Inhibition of HIV infection by structural proteins of the inner nuclear membrane is associated with reduced chromatin dynamics

Abstract

The Human Immunodeficiency Virus (HIV) enters the nucleus to establish infection. HIV interacts with nuclear pore components to cross the nuclear envelope. In contrast, the role of other proteins of the nuclear envelope in HIV infection is not yet understood. The inner nuclear transmembrane proteins SUN1 and SUN2 connect lamins in the interior of the nucleus to the cytoskeleton in the cytoplasm. Increased levels of SUN1 or SUN2 potently restrict HIV infection through an unresolved mechanism. Here, we find that SUN1 and SUN2 exhibit a differential and viral strain-specific antiviral activity HIV-1 and HIV-2. In macrophages and HeLa cells, HIV-1 and HIV-2 are respectively preferentially inhibited by SUN1 and SUN2. This specificity maps to the nucleoplasmic domain of SUN proteins, which associates with Lamin A/C and participates to the DNA damage response. We find that etoposide, a DNA-damaging drug, stimulates infection. Inhibition of the DNA damage signaling kinase ATR, which induces a DNA damage response, also enhances HIV-1 infection. The proviral effect of ATR inhibition on infection requires the HIV-1 Vpr gene. Depletion of endogenous Lamin A/C, which sensitizes cells to DNA damage, also enhances HIV-1 infection in HeLa cells. SUN1 overexpression neutralizes these proviral effects, while the antiviral effect of SUN2 is rescued by etoposide treatment. Finally, we show that inhibition of HIV-1 infection by overexpressed SUN proteins and endogenous Lamin A/C is associated with reduced internal movements of chromatin and reduced rotations of the nucleus. Altogether, these results highlight distinct antiviral activities of SUN1 and SUN2 and reveal an emerging role of nuclear movements and the DNA damage response in the control of HIV infection by structural components of the nuclear envelope.