APOBEC3A Is a Specific Inhibitor of the Early Phases of HIV-1 Infection in Myeloid Cells

Abstract

Myeloid cells play numerous roles in HIV-1 pathogenesis serving as a vehicle for viral spread and as a viral reservoir. Yet, cells of this lineage generally resist HIV-1 infection when compared to cells of other lineages, a phenomenon particularly acute during the early phases of infection. Here, we explore the role of APOBEC3A on these steps. APOBEC3A is a member of the APOBEC3 family that is highly expressed in myeloid cells, but so far lacks a known antiviral effect against retroviruses. Using ectopic expression of APOBEC3A in established cell lines and specific silencing in primary macrophages and dendritic cells, we demonstrate that the pool of APOBEC3A in target cells inhibits the early phases of HIV-1 infection and the spread of replication-competent R5-tropic HIV-1, specifically in cells of myeloid origins. In these cells, APOBEC3A affects the amount of vDNA synthesized over the course of infection. The susceptibility to the antiviral effect of APOBEC3A is conserved among primate lentiviruses, although the viral protein Vpx coded by members of the SIVSM/HIV-2 lineage provides partial protection from APOBEC3A during infection. Our results indicate that APOBEC3A is a previously unrecognized antiviral factor that targets primate lentiviruses specifically in myeloid cells and that acts during the early phases of infection directly in target cells. The findings presented here open up new venues on the role of APOBEC3A during HIV infection and pathogenesis, on the role of the cellular context in the regulation of the antiviral activities of members of the APOBEC3 family and more generally on the natural functions of APOBEC3A.

Endogenous APOBEC3A DNA Cytosine Deaminase Is Cytoplasmic and Nongenotoxic

“…However, A3A has also been shown to be genotoxic under conditions of overexpression (22,23,26) and to mutate genomic DNA (24,25). CD14 ϩ cells are known to express high levels of A3A upon type I IFN induction (4,6,7), suggesting that these cells must either have a mechanism for regulating A3A activity or be subject to its genotoxic effects. Genotoxicity was determined to be proportional to A3A expression level by using the doxycycline-inducible T-REx 293 system to titrate A3A expression.…”

“…For instance, A3A has been shown to limit the retrotransposition of L1 and Alu elements (3,(11)(12)(13)(14)(15). A3A has also been implicated in inhibiting the replication of certain DNA viruses, including parvovirus (16), hepatitis B virus (17), and papillomavirus (18), as well as the retroviruses human T-lymphotropic virus type-I (19) and HIV (4,7,20,21).…”

Transient overexpression of exogenous APOBEC3A causes C-to-U RNA editing of thousands of genes

“…[12][13][14][15][16][17][18][19] The virusrestricting functions of A3A are typically demonstrated by reduced infectivity of the virus upon exogenous co-expression of the plasmids encoding the enzyme and viruses in a cell line such as HEK293T human embryonic kidney cells. [12][13][14][15][16][17]19 Although A3A's cytidine deaminase function is essential for its antiviral activities, 6,12,20,21 the mechanism by which A3A inhibits viruses is not understood well. A3A efficiently mutates single stranded DNA oligonucleotides in vitro 11 and transfected plasmid DNAs in overexpression systems.…”

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

“…In addition to inhibiting infection when packaged into virions, cellular APOBEC3 proteins can restrict incoming virus particles when expressed in target cells. For example, APOBEC3G expressed in recipient cells functions as a postentry restriction block for HIV in resting CD4 + T cells, monocytes, and immature dendritic cells (DCs) (23)(24)(25).…”