Early cART therapy reduces gut inflammation

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Earlier combination antiretroviral therapy (cART) may be beneficial to the health of HIV-infected individuals, but also indicates that CD4+ T cell depletion in the gut remains intractable with current therapy.

Combination antiretroviral therapy (cART) suppresses HIV replication and significantly slows the progression of disease, enabling HIV+ individuals to effectively manage infection for long periods.

One of the manifestations of HIV infection is chronic inflammation in the gut and damage to the gastrointestinal barrier, which is thought to contribute to immune system activation. Elevated immune system activation is associated with increased risk of non-Aids-associated disease and death in HIV+ individuals.

A research team led by Jacob Estes of the AIDS and Cancer Virus Programme at the Frederick National Laboratory for Cancer Research reports on the impact of cART on gut inflammation in acutely infected HIV patients. This group of patients is particularly unique as infection was identified on average 16 days after initial HIV infection.

By examining colon biopsies taken from acute and chronic infection phases, this study provides an unprecedented look at the impact of early cART on the gut.

The researchers found that all infected individuals already had reduced CD4+ T cells within the gut and showed signs of significant gut inflammation at the time infection, demonstrating that gastrointestinal tract damage occurs very early after infection.

Subsequent analysis showed that early cART blunts gastrointestinal inflammation and immune activation in acutely infected HIV patients but did not restore CD4+ T cell counts in the gut in the long-term.

These findings suggest that earlier cART may be beneficial to the health of HIV-infected individuals, but also indicates that CD4+ T cell depletion in the gut remains intractable with current therapy.

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 LK 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

JCI Insight material
JCI Insight abstract


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