Elevated Basal Pre-infection CXCL10 in Plasma and in the Small Intestine after Infection Are Associated with More Rapid HIV/SIV Disease Onset

Abstract

Elevated blood CXCL10/IP-10 levels during primary HIV-1 infection (PHI) were described as an independent marker of rapid disease onset, more robust than peak viremia or CD4 cell nadir. IP-10 enhances the recruitment of CXCR3+ cells, which include major HIV-target cells, raising the question if it promotes the establishment of viral reservoirs. We analyzed data from four cohorts of HIV+ patients, allowing us to study IP-10 levels before infection (Amsterdam cohort), as well as during controlled and uncontrolled viremia (ANRS cohorts). We also addressed IP-10 expression levels with regards to lymphoid tissues (LT) and blood viral reservoirs in patients and non-human primates. Pre-existing elevated IP-10 levels but not sCD63 associated with rapid CD4 T-cell loss upon HIV-1 infection. During PHI, IP-10 levels and to a lesser level IL-18 correlated with cell-associated HIV DNA, while 26 other inflammatory soluble markers did not. IP-10 levels tended to differ between HIV controllers with detectable and undetectable viremia. IP-10 was increased in SIV-exposed aviremic macaques with detectable SIV DNA in tissues. IP-10 mRNA was produced at higher levels in the small intestine than in colon or rectum. Jejunal IP-10+ cells corresponded to numerous small and round CD68neg cells as well as to macrophages. Blood IP-10 response negatively correlated with RORC (Th17 marker) gene expression in the small intestine. CXCR3 expression was higher on memory CD4+ T cells than any other immune cells. CD4 T cells from chronically infected animals expressed extremely high levels of intra-cellular CXCR3 suggesting internalization after ligand recognition. Elevated systemic IP-10 levels before infection associated with rapid disease progression. Systemic IP-10 during PHI correlated with HIV DNA. IP-10 production was regionalized in the intestine during early SIV infection and CD68+ and CD68neg haematopoietic cells in the small intestine appeared to be the major source of IP-10.

Systemic DPP4 activity is reduced during primary HIV‐1 infection and is associated with intestinal RORC+CD4+ cell levels: a surrogate marker candidate of HIV‐induced intestinal damage

“…A large serum library derived from cART‐naïve patients, including pre‐infection samples from patients enrolled in the Amsterdam Cohort Studies (ACS) of HIV infection and AIDS was used (Table , ). None of the 136 subjects studied here had started anti‐retroviral therapy when samples were collected.…”

“…The viremic cART‐naive subjects (VIR, n = 121) were part of the French ANRS C09 COPANA cohort (Table ) . A subgroup from the COPANA Cohort of 40 patients received cART (>24 months of follow‐up and >12 months with VL < 50 copies/mL) .…”

“…The HIC (n = 82) were enrolled in the French ANRS C021 CODEX cohort (Table , ). To be enrolled, patients had to be diagnosed as HIV‐infected for more than five years and to remain cART‐naive with viraemia below 400 copies/mL in at least five consecutive assays, regardless of their CD4 cell count .…”

“…The quantification of IP‐10 (also known as CXCL10) was previously reported and based on enzyme‐linked immunosorbent assays. Briefly, the IP‐10 concentrations were determined in stored plasma or sera samples (−80°C) using the commercially available Quantikine CXCL10 assay (R&D Systems, Minneapolis, Minnesota) according to the manufacturers’ instruction.…”

“…Total RNA was extracted and reverse‐transcribed as previously described . qPCR (Taqman chemistry) and commercial kits were used to quantify the expression levels of genes of interest in the simian samples as previously reported . Briefly, the Taqman primers and probes used were Hs00175210 for DPP4 , Hs01076112_m1 for RORc , Hs00203436_m1 for Tbx21 and 4310893 E for 18S.…”