Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV

Abstract

People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n = 600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n = 8111) from blood DNA-derived exome sequences. We observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p = 0.005). We also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH. Our results suggest that CHIP may contribute to the excess cardiovascular risk observed in PLWH.

Cardiovascular Disease Among Persons Living With HIV: New Insights Into Pathogenesis and Clinical Manifestations in a Global Context

“…48 In this study, the differences in CHIP frequency by HIV status may have been driven by older individuals in particular. 48 The role of CHIP as a mediator or marker of HIV-associated CAD risk requires further clarification, but does emphasize the potential for the absolute burden of excess CAD risk among PLWH to continue to increase with advancing age.…”

“…47 In a recent epidemiological analysis of data from the Swiss HIV Cohort Study and the ARIC study (Atherosclerotic Risk in the Community), PLWH had a 2-fold increase in CHIP prevalence that was replicated with sensitivity analyses that selected a case-control with propensity score matching. 48 In this study, the differences in CHIP frequency by HIV status may have been driven by older individuals in particular. 48 The role of CHIP as a mediator or marker of HIV-associated CAD risk requires further clarification, but does emphasize the potential for the absolute burden of excess CAD risk among PLWH to continue to increase with advancing age.…”

Genomic Aging, Clonal Hematopoiesis, and Cardiovascular Disease

“…People living with HIV, who are known to have heightened cardiovascular disease risk, are enriched for CHIP mutations. 102,103 Early studies indicate a greater relative enrichment of non-DNMT3A CHIP compared with unselected populations indicating the likelihood of unique selective pressures. Among PHW on stable antiretroviral therapy, CHIP was associated with low CD4 nadir and increased residual HIV-1 transcriptional activity.…”

Einfluss der klonalen Hämatopoese auf nicht-hämatologische Erkrankungen und Alterungsprozesse

“…CHIP ist nicht nur mit chronischen Erkrankungen des Herzens oder der Lunge assoziiert, sondern auch mit Infektionskrankheiten. Personen mit Human-immunodeficiency-virus(HIV)-Infektion wiesen eine 2‑fach erhöhte Prävalenz für CHIP auf [ 45 , 46 ]. Interessanterweise sind Mutationen im Gen ASXL1 bei Patient*innen mit HIV-Infektion sehr häufig der Auslöser für CHIP.…”