Interferon (IFN) production and IFN stimulated gene (ISG) induction is a fundamental innate response to viral infection. We have previously shown that HIV induces a subset of ISGs in macrophages in the absence of IFN induction. Using a panel of antiretroviral drugs that inhibit different stages of the virus life cyle we have now show that this induction occurs in two distinct phases. The first phase occurs early after infection (6-48 hpi) and is transient and the second phase later (>48hpi) and is persistent and induced as a result of transcription of newly synthesized viral mRNA. Recognition of HIV viral products by host cell pathogen recognition receptors (PRR) such as Toll-like receptors (TLR) and the RNA sensor RIGI may trigger signalling pathways that result in the induction of ISGs. Knocking down MyD88 (the adaptor for all TLRs except TLR3) or MAVS (the adaptor for RIG-I) had no effect on the first phase of ISG induction but they both inhibited the upregulation of ISGs in the second phase by >60%. The IFN regulatory factors (IRF) in particular IRF1 and 7 are known to bind to a site in the HIV promotor region (LTR) to stimulate HIV infection. Therefore we have also examined the role of IRF1 and IRF7 as well as another host transcription factor involved in innate immunity, NF-κβ and the viral protein Tat. We show that they are all essential for HIV replication and concsequently to the second phase of ISG induction in macrophages.
We are currently investigating how the first phase of ISGs is induced by assessing recognition of HIV ssRNA by TLR3 and whether trimeric envelope gp140 binding to CD4, CCR5 and mannose receptors or microvesicles present in the HIV inocula may trigger signalling pathways leading to ISG induction.
Supported by NHMRC Project grant APP1028014.