HIV inhibits LPS-induced IL-27 production via HIV tat through the inhibition of TRAF-6, and consequent inhibition of PI3K and p38 and JNK MAPKs in human macrophages (VIR9P.1140)

Abstract

Abstract Monocyte-derived macrophages (MDM) from HIV-infected patients and MDM infected in vitro with HIV manifest inhibition of cytokines including IL12. IL27, an IL12 family cytokine, was shown to inhibit HIV replication in macrophages. Whether HIV infection or HIV accessory protein(s) impact IL27 production in macrophages remains unknown. Herein, we show that in vitro HIV infection as well as intracellular HIV and HIV-tat peptides inhibited LPS-induced IL27 production in MDM suggesting that HIV-tat inhibits IL27 production by impairing TLR-4 signalling. To study the mechanism governing HIV-tat-mediated inhibition of LPS-induced IL27 production, we first established that p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK), the phosphoinositide-3-kinase (PI3K), SRC homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1) and Src kinases regulated LPS-induced IL27 production in MDM. HIV-tat caused TNF receptor associated factor (TRAF)-6 inhibition and consequent decreased phosphorylation of downstream PI3K, and p38 and JNK MAPKs implicated in LPS-induced IL27 production. However, SHP-1 and Src kinases were not involved in HIV-Tat-mediated inhibition of LPS-induced IL27 production. In contrast to HIV-tat, in vitro HIV infection of MDM inhibited LPS-induced p38 and JNK activation. Overall, HIV inhibits LPS-induced IL27 production via HIV tat through the inhibition of TRAF-6, and consequent inhibition of PI3K and p38 and JNK MAPKs in macrophages.