Characterization of type-1/type-2 cytokine and IgE responses of HIV-1 resistant Kenyan women, characterization of neonatal type-1/type-2 cytokine responses
Trivedi, Harsha N.
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Part I. Characterization of type-1/type-2 cytokine and IgE responses of HIV-1 resistant Kenyan women. A group of HIV-1 resistant Kenyan female prostitutes has been previously identified who remain HIV-1 specific serum antibody (Ab) and polymerase chain reaction (PCR) negative despite chronic ongoing exposure to human immunodeficiency virus type 1 (HIV-1) (3-14 years). The overall objective of this study was to characterize the type-1/type-2 cytokine and IgE responses of these women. Toward this goal, the initial hypothesis that the resistant women exhibit enhanced HIV-1 driven type-1 and reduced type-2 cytokine responses was tested. Results revealed that the resistant women exhibited markedly enhanced virus driven IFN-$\gamma$ and significantly reduced IL4 responses compared to susceptible women. Resistant women also exhibited marginally enhanced IL-5 and similar IL-13 and IL-10 responses. Analysis of virus driven type-2:type-1 cytokine balance revealed a selective imbalance in IL-4:IFN-$\gamma$, but not inother type-2:type-1 ratios examined. Furthermore, recall Ag (streptokinase (SK) and purified protein derivative (PPD)) driven cytokine responses indicated that the resistant women exhibited similar levels of Ag driven IFN-$\gamma$ and markedly reduced IL-4 responses compared to low risk Kenyan women. Subsequently, the hypothesis that HIV-1 resistant women exhibit enhanced responsiveness to IL-12 and IP-10 (bo h of which promote IFN-$\gamma$ synthesis) was tested. Although the resistant women exhibited significantly enhanced IL-12 and IP-10 responsiveness on virus mediated activation compared to susceptible women, they did not differ from low risk women. Finally, the hypothesis that HIV-1 resistant women may exhibit deficient HIV-1 specific IgE Ab was tested. Examination of their plasma confirmed this hypothesis. However, the resistant women did not exhibit a generalized defect of class switching to IgE isotype because their plasma levels of cat and dust mite allergen specific IgE antibodies and total IgE were similar to that of low risk women. In summary, this study has identified a potential cytokine mediated immune mechanism associated with the clinical resistance to HIV-1 infection among Kenyan women. These results may have implications in the prevention and treatment of HIV-1 infection and AIDS. Part II. Characterization of neonatal type-1/type-2 cytokine responses. It is widely believed that enhanced vulnerability of human neonates to infections is due to the immaturity of their immune system. In the present study, two hypotheses were tested: (1) neonatal T cells are immature with regard to type-1/type-2 cytokine synthesis; and (2) neonatal antigen presenting cells (APC) have a defect in stimulating type-1/type-2 cytokine synthesis. Comparison of neonatal cytokine responses to phytohemagglutinin (PHA) indicated an impaired IFN-$\gamma$ and similar IL4, IL-5 and IL-10 responses compared to adults. In contrast, examination of a more physiologically relevant, alloantigen mediated response revealed that neonates have very similar IFN-$\gamma$, IL-4 and IL-10 responses but higher IL-5 responses compared to adults. Finally, the capacity of neonatal versus adult APC to induce cytokine synthesis was assessed. Results indicated that neonatal APC exhibit a selective defect in stimulating IFN-$\gamma$ and IL-10, but not IL-4 and IL-5 synthesis. In summary, these data argue that, whereas neonatal T cells are functionally mature, their APCs exhibit a selective defect which may contribute to the vulnerability of neonates to pathogens.