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.
Highlights
Chronic immune activation is a hallmark of HIV infection and contributes in multiple ways to HIV persistence
We found that elevated systemic IP-10 levels before HIV-1 infection associate with a more rapid disease progression
The animal model showed that IP-10 expression was regionalized in the intestine and highest in the small intestine
Summary
Chronic immune activation is a hallmark of HIV infection [1]. Effective combined-antiretroviral therapy (cART) reduces HIV viremia to undetectable levels, but milder chronic immune activation persists and is associated with onset of both AIDS and non-AIDS illnesses [2, 3]. Studies of SIV+ non-human primates (NHP) such as Asian macaques (MAC) and natural hosts of SIV such as African green monkeys (AGM) support a role of immune activation and microbial translocation in HIV pathogenesis [1, 5, 6, 7, 8,9,10,11,12,13,14,15]. High inflammation level at Fiebig stages III and IV of PHI was associated with rapid loss of CD4+ T-cells. Among 28 pro-inflammatory factors tested, CXCL10/IP-10 was a strong and independent predictive marker of rapid CD4+ T-cell loss [17]. During PHI, IP-10 was even a more robust predictive marker than viremia or the CD4+ T-cell nadir
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
