CD4 T-cell hyperactivation and susceptibility to cell death determine poor CD4 T-cell recovery during suppressive HAART.
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/mul) and 135 were considered 'concordant'. Comparative and logistic regression analyses were performed.


RESULTS
Discordant patients showed higher levels of activated [human leukocyte antigen (HLA)-DRCD95 and CD38CD45RA] 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 (CD45RACD31 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.


CONCLUSIONS
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.
Massanella
Marta
M
Fundació irsiCaixa-HIVACAT, Institut de Recerca en Ciències de la Salut Germans Trias i Pujol (IGTP), Hospital Germans Trias, Universitat Autònoma de Barcelona, Spain.
Negredo
Eugenia
E
Pérez-Alvarez
Nuria
N
Puig
Jordi
J
Ruiz-Hernández
Raul
R
Bofill
Margarita
M
Clotet
Bonaventura
B
Blanco
Julià
J
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012044:Regression Analysis; D019562:Viral Load