Interferon block to HIV-1 transduction in macrophages despite SAMHD1 degradation and high deoxynucleoside triphosphates supply.

ABSTRACT:

Background

Interferon-? (IFN-?) is an essential mediator of the antiviral response, which potently inhibits both early and late phases of HIV replication. The SAMHD1 deoxynucleoside triphosphate (dNTP) hydrolase represents the prototype of a new antiviral strategy we referred to as "nucleotide depletion". SAMHD1 depletes dNTP levels in myeloid cells below those required for optimal synthesis of HIV viral DNA. HIV-2 and its SIVsm and SIVmac close relatives encode a protein termed Vpx, which counteracts SAMHD1. The potentiality of IFN-? to cooperate with nucleotide depletion has been poorly investigated so far. Here we wondered whether IFN-? affects SAMHD1 expression, Vpx-induced SAMHD1 degradation, Vpx-mediated rescue of HIV-1 transduction and the dNTP supply in monocyte-derived macrophages (MDMs).

Results

IFN-? inhibited HIV-1 transduction in monocytes and in MDMs while SAMHD1 expression was not up-regulated. Vpx triggered SAMHD1 degradation in IFN-? treated cells, and weakly restored HIV-1 transduction from the IFN-? block. Vpx helper effect towards HIV-1 transduction was gradually inhibited with increasing doses of IFN-?. dNTP levels were not significantly affected in MDMs and CD4+ primary activated T lymphocytes by IFN-? and, in correlation with SAMHD1 degradation, restoration of dNTP levels by Vpx was efficient in MDMs treated with the cytokine. In contrast, IFN-? inhibited Vpx-mediated SAMHD1 degradation in THP-1 cells, where, accordingly, Vpx could not rescue HIV-1 transduction.

Conclusion

Our results suggest that the early antiviral effect of IFN-? results from a mechanism independent of nucleotide depletion in MDMs. In addition, they indicate that the macrophage-like THP-1 cell line may provide a system to characterize an IFN-?-induced cell response that inhibits Vpx-mediated SAMHD1 degradation.

SUBMITTER: Dragin L 

PROVIDER: S-EPMC3599726 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature