Ceramide synthase 2 deletion decreases the infectivity of HIV-1

Abstract

The lipid composition of HIV-1 virions is enriched in sphingomyelin (SM), but the roles that SM or other sphingolipids (SLs) might play in the HIV-1 replication pathway have not been elucidated. In human cells, SL levels are regulated by ceramide synthase (CerS) enzymes that produce ceramides, which can be converted to SMs, hexosylceramides, and other SLs. In many cell types, CerS2, which catalyzes the synthesis of very long chain ceramides, is the major CerS. We have examined how CerS2 deficiency affects the assembly and infectivity of HIV-1. As expected, we observed that very long chain ceramide, hexosylceramide, and SM were reduced in CerS2 knockout cells. CerS2 deficiency did not affect HIV-1 assembly or the incorporation of the HIV-1 envelope (Env) protein into virus particles, but it reduced the infectivites of viruses produced in the CerS2-deficient cells. The reduced viral infection levels were dependent on HIV-1 Env, since HIV-1 particles that were pseudotyped with the vesicular stomatitis virus glycoprotein did not exhibit reductions in infectivity. Moreover, cell–cell fusion assays demonstrated that the functional defect of HIV-1 Env in CerS2-deficient cells was independent of other viral proteins. Overall, our results indicate that the altered lipid composition of CerS2-deficient cells specifically inhibit the HIV-1 Env receptor binding and/or fusion processes.

Absolute quantitative lipidomics reveals lipids profiling in liver of mice with early-stage alcoholic liver disease

“…Altered hexosylceramides (HCER) metabolism is an emerging area of ALD pathogenesis. Hexosylceramides is converted from ceramides in human cells [ 32 ]. Ceramides are a kind of bioactive lipids that can accumulate in the liver of both human and animal model of ALD, inducing oxidative stress, impairing insulin signaling, and increasing lipoprotein aggregation [ 33 – 35 ].…”

Ceramide and Related Molecules in Viral Infections

“…This suggests that membrane microdomains on virion membranes are similarly important for the interaction of viral glycoproteins with their cellular receptors in viral entry as microdomains on the cell-to-be-infected. In line with this, the glycoproteins of IAV [ 164 ], HIV [ 165 ], MV [ 166 , 167 ], EBOV and Marburg virus [ 168 ] have also been associated with membrane rafts and alterations of HIV-1 lipid composition reduced infectivity [ 136 , 169 ].…”

Mysterious sphingolipids: metabolic interrelationships at the center of pathophysiology

“…In the liver, haploinsufficiency of CerS2 led to diet-induced steatohepatitis and insulin resistance ( Raichur et al, 2014 ). Changes in the sphingolipid profile due to the deletion of CerS2 inhibit the packaging of human immunodeficiency virus envelop protein into virus particles ( Barklis et al, 2021 ). Very long-chain-containing sphingolipids are required during spermatogenesis.…”