The human immunodeficiency virus type 2 Vpx protein usurps the CUL4A-DDB1 DCAF1 ubiquitin ligase to overcome a postentry block in macrophage infection.
The human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) genomes encode several auxiliary proteins that have increasingly shown their importance in the virus-host relationship. One of these proteins, Vpx, is unique to the HIV-2/SIVsm lineage and is critical for viral replication in macrophages. The functional basis for this requirement, as well as the Vpx mode of action, has remained unexplained, and it is all the more enigmatic that HIV type 1 (HIV-1), which has no Vpx counterpart, can infect macrophages. Here, we underscore DCAF1 as a critical host effector of Vpx in its ability to mediate infection and long-term replication of HIV-2 in human macrophages. Vpx assembles with the CUL4A-DDB1 ubiquitin ligase through DCAF1 recruitment. Precluding Vpx present in the incoming virions from recruiting DCAF1 in target macrophages leads to a postentry block characterized by defective accumulation of HIV-2 reverse transcripts. In addition, Vpx from SIVsm functionally complements Vpx-defective HIV-2 in a DCAF1-binding-dependent manner. Altogether, our data point to a mechanism in which Vpx diverts the Cul4A-DDB1(DCAF1) ligase to inactivate an evolutionarily conserved factor, which restricts macrophage infection by HIV-2 and closely related simian viruses.
Bergamaschi
Anna
A
Institut Pasteur, Unité de Régulation des Infections Rétrovirales, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.
Ayinde
Diana
D
David
Annie
A
Le Rouzic
Erwann
E
Morel
Marina
M
Collin
Gilles
G
Descamps
Diane
D
Damond
Florence
F
Brun-Vezinet
Françoise
F
Nisole
Sebastien
S
Margottin-Goguet
Florence
F
Pancino
Gianfranco
G
Transy
Catherine
C
D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D044842:Cullin Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D015658:HIV Infections / Q000821:virology*; D015498:HIV-2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000378:metabolism / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D014779:Virus Replication
C114234:CUL4A protein, human; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C074286:VPX protein, Human immunodeficiency virus 2; D054334:Viral Regulatory and Accessory Proteins; D044767:Ubiquitin-Protein Ligases