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Substantial CD4+ T-cell Recovery and Reconstitution of Tissue Architecture in Gut-associated Lymphoid Tissue in Advanced HIV-1 Infection following Initiation of HAART with Nevirapine plus Trizivir
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Reported by Jules Levin
CROI, Feb 2007, Los Angeles
E Connick1, Derek Shenefelt*1,2, Derek Shenefelt*1,2, J Folkvord1, M Thrun3, S MaWhinney1, J Gathe4, S Lundy5, and S Becker6
1Univ of Colorado Hlth Sci Ctr, Denver, US; 2Weber State Univ, Ogden, UT, US; 3Denver Dept of Publ Hlth, CO, US; 4Therapeutic Concepts, Houston, TX, US; 5Pharma Product Devt, Inc, Menlo Park, CA, US; and 6AnorMED Inc, Langley, Canada
Gut-associated lymphoid tissue (GALT) harbors the majority of CD4+ T cells and is rapidly depleted in early HIV infection. Previous studies suggest that reconstitution of CD4+ T cells in HAART-treated individuals is less complete early in infection in GALT than in peripheral blood; particularly in the lamina propria (LP). Most studies have evaluated GALT by flow cytometry, which provides relative estimates of CD4+ T cells. We hypothesized that reconstitution of CD4+ T cells in GALT may have been underestimated by this method and that absolute numbers of CD4+ T cells reconstituted in GALT exceed those in peripheral blood. The aim was to characterize HAART-related CD4 T cell recovery in GALT using absolute cell counts in intact tissue.
14 subjects were recruited and the 8 untreated AIDS patients completed the study. 3 women, 5 men; 3 white, 3 black, 2 hispanic; median age 55 (range 23-78) yrs; median viral load 5.7 (range 4.4-5.9) log copies/ml.
They underwent colonic biopsies and provided peripheral blood samples at baseline, 24 and 48 weeks after starting nevirapine (NVP)/trizivir (TZV); 4-_m sections of GALT biopsies were stained with CD3 and CD4 antibodies, and analyzed by immunofluorescent microscopy. Numbers of lamina propria CD4+ T cells/mm3 were calculated and tissue histology observed. A mixed model was used to account for within subject correlations. Colonic tissue was obtained from 4 individuals at low risk for HIV infection for controls.
All but 1 subject achieved a viral load <400 copies/mL by week 48. One subject did not decline at 24 weeks but approached undetectable at week 48. Mean peripheral blood CD4+ T cells/mm3 increased from 65 at baseline to 192 at week 24 (p <0.15) and 216 at week 48 (p = 0.08 vs baseline). Mean GALT CD4+ T cells/mm3 were 279 at baseline, which was higher than that in peripheral blood (p = 0.08). Mean GALT CD4+ T cells increased through week 24 to 895 cells/mm3 (p <0.0001), a larger increase than was observed in peripheral blood (p = 0.0006). Mean GALT CD4+ T cells decreased to 759 cells/mm3 at week 48, but remained significantly different than baseline (p <0.0001) and still reflected a larger increase than in peripheral blood (p = 0.0096). At each time point GALT was substantially greater than in peripheral blood.
Peripheral blood and GALT reconstitution were calculated as a percentage of normal values assuming a norm of 1000 cells/mm3 in peripheral blood and using values for GALT CD4+ T cells obtained in 4 control colonic biopsies (2200 cells/mm3. At baseline, mean CD4+ T cells were 7% in peripheral blood and 12% in GALT of normal values (p = 0.21). At week 24, peripheral blood and GALT values were 19% and 40% (p =0.011 GALT vs peripheral blood increase), and at week 48, 22% and 34% (p = 0.12 GALT vs peripheral blood increase over baseline) of normal values. (abstract: Lymphoid aggregates were observed in colonic tissue of 1 subject at baseline, 6 subjects at week 24 (p = 0.04), and 5 subjects at week 48 (p = 0.12 vs baseline).
An unexpected finding in this study was the reconstitution of lymphoid aggregates in the GALT tissue. At baseline 1 subject had defined lymphoid aggregates, at 24 weeks 6 had defined lymphoid aggregates, and week 48 5 individuals had defining lymphoid aggregates. Previous studies have recorded reconstitution of lymphoid follicles in tonsil and other lymphoid tissue but to their knowledge the authors said this was the first report of reconstitution of lymphoid aggregates in GALT tissue as a result of HAART.
The authors concluded: NVP/TZV in advanced HIV-1 infection results in substantial recovery of CD4+ T cells and reconstitution of tissue architecture in GALT. Increases in CD4+ T cells are significantly larger in GALT than peripheral blood, particularly during the first 24 weeks of therapy. Numerical recovery of CD4 T cells per unit volume was significantly greater in GALT LP than in peripheral blood. The author said "When taking into account the greater volume of GALT tissue compared to peripheral blood the reconstitution of the GALT CD4 T cells is even more impressive to the total body counts".
When expressed as a percentage of control values, there was no evidence of inferior recovery of CD4 T cells in LP compared to PB. In both compartments, recovery of CD4 T cells was most profound during the first 24 weeks of HAART and then slowed. These data provide - "Substantial immune reconstitution occurs in GALT during HAART".
Future Directions for studies:
--quantify CD4 T cells in lymphoid aggregates
--characterize the LP CD4 T cells that are reconstituted
--evaluate the dynamics of CD8 T cell counts in GALT during HAART
--determine the long term magnitude of CD4 T cell reconstitution in GALT during HAART
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