APOBEC3G upregulation by alpha interferon restricts human immunodeficiency virus type 1 infection in human peripheral plasmacytoid dendritic cells

Abstract

APOBEC3G (A3G), a member of cytidine deaminase family, has potent anti-human immunodeficiency virus type 1 (HIV-1) activity. It has been demonstrated that alpha interferon (IFN-a) can significantly enhance the expression of A3G in human primary resting CD4 + T-cells, macrophages and primary hepatocytes, subsequently decreasing their viral susceptibility. Plasmacytoid dendritic cells (pDCs) are key effectors in innate host immunity, mediating adaptive immune responses and stimulating IFN-a production in reaction to various stimuli. In this report, we demonstrate that IFN-a, either exogenously added to-or endogenously secreted by pDCs, can enhance the expression of A3G and its family members such as A3A, A3C and A3F. We have also shown that IFN-a can inhibit HIV-1 expression in pDCs. This inhibitory effect could be countered by addition of an A3G-specific short interfering RNA, indicating that IFN-a-induced A3G plays a key role in mediating pDCs response to HIV-1. Given the central role played by pDCs in orchestrating the IFN-a/A3G intercellular network and intracellular signal pathway, our data indicate that pDCs themselves are also protected by an IFN-a/A3G-mediated innate immunity barrier from HIV-1 infection.

Exosomes Packaging APOBEC3G Confer Human Immunodeficiency Virus Resistance to Recipient Cells

“…Since A3G in exosomes is enzymatically active and thus most likely present in low-molecular-mass form (11), we speculate that A3G delivered by exosomes to cytosol does not convert into HMM form. Consequently, exosomal A3G would function as a postentry restriction factor as proposed for cellular low-molecular-mass A3G in resting CD4 ϩ T cells (8,11), monocytes and monocyte-derived dendritic cells (47,48), or peripheral plasmacytoid dendritic cells (77). This notion is consistent with our observations showing reduced accumulation of HIV-1 reverse transcription products and nuclear two-LTR circles in cells exposed to H9 exosomes.…”

“…The most prominent member of this family, APOBEC3G (A3G), has a potent activity against vif-deficient human immunodeficiency virus type 1 (HIV-1) (63) but can also function as a postentry restriction factor against wild-type viruses (11,48,77). An antiretroviral function of A3G has been linked with its DNA-editing activity (40,59); however, recent studies point to the existence of additional, editing-independent activities of A3G that may contribute to its antiviral function (21,43,71).…”

APOBEC3G Restricts HIV-1 to a Greater Extent than APOBEC3F and APOBEC3DE in Human Primary CD4 + T Cells and Macrophages

“…A3G mRNA is 3-to 10-fold more abundant in primary cells than A3F mRNA, suggesting that A3G protein levels and antiviral activity may be higher in these cells (53,54). Alpha interferon (IFN-␣) increases the mRNA expression levels of A3G, A3F, A3DE, and A3H, suggesting a greater potential for inhibition of virus replication in primary cells after IFN-␣ treatment in the absence of Vifinduced degradation (53)(54)(55)(56).…”

Somatic hypermutation of human mitochondrial and nuclear DNA by APOBEC3 cytidine deaminases, a pathway for DNA catabolism

“…Activation-induced cytidine deaminase (AICDA) is presently the only enzyme known to induce mutations in the human genome and initiates class-switch recombination and somatic hypermutation of rearranged Ig genes (3). Several human A3 genes are up-regulated in inflammatory settings by type I and II interferons, although activation depends to some degree on the cell type (4)(5)(6)(7)(8). Given this finding, it is not surprising that A3F and A3G are involved in the restriction of retroviruses and hepadnaviruses where nascent single-stranded cDNA remains vulnerable until double-strand synthesis is completed (9)(10)(11)(12)(13)(14)(15)(16).…”