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.
Highlights
The apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 family (APOBEC3s) comprises 6 members of highly related cytidine deaminases [1]
Macrophages and dendritic cells represent important targets for HIV-1 and the understanding of the complex relationship established between these cells and the virus is of the outmost importance
We show that APOBEC3A, the least known member of the APOBEC3 family of cytidine deaminases, restricts HIV-1 in these cells
Summary
The apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 family (APOBEC3s) comprises 6 members of highly related cytidine deaminases [1]. The prototype of the family, APOBEC3G (or A3G), has been identified on the basis of its ability to inhibit HIV-1 infection in the absence of the Vif protein [2] In this case, the antiviral effect of A3G is exerted via its incorporation into virion particles in virus-producing cells. The antiviral effect of A3G is exerted via its incorporation into virion particles in virus-producing cells This incorporation leads to the deamination of newly synthesized viral DNA during the subsequent cycle of infection [3,4,5,6], a non-deaminase dependent mechanism of inhibition has been described [7,8]. In the case of HIV-1, Vif has been proposed to promote structural changes in A3G that negatively affect its ability to be incorporated into virion particles [22,23]
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