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 SIV(SM)/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.