gp340 Expressed on Human Genital Epithelia Binds HIV-1 Envelope Protein and Facilitates Viral Transmission

Abstract

During sexual transmission of HIV in women, the first cells likely to be infected are submucosal CD4+ T cells and dendritic cells of the lower genital tract. HIV is segregated from these target cells by an epithelial cell layer that can be bypassed even when healthy and intact. To understand how HIV penetrates this barrier, we identified a host protein, gp340, that is expressed on genital epithelium and binds the HIV envelope via a specific protein-protein interaction. This binding allows otherwise subinfectious amounts of HIV to efficiently infect target cells and allows this infection to occur over a longer period of time after binding. Our findings suggest a mechanism of viral entry during heterosexual transmission where HIV is bound to intact genital epithelia, which then promotes the initial events of infection. Understanding this step in the initiation of infection will allow for the development of tools and methods for blocking HIV transmission.

Exosomes in human semen restrict HIV-1 transmission by vaginal cells and block intravaginal replication of LP-BM5 murine AIDS virus complex

“…It is still debatable whether or not these cell types support active HIV-1 infection (Asin et al, 2004). Although epithelial cells of the FRT may or may not support active HIV-1 infection, they have been shown to transmit infectious virus to target cells (Stoddard et al, 2007). …”

HIV infection of the genital mucosa in women

“…A few studies have proposed that HIV-1 gp120 interacts with transmembrane heparan sulfate proteoglycans (syndecans) on genital epithelial cells [18,20]. Another study found that glycoprotein 340-a splice variant of salivary agglutinin expressed on cervical and vaginal epithelia-specifi cally bound the HIV envelope and enhanced passage of HIV to susceptible leukocytes [24]. One group found that β1-integrin on explant cervical epithelium bound virions, presumably via fi bronectin, which is abundant in human semen and may coat the envelope of seminal virions, although this fi nding was not observed in all explants [12].…”

Involvement of Envelope-Glycoprotein Glycans in HIV-1 Biology and Infection

“…Therefore, HS contributes preferentially to the transcytosis of X4-specific HIV-1 (Vives et al 2005). gp340 is a scavenger receptor on macrophages and endometrial and endocervical epithelial cells (Cannon et al 2008;Stoddard et al 2007). Splice variant of gp340, called salivary agglutinin (SAG), binds HIV-1 and inhibits infection (Wu et al 2003(Wu et al , 2004.…”

“…Splice variant of gp340, called salivary agglutinin (SAG), binds HIV-1 and inhibits infection (Wu et al 2003(Wu et al , 2004. gp340/SAG binds HIV-1 gp120 near to the base of V3 loop at the site which contributes to CDi epitope formation, including the peptide CTRPNYNKRKRIHIG (Stoddard et al 2007;Wu et al 2004). This interaction seems to be protein-protein based, without direct contribution of gp120 glycans.…”

“…Indirectly, however, glycans affect the folding of the HIV-1 Env protein. gp340, together with HS, plays a dominant role in mediating HIV-1 adhesion and trans-infection of endometrium and endocervical epithelial cells (Stoddard et al 2007). In macrophages, it was shown that gp340 enhances cis-infection by HIV-1, likely through increasing the local concentration of HIV-1 at the cell surface (Cannon et al 2008).…”