Interleukin-27 inhibition of HIV-1 involves an intermediate induction of type I interferon.
Infection of CD4(+) chemokine coreceptor(+) 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. The ability of interferon-alpha (IFN-alpha) 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-alpha using microarrays, with the intention to identify and dissociate retroviral countermaneuvers from associated toxicities, revealed multiple molecules with suspected antiviral activity, including IL-27. To establish whether IFN-alpha 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-alpha and/or IFN-beta, which in turn, induces APOBEC3, inhibited by IFN-alpha/beta receptor blockade. In addition to macrophages, the IL-27-IFN-alpha connection is operative in CD4(+) T cells, consistent with an IFN-alpha-dependent pathway underlying host cell defense to HIV.
Greenwell-Wild
Teresa
T
Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4352, USA.
Vázquez
Nancy
N
Jin
Wenwen
W
Rangel
Zoila
Z
Munson
Peter J
PJ
Wahl
Sharon M
SM
D000071478:APOBEC Deaminases; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000821:virology*; D003564:Cytidine Deaminase / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D043525:Cytosine Deaminase / Q000378:metabolism; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis
D016207:Cytokines; D007370:Interferon Type I; D016898:Interferon-alpha; D020381:Interleukin-17; D008070:Lipopolysaccharides; D016899:Interferon-beta; D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase