HIV-1 Gag Assembly and Maturation

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Starting with our early work showing that cholesterol-enriched lipid raft microdomains are the sites of HIV 1 assembly and that the phospholipid PI(4,5)P2 is a key determinant for binding of HIV-1 Gag to the inner leaflet of the host cell plasma membrane, we have a long-standing interest in the connection between lipids and HIV-1 replication. The enzyme nSMase2 plays a key role in the synthesis of the lipid raft component ceramide by hydrolyzing sphingomyelin to phosphocholine and ceramide. In this review cycle, we demonstrated that disruption of nSMase2 in virus-producing cells potently inhibits HIV-1 Gag processing and particle maturation. These results indicate that the lipid composition of the viral envelope is a key determinant in HIV-1 maturation. Because what triggers Gag processing and particle maturation remains incompletely understood, deciphering the basis for inhibition mediated by nSMase2 disruption will provide valuable insights into this key biological question. Interestingly, we found that inhibition of nSMase2 has little effect on the maturation of non-primate lentiviruses, and no effect on other retroviruses, suggesting fundamental differences in the mechanism of virion maturation across Retroviridae. Our collaborators on this project showed that treatment of HIV-1-infected humanized mice with an nSMase2 inhibitor suppresses HIV-1 replication in humanized mice, and, remarkably, this suppression continues after removal of the nSMase2 inhibitor. This latter result has potential implications for cure research. In the current review cycle, we have also contributed to a growing body of work demonstrating that the host metabolite IP6 plays a key role in HIV-1 assembly, maturation, and infection. We have also embarked on work aimed at deciphering the effect of MA lattice maturation on HIV-1 replication. This project contains three specific aims: a) Elucidate the roles of IP6 in HIV-1 assembly and infection, b) Define the roles of the virion lipid composition in HIV-1 Gag processing and particle maturation, and c) Elucidate the role of MA lattice maturation in HIV-1 replication.