title: Immunologic and virologic evolution during periods of intermittent and persistent low-level viremia.
abstract: BACKGROUND
  HIV replication, HIV-specific T-cell responses and T-cell activation each contributes to disease outcome during untreated HIV infection. The interaction of these factors is not well understood, particularly in the setting of antiretroviral therapy.
  
  
  METHODS
  This is a longitudinal study of antiretroviral-treated patients with plasma HIV RNA levels < 1000 copies/ml. Patients were divided into three groups: suppressed viremia, intermittent viremia ('blips') and persistent low-level viremia. HIV-specific immunity was measured using interferon-gamma ELISPOT. T-cell activation was defined by CD38 and HLA-DR co-expression. Drug resistance was quantified using a phenotypic susceptibility assay.
  
  
  RESULTS
  The breadth and the magnitude of the HIV-specific CD8 T-cell response was greater in patients with either intermittent or persistent viremia compared to patients with suppressed viremia. In contrast, T-cell activation was significantly elevated only in those patients with persistent viremia. Patients with persistent low-level viremia had moderate levels of phenotypic antiretroviral drug resistance that increased over time. Virologic failure (confirmed increase in viral load > 1000 HIV RNA copies/ml) was primarily observed in the persistently viremic group.
  
  
  CONCLUSIONS
  Antiretroviral-treated individuals with intermittent viremia appear to mount an effective HIV-specific T-cell response while not experiencing increases in the level of immune activation. This may limit viral evolution and emergence of drug resistance. In contrast, antiretroviral-treated individuals with persistent low-level viremia exhibit significant increases in overall immune activation and a substantial risk of subsequent treatment failure. It is likely that higher viremia and stronger immune activation act synergistically to accelerate the development of systemic drug resistance.
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California, San Francisco, USA.
authors.forename: Annika C
authors.initials: AC
authors.lastname: Karlsson
authors.forename: Sophie R
authors.initials: SR
authors.lastname: Younger
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Martin
authors.forename: Zvi
authors.initials: Z
authors.lastname: Grossman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sinclair
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hunt
authors.forename: Elilta
authors.initials: E
authors.lastname: Hagos
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000096:biosynthesis; D008137:Longitudinal Studies; D008213:Lymphocyte Activation / Q000276:immunology; D012367:RNA, Viral / Q000097:blood; D014766:Viremia / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D007371:Interferon-gamma