Five normal controls and 20 combination antiretroviral therapy (cART)-naïve HIV patients underwent duodenal biopsy. Normal subjects had virtually no fibrosis evident on both trichrome-stained biopsies and specimens examined by confocal microscopy. In contrast, HIV patients had variable amounts of fibrosis evident in the lamina propria. Immunostaining demonstrated that myofibroblasts were immediately adjacent to areas of collagen deposition, and these intestinal myofibroblasts (IMFs) expressed fibroblast activation protein (FAP). Confocal microscopy also revealed that in HIV patients, TLR4 was abundantly expressed in intestinal lamina propria. Primary cultures of HIV patient-derived IMFs were stimulated with lipopolysaccharide (LPS) and showed significantly increased mRNA expression of both TGF-B and IL-6 by real-time RT-PCR.

Using real-time RT-PCR to assess mRNA expression in intestinal tissue, HIV patients demonstrated significantly greater TGF-B expression than did normal controls, and that the level of TGF-B expression was positively correlated with pro-collagen type 1 expression and was negatively correlated with both baseline duodenal CD4+ T-cell count and change in peripheral CD4+ T-cell count measured 9 months after initiation of cART.

COMMENTARY

I remember attending a lecture back in the 1980s at one of the first International AIDS conferences and hearing Hans Wigzell (now president of the Karolinska Institute) presciently say, “The final battle of HIV is fought in the lymph nodes.” He was (and is) right. Later, many researchers correctly focused on the largest lymphoid organ in our bodies, gut-associated lymphoid tissue (GALT). A large body of evidence has emerged from both the study of humans and primate models of HIV that demonstrate profound and early (often within days of infection) depletion of CD4+ T-cells from GALT and an inflammatory response within the intestine. This inflammation is correlated with microbial translocation (elevated serum levels of bacterial 16 rDNA and endotoxin) as well as pro-inflammatory cytokines (TNF alpha, IL-6, sCD14, etc.) and markers of activation of the coagulation system (D-dimer).

The elegant work reported in this paper adds further understanding of these complex interactions between HIV and both inflammation and fibrosis within the intestine. The relationship between GALT IMF activation, inflammation, fibrosis, intestinal CD4+ T-cell depletion, and the effect on peripheral CD4+ lymphocyte recovery with cART is an important observation. Sadly, these patients who have poor immunological recovery despite effective viral suppression with cART have not responded to experimental treatment with hyper-intense cART regimens or immune enhancement therapy. The observations reported in this paper potentially open the door to other modes of treatment, including intestine-specific modulation of inflammation/fibrosis or microbiome manipulation. If effective interventions are eventually identified, beneficial effects on both immune reconstitution and amelioration of many of the adverse effects of HIV-associated inflammation (including accelerated vascular disease) can be anticipated.