Mechanisms involved in CD4 cell gains in HIV-infected patients switched to raltegravir.
BACKGROUND
CD4 gains in HIV patients on HAART result from release of T cells recently migrated from the thymus, redistribution from lymphoid tissues, proliferation in the periphery and/or reduced apoptosis. The relative contribution of each mechanism in CD4 restoration in patients with suppressed viremia switching antiretrovirals is unclear.


METHODS
HIV patients with undetectable viremia on HAART were identified at our clinic. A subset switched to raltegravir was compared with another group that kept therapy unmodified. Naive and memory CD4 T-cells were measured by flow cytometry using CD45RA and CD27, respectively. Activation was examined using CD38 and recent thymic emigrants using CD31. Apoptosis was analyzed measuring soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL).


RESULTS
Thirty-seven patients were examined, 19 switched to raltegravir and 18 controls, after a median of 26 months of suppressed viremia. At 6 months, mean CD4 cell counts significantly increased in raltegravir patients from 322 to 448 cells/μl (P = 0.026) but not in controls (from 312 to 330 cells/μl; P  = 0.813). No significant changes were recognized in activation or CD31 expression in any group. In raltegravir patients, however, the proportion of naive CD4 T cells significantly increased (P = 0.014) as well as CD38 expression in these cells (P = 0.036). A positive correlation was found between CD38 and CD31 expression in naive CD4 T cells (R  = 0.51, P < 0.001). TRAIL and FasL did not decline significantly in any group.


CONCLUSIONS
HIV patients with prolonged undetectable viremia on HAART experience more pronounced CD4 gains after raltegravir switching than keeping the same regimen. An increased production of naive CD4 T cells largely explains this effect.
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
Carolina
C
Garrido
Norma
N
Rallón
Vincent
V
Soriano
Mariola
M
Lopez
Natalia
N
Zahonero
Carmen
C
de Mendoza
Jose M
JM
Benito
D051997:ADP-ribosyl Cyclase 1 / Q000187:drug effects / Q000276:immunology; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D053222:Fas Ligand Protein / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D017493:Leukocyte Common Antigens / Q000187:drug effects / Q000276:immunology; D008875:Middle Aged; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects / Q000276:immunology; D011760:Pyrrolidinones / Q000627:therapeutic use*; D000068898:Raltegravir Potassium; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000187:drug effects / Q000276:immunology
D053222:Fas Ligand Protein; D019428:HIV Integrase Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011760:Pyrrolidinones; D053221:TNF-Related Apoptosis-Inducing Ligand; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D000068898:Raltegravir Potassium; D017493:Leukocyte Common Antigens; D051997:ADP-ribosyl Cyclase 1