HIV-1-induced nuclear invaginations mediated by VAP-A, ORP3, and Rab7 complex explain infection of activated T cells

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The mechanism of human immunodeficiency virus 1 (HIV-1) nuclear entry, required for productive infection, is not fully understood. Here, we report that in HeLa cells and activated CD4+ T cells infected with HIV-1 pseudotyped with VSV-G and native Env protein, respectively, Rab7+ late endosomes containing endocytosed HIV-1 promote the formation of nuclear envelope invaginations (NEIs) by a molecular mechanism involving the VOR complex, composed of the outer nuclear membrane protein VAP-A, hyperphosphorylated ORP3 and Rab7. Silencing VAP-A or ORP3 and drug-mediated impairment of Rab7 binding to ORP3-VAP-A inhibited the nuclear transfer of the HIV-1 components and productive infection. In HIV-1-resistant quiescent CD4+ T cells, ORP3 was not hyperphosphorylated and neither VOR complex nor NEIs were formed. This new cellular pathway and its molecular players are potential therapeutic targets, perhaps shared by other viruses that require nuclear entry to complete their life cycle.


Original languageEnglish
Article number4588
Pages (from-to)1-22
Number of pages22
JournalNature Communications
Issue number1
Publication statusPublished - 10 Aug 2023

External IDs

Scopus 85167709726
PubMed 37563144
Mendeley 280046de-85d4-3909-8c6e-e5def9a5e481
ORCID /0000-0003-1181-3659/work/142252263
ORCID /0000-0001-7687-0983/work/142253735


DFG Classification of Subject Areas according to Review Boards

Subject groups, research areas, subject areas according to Destatis

Sustainable Development Goals


  • Humans, HIV-1/metabolism, HeLa Cells, CD4-Positive T-Lymphocytes/metabolism, Gene Products, env/metabolism, Membrane Proteins/metabolism, HIV Infections

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