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Enteric microtubule depolymerization in HIV infection: a possible cause of HIV-associated enteropathy

Clayton, Frederica; Kapetanovic, Suada; Kotler, Donald P.b

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aDepartment of Pathology, Salt Lake VAMC, and University of Utah, Salt Lake City, UT, USA; and bDepartment of Gastroenterology, St Luke's/Roosevelt Hospital and Columbia University, New York, NY, USA.

Sponsorship: F.C. was supported by VA research office funds. D.P.K. was supported by NIH grant A12 1414.

Received: 12 September 2000;

revised: 4 October 2000; accepted: 10 October 2000.

HIV-infected individuals often develop malabsorption of carbohydrates [1] and lipids [2], and increased small bowel transepithelial permeability with altered bowel habits [3] in the absence of enteric infections or other known etiology, a condition called HIV-associated enteropathy. The histological changes are subtle and correlate poorly with the physiological changes. Microtubules are normally present in enteric epithelium and are important for intracellular transport. Microtubule disrupting agents such as colchicine and nocodazole decrease lipid transport [4], increase intestinal permeability [5], cause diarrhea [6], and in vitro reduce sodium–glucose co-transport [7]. Microtubules are labile and difficult to study in biopsies, but modifications found in stable microtubules, such as acetylated tubulin [8] can be studied immunocytochemically. We thus examined intestinal epithelial microtubule changes in HIV-infected individuals by staining for acetylated tubulin.

The rectal biopsies were from eight healthy, uninfected controls and 28 HIV-infected individuals. The HIV-infected individuals had altered bowel habits but no enteric opportunistic infections. Eleven individuals were antiretroviral naive, and were biopsied before and one week after initiating combination antiretroviral treatment [9]. The proximal small bowel biopsies were from seven healthy, uninfected controls and 10 HIV-infected individuals. Frozen sections were treated with 10% normal goat serum, stained with monoclonal anti-acetylated tubulin (Sigma, St Louis, MO, USA; 4 μg/ml), then Cy3 conjugated goat anti-mouse IgG (Jackson Immunoresearch, West Grove, PA, USA). Each took 30 min at room temperature. DAPI (4′, 6-diamidino-2-phenylindole) and Alexa 488 phalloidin (Molecular Probes, Eugene, OR, USA) were used as counterstains. The percentage of rectal surface epithelial cells or small bowel villus epithelial cells with reduced or absent acetylated tubulin staining was estimated in a blinded manner.

In the HIV-infected individuals, 36 ± 6% (mean ± standard error of the mean) of the small bowel villus epithelial cells had weak or absent acetylated tubulin staining, versus 8 ± 3% for the controls (see Fig. 1). In the rectal biopsies, HIV-infected individuals without antiretroviral treatment had a mean of 75 ± 7% of surface epithelial cells and weak or absent staining for acetylated tubulin versus 15 ± 3% for the controls. Both changes were statistically significant (P < 0.01, Mann–Whitney U-test). Small bowel and rectal crypt acetylated tubulin staining was reduced only near lymphoid aggregates. AIDS patients and HIV-infected individuals who had not developed AIDS had similar acetylated tubulin staining. Ten out of 11 individuals receiving one week of antiretroviral treatment had increased staining for acetylated tubulin (P = 0.006, Wilcoxon matched pairs test) but the staining remained less than that of the normal controls.

Fig. 1
Fig. 1
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The loss of a stable microtubule marker suggests that microtubule depolymerization is present in vivo. In a previous study [7], gp120-treated HT-29 cells had increased cytosolic calcium, tubulin depolymerization, decreased glucose absorption, and decreased transepithelial resistance. Nocodazole caused similar changes. Increased calcium can directly depolymenze microtubules [10]. We suspect that gp120 activation of a G protein coupled receptor/HIV co-receptor causes the calcium release and microtubule changes.

Microtubule depolymerization interferes with enterocyte lipid transport, causing lipid malabsorption [4]. Microtubule disruption alters rac1 and rhoA activation, increasing actin–myosin contractility [11]. Perijunctional actin–myosin ring contraction dilates the intercellular spaces near the tight junctions, increasing transepithelial permeability [12].

In summary, these results suggest that small bowel and rectal epithelial cell microtubule depolymenzation occurs in vivo. Previous in-vitro studies [7] suggested that gp120 causes calcium signaling and microtubule depolymerization. Microtubule-disrupting agents cause physiological changes similar to those of HIV-associated enteropathy [4–7]. Microtubule depolymerization, possibly by gp120-induced HIV co-receptor activation, could be an important mechanism causing the physiological changes of HIV-associated enteropathy.

Frederic Claytona

Suad Kapetanovica

Donald P. Kotlerb

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References

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3. Stockmann M, Fromm M, Schmitz H, Schmidt W, Riecken EO, Schulzke JD. Duodenal biopsies of HIV-infected patients with diarrhoea exhibit epithelial barrier defects but no active secretion. AIDS 1998, 12: 43 –51.

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7. Delezay O, Yahi N, Tamalet C, Baghdiguian S, Boudier JA, Fantini J. Direct effect of type 1 human inununodeficiency virus (HIV-1) on intestinal epithelial cell differentiation: relationship to HIV-1 enteropathy. Virology 1997, 238: 231 –242.

8. Piperno G, LeDizet M, Chang XJ. Microtubules containing acetylated alpha-tubulin in mammalian cells in culture. J Cell Biol 1987, 104: 289 –302.

9. Kotler DP, Shimada T, Snow G. et al. Effect of combination antiretroviral therapy upon rectal mucosal HIV RNA burden and mononuclear cell apoptosis. AIDS 1998, 12: 597 –604.

10. O'Brien ET, Salmon ED, Erickson HP. How calcium causes microtubule depolymerization. Cell Motil Cytoskeleton 1997, 36: 125 –135.

11. Waterman Storer CM, Salmon E. Positive feedback interactions between microtubule and actin dynamics during cell motility. Curr Opin Cell Biol 1999, 11: 61 –67.

12. Madara JL, Pappenheimer JR. Structural basis for physiological regulation of paracellular pathways in intestinal epithelia. J Membr Biol 1987, 100: 149 –164.

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© 2001 Lippincott Williams & Wilkins, Inc.

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