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Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy

Piconi, Stefaniaa,*; Trabattoni, Dariac,*; Gori, Andreab; Parisotto, Serenac; Magni, Carloa; Meraviglia, Paolaa; Bandera, Alessandrab; Capetti, Amedeoa; Rizzardini, Giulianoa; Clerici, Marioc,d

doi: 10.1097/QAD.0b013e32833c93ce
Basic Science

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.

Materials and methods: Sixty-seven HIV-infected patients with undetectable viremia (<50 copies/μl) after more than 7 years of ART were enrolled in the study and divided into two groups (CD4 cell counts >500 cells/μl or <500 cells/μl). 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)-β 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/μl 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.

Conclusion: 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.

aDepartments of Infectious Diseases of the Luigi Sacco Hospital, Milano, Italy

bSan Gerardo, Hospital, Monza, Italy

cChair of Immunology, University of Milano, Milano, Italy

dFondazione Don C. Gnocchi, IRCCS, Milano, Italy.

*S. Piconi and D.T. contributed equally to the writing of this article.

Received 21 December, 2009

Revised 5 May, 2010

Accepted 27 May, 2010

Correspondence to Mario Clerici, MD, Chair of Immunology, University of Milano, Department of Biomedical Sciences and Technologies, Via F.lli Cervi 93; 20090 Segrate (Milano), Italy. Tel: +39 02 50319679; fax: +39 02 50319677; e-mail: mario.clerici@unimi.it

© 2010 Lippincott Williams & Wilkins, Inc.