The Virotoxin Model of HIV-1 Enteropathy: Involvement of GPR15/Bob and Galactosylceramide in the Cytopathic Effects Induced by HIV-1 gp120 in the HT-29-D4 Intestinal Cell Line

Abstract

Background: Malabsorption and diarrhea are common, serious problems in AIDS patients, and are in part due to the incompletely understood entity HIV enteropathy. Our prior in vitro work has shown that increased transepithelial permeability and glucose malabsorption, similar to HIV enteropathy, are caused by HIV surface protein gp120, although the mechanism remains unclear. Results: We studied the effects of HIV surface protein gp120 on the differentiated intestinal cell line HT-29-D4, specifically the effects on microtubules, transepithelial resistance, and sodium glucose cotransport. gp120 induced extensive microtubule depolymerization, an 80% decrease in transepithelial resistance, and a 70% decrease in sodium-dependent glucose transport, changes closely paralleling those of HIV enteropathy. The effects on transepithelial resistance were used to study potential inhibitors. Neutralizing antibodies to GPR15/Bob but not to CXCR4 (the coreceptor allowing infection with these HIV strains) inhibited these effects. Antibodies to galactosylceramide (GalCer) and a synthetic analog of GalCer also inhibited the gp120-induced changes, suggesting the involvement of GalCer-enriched lipid rafts in gp120 binding to intestinal epithelial cells. Conclusion: We conclude that direct HIV infection and gp120-induced cytopathic effects are distinct phenomena. While in vivo confirmation is needed to prove this, gp120 could be a virotoxin significantly contributing to HIV enteropathy.

Simian Immunodeficiency Virus–Induced Intestinal Cell Apoptosis Is the Underlying Mechanism of the Regenerative Enteropathy of Early Infection

“…Peak gut epithelial cell apoptosis coincided with visible interactions between virus and GPR15/ Bob, an alternative coreceptor for SIV [21] and HIV [22] and a mediator of CD4-independent entry [23] that has been found to be implicated in HIV enteropathy [24,25]. Before and at the onset of gut infection in the animals, we detected only background levels of viral RNA in a particulate pattern characteristic of virions deposited along the basal surfaces of gut epithelium (figure 6A), and GPR15/Bob was mainly detectable at the basal surfaces of gut epithelium, to a lesser extent at apical surfaces, and in MNCs in lamina propria of the small and large bowel ( figure 6B and 6C), just as has been described as occurring in human gut tissues [24].…”

Functional CD8+ CTLs in mucosal sites and HIV infection: moving forward toward a mucosal AIDS vaccine

“…Neutralizing antibodies to G protein-coupled receptor 15 and brother of Bonzo (GPR15/Bob, the HIV and SIV co-receptor, respectively) but not to CXCR4 inhibited these effects [47]. Antibodies to GalCer also inhibited the gp120-induced changes, suggesting the involvement of GalCer-enriched lipid rafts in gp120 binding to intestinal epithelium [47]. Thus, this in vitro study suggests that direct HIV infection and gp-120-induced cytopathic effects are distinct phenomena [47].…”

“…Antibodies to GalCer also inhibited the gp120-induced changes, suggesting the involvement of GalCer-enriched lipid rafts in gp120 binding to intestinal epithelium [47]. Thus, this in vitro study suggests that direct HIV infection and gp-120-induced cytopathic effects are distinct phenomena [47]. HAART therapy has been shown to reduce HIV enteropathy when administered early in infection [48]; however, the 'direct damage mechanism' on enterocytes by virus is not very well understood [39].…”

“…'HIV enteropathy' in the early phase of infection can be characterized by significant levels of intestinal inflammation with infiltrates of lymphocytes and macrophages, concurrent with villous atrophy, crypt hyperplasia and villous blunting [44][45][46]. It has been shown that increased transepithelial permeability and glucose malabsorption associated with HIV enteropathy can be replicated in vitro by gp120 binding to intestinal epithelium surface protein gp120 [47]. Neutralizing antibodies to G protein-coupled receptor 15 and brother of Bonzo (GPR15/Bob, the HIV and SIV co-receptor, respectively) but not to CXCR4 inhibited these effects [47].…”

“…It has been shown that increased transepithelial permeability and glucose malabsorption associated with HIV enteropathy can be replicated in vitro by gp120 binding to intestinal epithelium surface protein gp120 [47]. Neutralizing antibodies to G protein-coupled receptor 15 and brother of Bonzo (GPR15/Bob, the HIV and SIV co-receptor, respectively) but not to CXCR4 inhibited these effects [47]. Antibodies to GalCer also inhibited the gp120-induced changes, suggesting the involvement of GalCer-enriched lipid rafts in gp120 binding to intestinal epithelium [47].…”