Endogenous cytokine production protects T cells from spontaneous apoptosis during highly active antiretroviral therapy.
BACKGROUND
The availability of therapeutic regimens that effectively interfere with HIV-1 replication provides novel opportunities to investigate mechanisms of T-cell depletion as well as repopulation in infected individuals.


METHODS
Nineteen HIV-1-infected individuals were investigated during one-year follow-up of highly active retroviral therapy (HAART). The frequencies of apoptotic T cells, as determined by propidium iodide, staining, TUNEL assay and analysis of annexin V, were assessed either in the absence or in the presence of anti-interleukin (IL)2 and anti-IL-4 neutralizing Ab. Spontaneous and lectin-induced cytokine production were assessed by ELISA.


RESULTS
Increments of both naive and memory CD4 and CD8 T cells during HAART are accompanied by a decrease of T-cell apoptosis that, after 12 months of HAART, reaches normal levels. This is associated with increments of both spontaneous and activation-induced production of IL-2 and IL-4 by peripheral blood mononuclear cells (PBMCs), though only the latter was found defective at enrolment. During HAART, blocking of either IL-2 or IL-4 production by PBMCs using neutralizing Ab restores levels of T-cell apoptosis consistent with those determined at enrolment. These data suggest that both IL-2 and IL-4 produced by PBMCs during HAART provide anti-apoptotic signals that can contribute to an increased survival of T cells and may thus play a part in long-term immune reconstitution.


CONCLUSIONS
An effective viral suppression and, possibly, effects of PI on molecular targets other than viral components, can support a progressive normalization of T-cell survival that, at least in part, depends upon the restoration of proper soluble signals. These results provide evidence of a supporting role of endogenous cytokine production in peripheral T-cell repopulation during an effective and prolonged viral suppression. This may be relevant for the definition of immune-intervention targets aimed at immune reconstitution in HIV-1-infected patients.
Ensoli
F
F
Department of Allergy and Clinical Immunology, University of Rome 'La Sapienza', Rome, Italy. ensolifior@niroma1.it
Fiorelli
V
V
De Cristofaro
M
M
Collacchi
B
B
Santini Muratori
D
D
Alario
C
C
Sacco
G
G
Iebba
F
F
Aiuti
F
F
D000911:Antibodies, Monoclonal / Q000276:immunology; D023241:Antiretroviral Therapy, Highly Active; D017209:Apoptosis / Q000276:immunology*; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000276:immunology; D009500:Neutralization Tests; D013601:T-Lymphocytes / Q000378:metabolism*; D019562:Viral Load
D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D015847:Interleukin-4; D007371:Interferon-gamma