title: Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy.
abstract: BACKGROUND
  Persistently reduced CD4(+) T-lymphocyte counts in the face of undetectable HIV viremia are seen in a sizable percentage of HIV-infected patients undergoing antiretroviral therapy (ART). We analyzed the immune correlates of this phenomenon.
  
  
  METHODS
  Sixty-seven HIV-infected patients with undetectable viremia (<50 copies/microl) after more than 7 years of ART were enrolled in the study and divided into two groups (CD4 cell counts >500 cells/microl or <500 cells/microl). Duration of HIV infection (>16 years) was comparable. Peripheral blood mononuclear cell were stimulated with gag+env or with cytomegalovirus peptides. Activated T cells (Ki67(+)), Treg lymphocytes (CD4(+)/CD25high/Foxp3+), divided into naive and activated cells based on PD1 expression, interleukin (IL)-10 and transforming growth factor (TGF)-beta production, annexin V, activation of caspases 8 and 9, Toll-like receptor (TLR)2 and TLR4 expression on immune cells, and plasma lipopolysaccharide (LPS) concentration were analyzed.
  
  
  RESULTS
  CD4(+)/Ki67(+) T cells; plasma LPS; total, naive, and activated Treg; TLR2-expressing and TLR4-expressing Treg; IL-10 production; and early and late apoptotic CD4 T cells, were significantly increased in patients with undetectable viremia and CD4 cell counts less than 500 cells/microl after more than 7 years of ART. As previously shown, CD4 nadir were also lower in these individuals. Immune activation, LPS concentration, Treg, and degree of apoptosis were negatively correlated with CD4 cell counts.
  
  
  CONCLUSIONS
  Lack of CD4 recovery in individuals in whom ART suppresses HIV replication is associated with complex immune alterations. Immune activation, likely driven by altered gut permeability and resulting in augmented Treg activity could play a pivotal role in this process.
authors.affiliation: Department of Infectious Diseases of the Luigi Sacco Hospital, Milano, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Piconi
authors.forename: Daria
authors.initials: D
authors.lastname: Trabattoni
authors.forename: Andrea
authors.initials: A
authors.lastname: Gori
authors.forename: Serena
authors.initials: S
authors.lastname: Parisotto
authors.forename: Carlo
authors.initials: C
authors.lastname: Magni
authors.forename: Paola
authors.initials: P
authors.lastname: Meraviglia
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bandera
authors.forename: Amedeo
authors.initials: A
authors.lastname: Capetti
authors.forename: Giuliano
authors.initials: G
authors.lastname: Rizzardini
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D000328:Adult; D000368:Aged; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000276:immunology*; D019562:Viral Load
chemical_list: D012367:RNA, Viral