title: CD4+ T-cell recovery with suppressive ART-induced rapid sequence evolution in hepatitis C virus envelope but not NS3.
abstract: OBJECTIVE
  CD4 T-cell depletion from HIV infection leads to a global decline in anti-hepatitis C virus (HCV) envelope neutralizing antibody (nAb) response, which may play a role in accelerating liver fibrosis. An increase in anti-HCV nAb titers has been reported during antiretroviral therapy (ART) but its impact on HCV remains poorly understood. The objective of this study is to determine the effects of ART on long-term HCV evolution.
  
  
  METHODS
  We examined HCV quasispecies structure and long-term evolution in HIV/HCV coinfected patients with ART-induced CD4 T-cell recovery, and compared with patients with CD4 T-cell depletion from delayed ART. We applied a single-variant sequencing (SVS) method to construct authentic viral quasispecies and compared sequence evolution in HCV envelope, the primary target for humoral immune responses, and NS3, a target for cellular immunity, between the two cohorts.
  
  
  RESULTS
  The SVS method corrected biases known to skew the proportions of viral variants, revealing authentic HCV quasispeices structures. We observed higher rates of HCV envelope sequence evolution in patients with ART-induced CD4 T-cell recovery, compared with patients with CD4 T-cell depletion from delayed ART (P = 0.03). Evolutionary rates for NS3 were considerably lower than the rates for envelope (P < 0.01), with no significant difference observed between the two groups.
  
  
  CONCLUSIONS
  ART-induced CD4 T-cell recovery results in rapid sequence evolution in HCV envelope, but not in NS3. These results suggest that suppressive ART disproportionally enhances HCV-specific humoral responses more than cellular responses, resulting in rapid sequence evolution in HCV envelope but not NS3.
authors.affiliation: aDivision of Infectious Diseases and Global Medicine, Department of Medicine bDepartment of Pharmacology, University of Florida College of Medicine cNorth Florida/South Georgia Veterans Health System, Gainesville, Florida, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: David
authors.initials: D
authors.lastname: Nardo
authors.forename: Eric
authors.initials: E
authors.lastname: Li
authors.forename: Gary P
authors.initials: GP
authors.lastname: Wang
mesh_terms: D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019143:Evolution, Molecular; D015686:Gene Products, env / Q000235:genetics*; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D016174:Hepacivirus / Q000145:classification / Q000235:genetics*; D018937:Hepatitis C Antibodies / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology / Q000821:virology*; D006801:Humans; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D044966:Anti-Retroviral Agents; D057134:Antibodies, Neutralizing; D015686:Gene Products, env; D018937:Hepatitis C Antibodies; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases