: Mary E
authors.initials: ME
authors.lastname: Pacold
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Richman
authors.forename: Sergei Kosakovsky
authors.initials: SK
authors.lastname: Pond
authors.forename: Davey M
authors.initials: DM
authors.lastname: Smith
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D044466:Asian People; D024882:Drug Resistance, Viral / Q000235:genetics* / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D016333:HIV Protease / Q000235:genetics*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic
chemical_list: D044966:Anti-Retroviral Agents; D016333:HIV Protease