HIV-1 Tat plays a role in dysregulating lipopolysaccharide-induced cytokine expression: implications for immune defects in AIDs

Introduction: During bacterial infection, macrophages/ monocytes are activated by lipopolysaccharides (LPS), the bacterial cell wall-associated endotoxins, to trigger innate and adaptive immune responses. However, these responses are impaired in HIV-infected patients especially in children, and such immune defects may contribute to the higher incidence of secondary bacterial infections and rapid progression of AIDS. The mechanisms on how HIV impairs these immune responses are not fully understood. Previous reports including ours indicated that Tat, the transactivator for transcriptional activation of the HIV genome, is partly responsible for mediating the retrovirus-induced subversion of immunity and enhancement of HIV replication. Therefore, we hypothesise that Tat plays a role in the dysregulation of the LPS-induced immune responses, thereby contributing to the pathogenesis of AIDS. Methods: Primary human blood monocytes were pretreated with recombinant Tat protein prior to LPS addition. Expression levels of specific cytokines were assayed by Q-RTPCR and ELISA. Levels of signalling kinases and nuclear factors were examined by Western analysis. Results: Our results demonstrated that Tat differentially suppresses the LPS-induction of IFN-β but enhances the induction of IL-6. On the contrary, Tat was shown to have a slight enhancing effect on the LPS-induction of TNF-α. To investigate the underlying mechanisms of Tat in cytokine dysregulation, we showed that the HIV protein inhibits LPSinduced activation of ERK1/2 but not p38 MAP kinase. We also demonstrated that Tat suppresses LPS-induced degradation of IκBα, resulting in the release and activation of NFκB for subsequent transcription of downstream cytokines and targeted genes. Conclusion: Taken together, these results imply that Tat may suppress the host anti-viral responses due to IFN-β suppression and yet promote HIV replication via the enhancement of IL-6 expression. Hence, during Gramnegative bacterial infection in AIDS patients, Tat may play a role in dysregulating the immune responses induced by the bacteria for providing a favourable environment for HIV survival and replication. Conflict of Interest Statements: There is no conflict of interest. Parts of the results were presented in Annual Scientific Meeting 2008, Hong Kong Society for Immunology. (Supported in part by HK Research Grants Council, HKU7408/04M and HKU7594/06M