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

Mark F. Santos, Germana Rappa, Jana Karbanová, Patrizia Diana, Girolamo Cirrincione, Daniela Carbone, David Manna, Feryal Aalam, David Wang, Cheryl Vanier, Denis Corbeil () and Aurelio Lorico ()
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Mark F. Santos: Touro University Nevada College of Osteopathic Medicine
Germana Rappa: Touro University Nevada College of Osteopathic Medicine
Jana Karbanová: Technische Universität Dresden
Patrizia Diana: University of Palermo
Girolamo Cirrincione: University of Palermo
Daniela Carbone: University of Palermo
David Manna: Touro College of Osteopathic Medicine, Middletown
Feryal Aalam: Touro University Nevada College of Osteopathic Medicine
David Wang: Touro University Nevada College of Osteopathic Medicine
Cheryl Vanier: Touro University Nevada College of Osteopathic Medicine
Denis Corbeil: Technische Universität Dresden
Aurelio Lorico: Touro University Nevada College of Osteopathic Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40227-8

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