title: Lack of a significant impact of Gag-Protease-mediated HIV-1 replication capacity on clinical parameters in treatment-naive Japanese individuals.
abstract: BACKGROUND
  HLA class I-associated escape mutations in HIV-1 Gag can reduce viral replication, suggesting that associated fitness costs could impact HIV-1 disease progression. Previous studies in North American and African cohorts have reported reduced Gag-Protease mediated viral replication capacity (Gag-Pro RC) in individuals expressing protective HLA class I alleles including HLA-B*57:01, B*27:05, and B*81:01. These studies also reported significant positive associations between Gag-Pro RCs and plasma viral load (pVL). However, these HLA alleles are virtually absent in Japan, and the importance of Gag as an immune target is not clearly defined in this population.
  
  
  RESULTS
  We generated chimeric NL4-3 viruses carrying patient-derived Gag-Protease from 306 treatment-naive Japanese individuals chronically infected with HIV-1 subtype B. We analyzed associations between Gag-Pro RC and clinical markers of HIV-1 infection and host HLA expression. We observed no significant correlation between Gag-Pro RC and pVL in Japan in the overall cohort. However, upon exclusion of individuals expressing Japanese protective alleles HLA-B*52:01 and B*67:01, Gag-Pro RC correlated positively with pVL and negatively with CD4 T-cell count. Our results thus contrast with studies from other global cohorts reporting significantly lower Gag-Pro RC among persons expressing protective HLA alleles, and positive relationships between Gag-Pro RC and pVL in the overall study populations. We also identified five amino acids in Gag-Protease significantly associated with Gag-Pro RC, whose effects on RC were confirmed by site-directed mutagenesis. However, of the four mutations that decreased Gag-Pro RC, none were associated with reductions in pVL in Japan though two were associated with lower pVL in North America.
  
  
  CONCLUSIONS
  These data indicate that Gag fitness does not affect clinical outcomes in subjects with protective HLA class I alleles as well as the whole Japanese population. Moreover, the impact of Gag fitness costs on HIV-1 clinical parameters in chronic infection is likely low in Japan compared to other global populations.
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, 860-0811, Japan. sakai001@kumamoto-u.ac.jp.
authors.forename: Keiko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, 860-0811, Japan. tchikata@kumamoto-u.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Chikata
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada. zbrumme@sfu.ca.|Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada. zbrumme@sfu.ca.
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada. cbrumme@cfenet.ubc.ca.
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, 860-0811, Japan. higatana@acc.ncgm.go.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanag
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, 860-0811, Japan. oka@acc.ncgm.go.jp.|National Center for Global Health and Medicine, Tokyo, 162-8655, Japan. oka@acc.ncgm.go.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, 860-0811, Japan. masafumi@kumamoto-u.ac.jp.|International Research Center for Medical Sciences, Kumamoto University, Kumamoto, 860-0811, Japan. masafumi@kumamoto-u.ac.jp.|Nuffield Department of Medicine, University of Oxford, Oxford, UK. masafumi@kumamoto-u.ac.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
mesh_terms: D000328:Adult; D000483:Alleles; D018791:CD4 Lymphocyte Count; D002460:Cell Line; D018450:Disease Progression; D005260:Female; D005805:Genes, MHC Class I; D056084:Genetic Fitness; D015658:HIV Infections / Q000188:drug therapy / Q000208:ethnology / Q000276:immunology* / Q000821:virology*; D016333:HIV Protease / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015235:HLA-B Antigens / Q000276:immunology; D059950:HLA-B52 Antigen / Q000276:immunology; D006801:Humans; D007564:Japan; D008297:Male; D009154:Mutation; D009656:North America; D011993:Recombinant Fusion Proteins / Q000276:immunology; D019562:Viral Load; D014779:Virus Replication / Q000235:genetics; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D015235:HLA-B Antigens; C501279:HLA-B*52:01 antigen; D059950:HLA-B52 Antigen; C103707:HLA-B57 antigen; D011993:Recombinant Fusion Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1