Circulating LOXL2 Levels Reflect Severity of Intestinal Fibrosis and GALT CD4(+) T Lymphocyte Depletion in Treated HIV Infection

BACKGROUND: Incomplete immune reconstitution may occur despite successful antiretroviral therapy (ART). Gut-associated lymphoid tissue (GALT) fibrosis may contribute via local CD4(+) T lymphocyte depletion, intestinal barrier disruption, microbial translocation, and immune activation. METHODS: In a cross-sectional analysis, we measured circulating fibrosis biomarker levels on cryopreserved plasma from adult HIV-infected (HIV+) SCOPE study participants on suppressive ART who also had fibrosis quantification on recto-sigmoid biopsies. Relationships among biomarker levels, clinical and demographic variables, GALT lymphoid aggregate (LA) collagen deposition, and LA CD4(+) T lymphocyte density were analyzed using simple regression. Biomarker levels were also compared to levels in HIV+ viremic SCOPE participants and a convenience sample of HIV-uninfected (HIV-) samples. RESULTS: HIV+ aviremic participants (n = 39) were 92% male and 41% non-white, with median age 48 years, CD4(+) T lymphocyte count 277 cells/mm(3), and 17 years since HIV diagnosis. Most biomarkers were lower in HIV− (n = 36) vs HIV+ aviremic individuals, although CXCL4 levels were higher. HIV+ viremic individuals (N = 18) had higher median TGF-ß(3), CIC-C1Q, and TIMP-1 (P < 0.05) and lower LOXL2 levels (P = 0.08) than HIV+ aviremic individuals. Only higher LOXL2 levels correlated with more GALT collagen deposition (R = 0.44, P = 0.008) and lower LA CD4(+) T lymphocyte density (R = −0.32, P = 0.05) among aviremic individuals. CONCLUSIONS: Circulating LOXL2 levels may be a noninvasive measure of intestinal fibrosis and GALT CD4(+) T lymphocyte depletion in treated HIV infection. LOXL2 crosslinks elastin and collagen, and elevated LOXL2 levels occur in pathologic states, making LOXL2 inhibition a potential interventional target for intestinal fibrosis and its sequelae.