Abstract
ObjectiveSerious non-AIDS disease events (SNAE) are experienced disproportionately by immunologic non-responders (INRs), HIV-infected individuals who do not restore CD4 T cells in blood despite effective viral suppression. We aimed to characterize the inflammatory biomarker profile of the INR phenotype.MethodsBlinded cross-sectional cohort study comparing markers of immune activation and gut homing between INR and non-INR individuals. HIV-positive participants had HIV RNA suppression on antiretroviral therapy and were categorized as either INR (N = 36) or Clinical Responders (“CR”; CD4>350/mm3; N = 47). 18 HIV-negative comparator individuals were included. Cellular markers were assessed by flow cytometry, with soluble markers assessed by ELISA and LC/MS-MS. Multivariable linear regression models estimated the association between INR phenotype and markers, adjusting for age, sex, duration of ART, and recent infection/vaccination.ResultsINR participants demonstrated a reduced CD4/CD8 ratio (p<0.001), 35% more CD8 activation (p = 0.02), 36% greater α4β7+ CD4 T cells (p<0.01), 54% more HLA-DR+ CD4 T cells (p<0.001), and 20% higher plasma VCAM (p<0.01) compared to CRs. The INR phenotype was not associated with levels of Kyn/Trp, CRP, TNF, IFNγ, IL-8, IL-6, sCD14, D-Dimer, I-FABP, MCP-1, ICAM or CD8%HLA-DR+.ConclusionsPeripheral CD4 non-recovery during long-term treated HIV infection is characterized by elevated CD8 activation and CD4 gut homing. Gut-focused interventions may be warranted in the INR context, and CD8 activation may serve as a surrogate endpoint for clinical interventions.
Highlights
Effective antiretroviral therapy (ART) has dramatically improved life expectancy for individuals living with HIV
immunologic non-responders (INRs) participants demonstrated a reduced CD4/CD8 ratio (p
The INR phenotype was not associated with levels of Kyn/Trp, CRP, TNF, IFNγ, IL-8, IL-6, sCD14, D-Dimer, IFABP, MCP-1, ICAM or CD8%HLA-DR+
Summary
Effective antiretroviral therapy (ART) has dramatically improved life expectancy for individuals living with HIV. HIV infection remains linked to an increased risk of premature death and serious non-AIDS health events (SNAE) such as cardiovascular events, nonAIDS cancers, and renal or liver disease [1]. The fundamental drivers of SNAE are poorly defined, but thought to be linked to chronic immune activation [3], which in turn may be a consequence of viral coinfections, low-level HIV replication, microbial translocation across the damaged mucosa of the gastrointestinal tract [4,5,6], antiretroviral therapy and/or lifestyle-related factors, such as smoking and high cholesterol [3, 7]. It has become clear that SNAEs disproportionately affect individuals with suboptimal immune restoration despite viral RNA suppression with ART. A low number of blood CD4+ T cells (CD4 count) at the time of ART initiation, and slow recovery of blood CD4 count thereafter, have been associated with SNAE and premature death [2, 8,9,10]
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