*4.1. Glycosphingolipids and HIV Entry*

Glycosphingolipids are also key players in HIV infection. HIV-1 infection of susceptible cells involves fusion of the HIV membrane with the host cell membrane. This process involves interactions between the viral gp120 and gp 41 envelope glycoproteins and CD4 and chemokine coreceptors (CXCR4 or CCR5) on the host cell. Several studies have implicated glycosphingolipids in the fusion process. Hug et al. demonstrated that glucosylceramide-derived glycosphingolipids found on the target cell membrane are involved in the organization of gp120–gp41, CD4, and chemokine receptors into a membrane fusion complex [55]. Rawat et al. reported that expression levels of the membrane ganglioside GM3 impact CD4-dependent viral fusion and infection [56]. Furthermore, several glycosphingolipids (galactosylceramide, GD3, Gb3, and GM3) have been reported to bind to the HIV gp120 envelope protein and contribute in some cases to the HIV infection of CD4 negative cells [57–60]. Specifically, HIV-1 entry was impaired in human colonic cells (HT29; CD4 negative cells) with a synthetic analog or a monoclonal antibody to galactosylceramide (GalCer) [60,61], implying that GalCer is an alternative receptor for HIV replication entry. Similarly, antibodies to GalCer reduced HIV infectivity andinternalization in two CD4-negative neural cell lines, U373-MG and SK-N-MC [58]. Altogether, these findings imply that glycosphingolipids contribute to HIV membrane fusion and can serve as alternative receptors for HIV entry in some cells.

#### *4.2. Glycosphingolipids and HIV Budding*

HIV particle assembly and budding takes place in the plasma membrane's lipid rafts which contain high levels of cholesterol, sphingolipid (sphingomyelin), and glycosphingolipids. Notably, genetic analysis and lipid mass spectrometry showed that the HIV particle is enriched in sphingolipids (sphingomyelin and dihydro sphingomyelin) and glycosphingolipids (hexosylceramide, GM3, GM2, GM1) [62–65], implying that sphingolipids contribute to the biogenesis of infectious HIV particle and are acquired during HIV budding. There is also increasing evidence that glycosphinolipids help facilitate HIV's infection of macrophages. Indeed, multiple studies have shown that GM3, GM2, and GM1 in HIV's envelope interact with Siglec-1, a molecule that specifically binds to the sialyllactose moiety in glycosphinolipids [64–66]. This interaction between glycosphinolipids and Siglec-1 captures HIVs on macrophages, which might exist as a reservoir for HIV's transmission to T cells.
