TH1 and TH2 Cytokine mRNA and Protein Levels in Human Immunodeficiency Virus (HIV)-Seropositive and HIV-Seronegative Youths

Abstract

The roles of cytokines in the progression of human immunodeficiency virus (HIV)-associated disease are controversial. The patterns of innate cytokine production have been postulated to shift from TH1-to TH2-type cytokines with the progression of HIV-associated disease. Although there have been studies of cytokines in children and adults, no data are available on cytokine production in healthy or HIV-infected adolescents. We analyzed and characterized cytokine mRNA and protein levels for gamma interferon, interleukin 2 (IL-2), IL-4, and tumor necrosis factor alpha and protein levels of IL-6 in both stimulated and unstimulated peripheral blood mononuclear cells obtained from a large longitudinal, observational cohort study of HIV-seropositive and -seronegative adolescents. We correlated cytokine results with viral load and CD4 ؉ -T-cell counts as critical markers of disease progression in HIV-infected adolescents. These data were used to examine hypotheses related to the TH1-to-TH2 cytokine shift in a sample of HIV-infected adolescents. Five hundred twenty subjects participating in the REACH (Reaching for Excellence in Adolescent Care and Health) Project of the Adolescent Medicine HIV/AIDS Research Network contributed blood samples. Samples selected for the cross-sectional data set analyzed had to meet selection criteria developed to minimize the potential confounding effects of acute intercurrent illnesses or infections, recent vaccination for hepatitis, and altered hormone status and to optimize congruence of cytokine measurements with assays of viral load and CD4؉ -T-cell counts. Group differences in the proportions of subjects with detectable levels of each cytokine marker were compared. In the subset of subjects with detectable cytokine values, differences in detected values were compared across subgroups defined by HIV serostatus and among HIV-seropositive subjects by three viral load classifications. The study sample was 65% HIV seropositive, 71% African-American, and 75% female with a mean age of 17.4 years. HIV-seropositive subjects were relatively healthy with mean and median CD4؉ -T-cell counts of 534 and 499 cells/mm 3 , respectively. Only 8.1% of subjects had CD4 ؉ -T-cell counts below 200 cells/mm 3 , and 25% had viral loads that were below the threshold of detection (<400 copies/ml). Detailed analyses of these data indicate that there were no differences in cytokines detected in HIV-seropositive and HIV-seronegative adolescents, and there was no apparent relationship between the cytokine measurements and the viral load or CD4؉ -T-cell categorization, the parameters selected as markers of HIV-associated disease status. These adolescents, including the HIV-seropositive subjects, were relatively healthy, and the HIV-infected subjects were at an early stage in the course of their HIV-associated disease. On the basis of our data, we conclude that, early in the course of HIV-associated disease in adolescents, there are no detectable shifts from TH1 to TH2 cytokine production.

Identification of Three Immunologic Correlates for HIV Type 1 Pathogenesis in Youth

“…The results were highly reproducible (coefficients of variation <20% in >80% of test samples). Testing of the first eight analytes was based on (1) initial screening of 42 analytes (representing T H 1 and T H 2 cytokines, C-X-C and C-C motif chemokines, growth factors, as well as markers of inflammation and angiogenesis) using the Human Cytokine Array III (RayBiotech Inc., Norcross GA), 33 (2) dismissal of IFN-g, IL-2, IL-4, IL-6, and tumor necrosis factor alpha (TNF-a) as informative markers of HIV-1 pathogenesis in the REACH cohort, 34 (3) analysis of serum samples from the REACH cohort, 26 and (4) successful quantification in over 90% of samples from HIV-1 þ youth. Inclusion of C-reactive protein (CRP) was based on its frequent recognition as a reliable marker of chronic inflammation related to various immune disorders.…”

Expression of γ‐chain cytokine receptors on CD8+ T cells in HIV infection with a focus on IL‐7Rα (CD127)

“…Another γ C cytokine whose production is increased in HIV infection is IL‐4 83 , 84 , 85 , 86 , 87 . It is thought that IL‐4‐mediated Th2 responses contribute to the onset of AIDS 88 .…”

Teaching tired T cells to fight HIV: time to test IL-15 for immunotherapy?

“…Type 1 cytokines, generally, are decreased with the progression of HIV disease, whereas type 2 cytokines are increased. However, some authors have shown that there are no detectable shifts from Th1 to Th2 cytokine production in HIV infection [14,15]. Little is known in the literature about IL-15 production in HIVinfected individuals.…”