HIV-1 Tat dysregulation of lipopolysaccharide-induced cytokine responses: microbial interactions in HIV infection

Howard Yim, James Li, Jonathan Lau, Allan Lau

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Abstract

OBJECTIVE: To examine whether the HIV-1 Tat protein impairs the lipopolysaccharide (LPS)-induced cytokine responses. DESIGN: Concurrent infections with pathogens including bacteria and viruses are common in AIDS patients. However, cytokine and interferon responses during infection with or translocation from the gut of these pathogens in HIV-infected patients are not well studied. As HIV-1 Tat contributes partly to the HIV-induced immune dysregulation, we investigated whether the protein may play a role in perturbing the LPS-induced cytokine responses. METHODS: Expression levels of cytokines in human primary blood monocytes/macrophages were determined by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Expression level of the cell surface Toll-like receptor 4 was examined by flow cytometry. Activations of signaling molecules were assayed by western blot and immunofluorescence. RESULTS: We demonstrated that HIV-1 Tat downregulated the LPS-induction of IFN-beta and concomitantly upregulated IL-6 expression in primary blood monocytes/macrophages, whereas the viral protein had no significant effects on TNF-alpha expression. To delineate the underlying mechanism, we showed that Tat inhibited the LPS-activation of ERK1/2 but not the p38 mitogen-activated protein kinases. The viral protein suppressed the LPS-induced activation of NFkappaB p65 via its induction of IkappaBalpha expression, which resulted in retention of NFkappaB p65 in the cytosol. CONCLUSION: These findings suggest that Tat may play a role in modulating the immune responses triggered by other coinfecting pathogens and thus providing a permissive environment for both HIV and other opportunistic microbes.
Original languageEnglish
Pages (from-to)1473 - 1484
Number of pages12
JournalAIDS
Volume23
Issue number12
DOIs
Publication statusPublished - 2009
Externally publishedYes

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