Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CD4 T-cell hyperactivation and susceptibility to cell death determine poor CD4 T-cell recovery during suppressive HAART Marta Massanella a,M , Eugenia Negredo b,M , Nuria Pe ´rez-A ´ lvarez b,c , Jordi Puig b , Raul Ruiz-Herna ´ndez a , Margarita Bofill a,d , Bonaventura Clotet a,b and Julia ` Blanco a Background: The failure to increase CD4 T-cell counts in some HAART-treated HIV- infected patients with satisfactory virological responses has been related to low CD4 T-cell production, high turnover and death. However, the relative contribution of these factors is still unclear, strongly limiting the definition of appropriate therapeutic strategies for these patients. Methods: A cross-sectional study was designed to evaluate the contribution of thymic activity, microbial translocation, cellular activation and death to CD4 T-cell recovery. We included 230 HIV-infected individuals on suppressive HAART (>2 years); 95 of them were considered ‘discordant’ (CD4 T-cell count <350 cells/ml) and 135 were considered ‘concordant’. Comparative and logistic regression analyses were performed. Results: Discordant patients showed higher levels of activated [human leukocyte antigen (HLA)-DR þ CD95 þ and CD38 þ CD45RA  ] cells in both the CD8 and CD4 T-cell compartments. Notably, the most significant differences were observed in CD4 T cells. Discordant patients showed lower naive CD4 T-cell production (CD45RA þ CD31 þ cells), higher spontaneous ex-vivo CD4 T-cell death and higher plasma levels of soluble CD14. Multivariate analysis showed that activation and death of CD4 T cells, along with nadir CD4 T-cell counts, were the only predictive factors for poor immune recovery. Moreover, the low correlations found between CD4 T-cell activation or death with thymic output and bacterial translocation suggest that additional factors modulate cellular activation and death and, in turn, CD4 T-cell recovery. Conclusion: CD4 T-cell repopulation during HAART is determined by CD4 T-cell activation and death. Therefore, strategies aimed to reduce these parameters should be envisaged to treat discordant patients. ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2010, 24:959–968 Keywords: bacterial translocation, cell death, discordant patients, immune activation, thymus a Fundacio ´ irsiCaixa-HIVACAT, Institut de Recerca en Cie `ncies de la Salut Germans Trias i Pujol (IGTP), Hospital Germans Trias, Universitat Auto ` noma de Barcelona, b Lluita contra la SIDA Foundation, Institut de Recerca en Cie ` ncies de la Salut Germans Trias i Pujol, Hospital Universitari Germans Trias i Pujol, Universitat Auto ` noma de Barcelona, Badalona, Catalonia, c Statistics and Operation Research Department, Universitat Polite `cnica de Catalunya, and d Institucio ´ Catalana de Recerca i Estudis Avanc ¸ats, ICREA, Barcelona, Spain. Correspondence to Julia ` Blanco, Retrovirology Laboratory, Fundacio ´ irsiCaixa, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Catalonia, Barcelona, Spain. Tel: +34 93 4656374; fax: +34 93 4653968; e-mail: jblanco@irsicaixa.es  M.M. and E.N. contributed equally to the writing of this article. Received: 18 November 2009; revised: 18 January 2010; accepted: 19 January 2010. DOI:10.1097/QAD.0b013e328337b957 ISSN 0269-9370 Q 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins 959