Submitted March 18, 2009
Accepted June 1, 2009
IL-27 inhibition of HIV-1 involves an intermediate induction of type I IFN
Teresa Greenwell-Wild, Nancy Vazquez, Wenwen Jin, Zoila Rangel, Peter Munson, and Sharon M. Wahl*
Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, United States
Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD, United States
* Corresponding author; email: smwahl{at}dir.nidcr.nih.gov.
Infection of CD4+ chemokine co-receptor+ targets by HIV is aided and abetted by the proficiency of HIV in eliminating or neutralizing host cell-derived defensive molecules. Among these innate protective molecules, a family of intracellular apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases is constitutively expressed, but inactivated by HIV viral infectivity factor (Vif). The ability of IFN
to augment cytidine deaminases offered the possibility that the balance between virus and target cell might be altered in favor of the host. Further characterization of transcriptional profiles induced by IFN using microarrays, with the intention to identify and dissociate retroviral counter-maneuvers from associated toxicities, revealed multiple molecules with suspected anti-viral activity, including IL-27. To establish whether IFN toxicity might be sidestepped through the use of downstream IL-27 against HIV, we examined whether IL-27 directly regulated cytidine deaminases. Although IL-27 induces APOBECs, it does so in a delayed fashion. Dissecting the underlying regulatory events uncovered an initial IL-27-dependent induction of IFN and/or IFN
, which in turn, induces APOBEC3, inhibited by IFN/ receptor blockade. In addition to macrophages, the IL-27-IFN connection is operative in CD4+ T cells, consistent with an IFN-dependent pathway underlying host cell defense to HIV.
