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

Abstract

BackgroundInterferon-α (IFN-α) 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-α to cooperate with nucleotide depletion has been poorly investigated so far. Here we wondered whether IFN-α affects SAMHD1 expression, Vpx-induced SAMHD1 degradation, Vpx-mediated rescue of HIV-1 transduction and the dNTP supply in monocyte-derived macrophages (MDMs).ResultsIFN-α inhibited HIV-1 transduction in monocytes and in MDMs while SAMHD1 expression was not up-regulated. Vpx triggered SAMHD1 degradation in IFN-α treated cells, and weakly restored HIV-1 transduction from the IFN-α block. Vpx helper effect towards HIV-1 transduction was gradually inhibited with increasing doses of IFN-α. dNTP levels were not significantly affected in MDMs and CD4+ primary activated T lymphocytes by IFN-α and, in correlation with SAMHD1 degradation, restoration of dNTP levels by Vpx was efficient in MDMs treated with the cytokine. In contrast, IFN-α inhibited Vpx-mediated SAMHD1 degradation in THP-1 cells, where, accordingly, Vpx could not rescue HIV-1 transduction.ConclusionOur results suggest that the early antiviral effect of IFN-α 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-α-induced cell response that inhibits Vpx-mediated SAMHD1 degradation.

HIV Type 1 Infection of Plasmacytoid and Myeloid Dendritic Cells Is Restricted by High Levels of SAMHD1 and Cannot be Counteracted by Vpx

“…Treating the cells with a cocktail of antibodies against type-I IFN and the type-I IFN-R partially restored the ability of Vpx to induce SAMHD1 degradation and facilitated infection, suggesting that signaling through the type-I IFN-R rendered Vpx unable to induce SAMHD1 degradation. This result is similar to that of Dragin et al 45 who found that in differentiated THP1 cells, type-I IFN renders Vpx unable to induce SAMHD1 degradation. The mechanism by which type-I IFN blocked the Vpx-induced degradation of SAMHD1 is unclear.…”

Human T Cell Leukemia Virus Type 1 Infection of the Three Monocyte Subsets Contributes to Viral Burden in Humans

“…It is known that HTLV-1 infection causes local and systemic inflammation, and perhaps this inflammatory response alters SAMHD1 expression. In addition, SAMHD1 expression has been shown to be regulated by interferons (86)(87)(88)(89). We recently showed that expression of the HTLV-1 p30 protein dampens interferon responses in monocytes and dendritic cells by blocking the expression of interferon-responsive genes (40).…”

IFN-ε protects primary macrophages against HIV infection

“…IFN-ε had a slight ability to either promote (line 1) or inhibit (line 2) HIV infection of PMA-treated THP-1 cells, whereas IFN-α efficiently blocked infection ( Figure 1E), suggesting that pathways involved in the inhibitory activity of these two IFNs are not identical. SAMHD1 is a myeloid cell restriction factor that is induced in specific cell types by type I IFNs (34,35). To determine whether SAMHD1 plays a role in the IFN-ε antiviral activity, we assessed the effect of IFN-ε on HIV infection of THP-1 with an shRNA stable knockdown of SAMHD1 (36).…”