Neutral sphingomyelinase 2 is required for HIV-1 maturation

Abstract

HIV-1 assembly occurs at the inner leaflet of the plasma membrane (PM) in highly ordered membrane microdomains. The size and stability of membrane microdomains is regulated by activity of the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) that is localized primarily to the inner leaflet of the PM. In this study, we demonstrate that pharmacological inhibition or depletion of nSMase2 in HIV-1-producer cells results in a block in the processing of the major viral structural polyprotein Gag and the production of morphologically aberrant, immature HIV-1 particles with severely impaired infectivity. We find that disruption of nSMase2 also severely inhibits the maturation and infectivity of other primate lentiviruses HIV-2 and simian immunodeficiency virus, has a modest or no effect on nonprimate lentiviruses equine infectious anemia virus and feline immunodeficiency virus, and has no effect on the gammaretrovirus murine leukemia virus. These studies demonstrate a key role for nSMase2 in HIV-1 particle morphogenesis and maturation.

Disruption of Transmembrane Phosphatidylserine Asymmetry by HIV-1 Incorporated SERINC5 Is Not Responsible for Virus Restriction

“…The putative lipid-binding pocket in SER5 can bind cholesterol, cardiolipin, and other lipids [75]. Lipids, such as cardiolipin, PIP2, and SM have been implicated in HIV-1 fusion [76][77][78] and infection, and while SER5 does not appear to affect the overall lipid composition of virions [26], scrambling or redistribution of these lipids can have deleterious effects on viral fusion, leading to infectivity reduction. Indeed, it is known that SER5 can modulate Env conformation and predispose them to premature inactivation, and a lipid-mediated, indirect mechanism, as discussed above, is plausible [21,53].…”

Significance of Cellular Lipid Metabolism for the Replication of Rotaviruses and Other RNA Viruses

“…Based on previous findings that ceramide is required for capsid maturation in HIV-1, it was recently observed that the inhibition of neutral sphingomyelinase 2, the rate-limiting enzyme of ceramide biosynthesis, prevented the full maturation of HIV-1 capsids and full infectivity in vitro [ 38 ] and in vivo [ 39 ].…”

“…PDDC, an inhibitor of neutral sphingomyelinase 2 that prevents ceramide biosynthesis, was shown to block the maturation and full infectivity of HIV-1 particles [ 38 , 39 ].…”