title: Mechanisms of HIV non-progression; robust and sustained CD4+ T-cell proliferative responses to p24 antigen correlate with control of viraemia and lack of disease progression after long-term transfusion-acquired HIV-1 infection.
abstract: BACKGROUND
  Elite non-progressors (plasma viral load < 50 copies/ml while antiretroviral naive) constitute a tiny fraction of HIV-infected individuals. After 12 years follow-up of a cohort of 13 long-term non-progressors (LTNP) identified from 135 individuals with transfusion-acquired HIV infection, 5 remained LTNP after 23 to 26 years infection, but only 3 retained elite LTNP status. We examined the mechanisms that differentiated delayed progressors from LTNP in this cohort.
  
  
  RESULTS
  A survival advantage was conferred on 12 of 13 subjects, who had at least one host genetic factor (HLA, chemokine receptor or TLR polymorphisms) or viral attenuating factor (defective nef) associated with slow progression. However, antiviral immune responses differentiated the course of disease into and beyond the second decade of infection. A stable p24-specific proliferative response was associated with control of viraemia and retention of non-progressor status, but this p24 response was absent or declined in viraemic subjects. Strong Gag-dominant cytotoxic T lymphocyte (CTL) responses were identified in most LTNP, or Pol dominant-CTL in those with nef-defective HIV infection. CTL were associated with control of viraemia when combined with p24 proliferative responses. However, CTL did not prevent late disease progression. Individuals with sustained viral suppression had CTL recognising numerous Gag epitopes, while strong but restricted responses to one or two immunodominant epitopes was effective for some time, but failed to contain viraemia over the course of this study. Viral escape mutants at a HLA B27-restricted Gag-p24 epitope were detected in only 1 of 3 individuals, whereas declining or negative p24 proliferative responses occurred in all 3 concurrent with an increase in viraemia.
  
  
  CONCLUSIONS
  Detectable viraemia at study entry was predictive of loss of LTNP status and/or disease progression in 6 of 8, and differentiated slow progressors from elite LTNP who retained potent virological control. Sustained immunological suppression of viraemia was independently associated with preserved p24 proliferative responses, regardless of the strength and breadth of the CTL response. A decline in this protective p24 response preceded or correlated with loss of non-progressor status and/or signs of disease progression.
authors.affiliation: Australian Red Cross Blood Service, 153 Clarence Street, Sydney, NSW 2000, Australia. wdyer@arcbs.redcross.org.au
authors.forename: Wayne B
authors.initials: WB
authors.lastname: Dyer
authors.forename: John J
authors.initials: JJ
authors.lastname: Zaunders
authors.forename: Fang Fang
authors.initials: FF
authors.lastname: Yuan
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Learmont
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Geczy
authors.forename: Nitin K
authors.initials: NK
authors.lastname: Saksena
authors.forename: Dale A
authors.initials: DA
authors.lastname: McPhee
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.forename: John S
authors.initials: JS
authors.lastname: Sullivan
mesh_terms: D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D018450:Disease Progression; D015683:Gene Products, gag / Q000737:chemistry; D016655:HIV Core Protein p24 / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D012367:RNA, Viral / Q000097:blood; D065227:Transfusion Reaction; D019562:Viral Load; D014766:Viremia / Q000276:immunology* / Q000821:virology
chemical_list: D015683:Gene Products, gag; D016655:HIV Core Protein p24; D012367:RNA, Viral; C514799:p24 protein, Human Immunodeficiency Virus Type 1