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Investigating the relationship between structural elements of the inner nuclear membrane and HIV infection

Abstract : During infection by Human Immunodeficiency Virus (HIV), the virus crosses the nuclear envelope (NE) to invade the host genome. HIV gets access to the nucleus by passing through the nuclear pore complex (NPC). However, the underlying mechanism is not fully understood. It was recently described that SUN1 and SUN2, structural proteins of the inner nuclear membrane, play a role in the nuclear import of HIV. Modulating the levels of SUN1 or SUN2 inhibits HIV infection, revealing that the virus depends on a sweet-spot of SUN protein levels in cells. Intringuigly, increasing SUN protein levels in various cell types doesn’t impact cell viability but causes deformation of the nucleus and ruffling of the NE.We observed that overexpression of SUN1 and SUN2 led to reduced infection by both HIV-1 and HIV-2 in HeLa cells, primary monocyte-derived macrophages and CD4+ T cells, with the last two being physiologically relevant HIV target cells. We further validated that SUN proteins and Cyclophilin A (CypA) functionally interact in HIV infection.A strain-specific selectivity was observed in the fact that SUN1 shows stronger restriction of HIV-1 while SUN2 preferentially inhibits HIV-2. These preferential antiviral activities were mapped to the N-terminal, lamin-binding domains of SUN proteins. However, endogenous lamins are not required for SUN-mediated antiviral activity.By using lamin A/C knock down cells as a positive control of nuclear deformation, no simplistic correlation between deformation and infection was found: The absence of lamin A/C, unlike SUN1/2 overexpression, showed no anti-viral activity. Instead, we identified properties that were unique to SUN1 overexpressing nuclei: reduced chromatin mobility and a reduced DNA damage signature. We find that induction of exogenous DNA damage is beneficial for HIV-1 infection (but not HIV-2) in cells. This is not the case for SUN1 overexpressing cells where additional damage does not lead to increased infection, suggesting that SUN1 modulates HIV infection downstream of the DNA damage events.Overall our results suggest a role of SUN1 in modulation of nuclear dynamics, with subsequent interplay with the DNA damage pathway, that leads to control of productive HIV-1 infection.
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Submitted on : Saturday, October 1, 2022 - 1:01:36 AM
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Anvita Bhargava. Investigating the relationship between structural elements of the inner nuclear membrane and HIV infection. Human health and pathology. Université Paris sciences et lettres, 2020. English. ⟨NNT : 2020UPSLT013⟩. ⟨tel-03793326⟩

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