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.
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.


CONCLUSIONS
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.
Maresca
Marc
M
Institut Méditerranéen de Recherche en Nutrition, UMR-INRA 1111, Faculté des Sciences de St-Jérôme, Marseille, France.
Mahfoud
Radhia
R
Garmy
Nicolas
N
Kotler
Donald P
DP
Fantini
Jacques
J
Clayton
Frederic
F
D002460:Cell Line; D002712:Chlorides / Q000378:metabolism; D003599:Cytoskeleton; D004594:Electrophysiology; D005699:Galactosylceramides / Q000502:physiology*; D019053:HIV Enteropathy / Q000209:etiology* / Q000473:pathology; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology* / Q000821:virology; D021962:Membrane Microdomains / Q000502:physiology; D008954:Models, Biological; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide / Q000502:physiology*; D011991:Receptors, Virus / Q000502:physiology
D002712:Chlorides; C103539:GPR15 protein, human; D005699:Galactosylceramides; D015699:HIV Envelope Protein gp120; D010456:Peptides, Cyclic; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D011991:Receptors, Virus; C026460:virotoxins