Correlation between the degree of immune activation, production of IL-2 and FOXP3 expression in CD4+CD25+ T regulatory cells in HIV-1 infected persons under HAART.
Chronic immune activation is the leading event in the pathogenesis of HIV-1 infection and is associated with depletion of CD4+ T cells and Th1/Th2 imbalance. The role of Tregs in HIV infection is still controversial as these cells may control both immune activation and HIV-specific T cell responses. Aim of the present study was to correlate the degree of immune activation with FOXP3 expression and production of IL-2 and IL-10. Peripheral blood was obtained from 10 HIV-1-infected subjects with sustained response to HAART. Four cellular fractions were purified and simultaneously used in further experiments: PBMCs, CD4+CD45RO+, CD4+CD45RO+CD25- and CD4+CD45RO+CD25+. The level of immune activation was measured both by flow cytometry and radiometry as short-term 1-hour spontaneous lymphocyte proliferation; IL-2 and IL-10 production were determined by ELISA in supernatants of cultures non-stimulated or stimulated with PHA and p24 antigen. FOXP3 mRNA expression was detected by RT-PCR. A group of healthy subjects was used as control. Statistical analysis was performed by SPSS. The level of immune activation (total CD25 expression) was found correlated to both CD4+ and Tregs (CD4+CD25high+; FOXP3mRNA) and it was found higher in HIV-1 infected subjects in comparison to the healthy control group. The highest SLP-1 h was measured in the CD4+CD4+CD45RO+ CD25- population (T reg depleted), suggesting a role of Tregs in controlling immune activation during HIV-1 infection. In addition, CD4+ cells from HIV-infected individuals remained responsive to the negative regulation by Tregs (measured as IL-10 production) both spontaneously and upon stimulation. It is worth noting, however, that total PBMCs of these patients also responded well to specific antigen (p24) stimulation even though IL-2 release was impaired. The results obtained suggest that Tregs significantly influence the level of immune activation. At the same time, their function appears to be dependent on IL-2 production by the remaining T cells. These findings suggest that the control of Th1/Th2 balance could be an approach to immune-based therapy for HIV infection.
Terzieva
V
V
National Center for Infectious and Parasitic Diseases, Sofia, Bulgaria. terzieva@ncipd.org
Popova
D
D
Kicheva
M
M
Todorova
Y
Y
Markova
R
R
Martinova
F
F
Elenkov
I
I
Yankova
M
M
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D015704:CD4 Antigens; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D016655:HIV Core Protein p24 / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D019380:Anti-HIV Agents; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016655:HIV Core Protein p24; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10