Impact of early cART in the gut during acute HIV infection
Claire Deleage, … , Jacob D. Estes, on behalf of the RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups
Claire Deleage, … , Jacob D. Estes, on behalf of the RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups
Published July 7, 2016
Citation Information: JCI Insight. 2016;1(10):e87065. https://doi.org/10.1172/jci.insight.87065.
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Research Article AIDS/HIV

Impact of early cART in the gut during acute HIV infection

Abstract

Early after HIV infection there is substantial depletion of CD4+ T cells in the gastrointestinal (GI) tract lamina propria (LP), with associated epithelial barrier damage, leading to microbial translocation and systemic inflammation and immune activation. In this study, we analyzed these early events in the GI tract in a cohort of Thai acute HIV-infected patients and determined the effect of early combination antiretroviral treatment (cART). HIV-uninfected and chronically and acutely HIV-infected patients at different Fiebig stages (I–V) underwent colonic biopsies and then received cART. Immunohistochemistry and quantitative image analysis were performed on cross-sectional and longitudinal colon biopsy specimens (day 0 to week 96) to measure GI tract damage (infiltration of polymorphonuclear cells), inflammation (Mx1, TNF-α), immune activation (Ki-67), and the CD4+ T cell population in the LP. The magnitude of GI tract damage, immune activation, and inflammation was significantly increased, with significantly depleted CD4+ T cells in the LP in all acutely infected groups prior to cART compared with HIV-uninfected control participants. While most patients treated during acute infection resolved GI tract inflammation and immune activation back to baseline levels after 24 weeks of cART, most acutely infected participants did not restore their CD4+ T cells after 96 weeks of cART.

Authors

Claire Deleage, Alexandra Schuetz, W. Gregory Alvord, Leslie Johnston, Xing-Pei Hao, David R. Morcock, Rungsun Rerknimitr, James L.K. Fletcher, Suwanna Puttamaswin, Nittaya Phanuphak, Robin Dewar, Joseph M. McCune, Irini Sereti, Merlin Robb, Jerome H. Kim, Timothy W. Schacker, Peter Hunt, Jeffrey D. Lifson, Jintanat Ananworanich, Jacob D. Estes, on behalf of the RV254/SEARCH 010 and RV304/SEARCH 013 Study Groups

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Figure 1

CD4+ T cell count and vRNA in blood and sigmoid biopsies.

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CD4+ T cell count and vRNA in blood and sigmoid biopsies. Thai acute pat...
Thai acute patients presented no significant decrease of CD4+ T cell count in blood at the first visit compared with HIV chronic patients (A). Blood viral load (VL) was similar in Fiebig I/II (FI/II) (n = 19) or Fiebig III–V (FIII+) (n = 22) to that observed in chronically infected individuals (n = 6) (B). Colonic viral RNA (vRNA) increased significantly with progression of infection from FI/II to FIII+ (C). Representative ISH shows infected cells transcribing vRNA in the laminal propria (LP) of an FI/II individual in both the LP and lymphoid aggregates (LA) of an FIII+ patient (D). The number of CD4+ T cells in the blood increased gradually after initiation of the combined antiretroviral therapy (cART) (E), while the vRNA in blood (F) and in sigmoid colon biopsies (G) decreased. (E–G) For FI/II group at week 0, n = 19; week 24, n = 15; and week 96, n = 8. For FIII+ group at week 0, n = 22; week 24, n = 17; and week 96 n = 12. Each dot represents the median of at least 3 biopsies per participant. Within the FI/II group, lighter blue dots represent FI patients and darker blue represent the FII patients. Within FIII+ group, lighter blue dots represent FIII+ patients and darker dots represent FIV and FV patients. Scale bar: 100 μm. Following linear mixed-effects (lme) analyses, post-hoc lme contrasts and pairwise nonparametric (Wilcoxon) tests were performed. Benjamini-Hochberg adjusted P values are reported. Data are presented as box-and-whisker plots with the lower and upper limits (bounds) of the box representing Q1 (25th percentile) and Q3 (75th percentile), respectively. The median (Q2, 50th percentile) is represented by the horizontal line within the box. Whiskers, delineated as horizontal stems, extend to the limits of the data. Data points (superimposed) are “jittered” to avoid overplotting.