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¹ Department of Dermatology and Venereology and ² Department of Microbiology and Molecular Medicine, University Hospital and Medical School of Geneva, 1211 Geneva, Switzerland
³ Laboratory of Cellular Physiology and Immunology and ⁴ Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY 10021

CORRESPONDENCE Vincent Piguet: vincent.piguet{at}medecine.unige.ch

HIV-1 infects immature dendritic cells (iDCs), but infection is inefficient compared with activated CD4⁺ T cells and only involves a small subset of iDCs. We analyzed whether this could be attributed to specific cellular restrictions during the viral life cycle. To study env-independent restriction to HIV-1 infection, we used a single-round infection assay with HIV-1 pseudotyped with vesicular stomatitis virus G protein (HIV-VSVG). Small interfering RNA–mediated depletion of APOBEC3G/3F (A3G/3F), but not TRIM5, enhanced HIV-1 infection of iDCs, indicating that A3G/3F controls the sensitivity of iDCs to HIV-1 infection. Furthermore, sequences of HIV reverse transcripts revealed G-to-A hypermutation of HIV genomes during iDC infection, demonstrating A3G/3F cytidine deaminase activity in iDCs. When we separated the fraction of iDCs that was susceptible to HIV, we found the cells to be deficient in A3G messenger RNA and protein. We also noted that during DC maturation, which further reduces susceptibility to infection, A3G levels increased. These findings highlight a role for A3G/3F in explaining the resistance of most DCs to HIV-1 infection, as well as the susceptibility of a fraction of iDCs. An increase in the A3G/3F-mediated intrinsic resistance of iDCs could result in a block of HIV infection at its mucosal point of entry.

Abbreviations used: A3F and A3G, APOBEC3F and APOBEC3G, respectively; iDC, immature DC; JT, Jurkat CD4⁺ T cell; LMM, low molecular mass; LV, lentiviral vector; mDC, monocyte-derived DC; MOI, multiplicity of infection; mRNA, messenger RNA; P, pellet; siRNA, small interfering RNA; SN, supernatant; T5, Trim5; VSVG, vesicular stomatitis virus G.

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