Clonal hematopoiesis in people with advanced HIV and associated inflammatory syndromes

Abstract

People with HIV (PWH) have a higher age-adjusted mortality due to chronic immune activation and age-related comorbidities. PWH also have higher rates of clonal hematopoiesis (CH) than age-matched non-HIV cohorts; however, risk factors influencing the development and expansion of CH in PWH remain incompletely explored. We investigated the relationship between CH, immune biomarkers, and HIV-associated risk factors (CD4+ and CD8+ T cells, nadir CD4+ count, opportunistic infections [OIs], and immune reconstitution inflammatory syndrome [IRIS]) in a diverse cohort of 197 PWH with median age of 42 years, using a 56-gene panel. Seventy-nine percent had a CD4+ nadir below 200 cells/μL, 58.9% had prior OIs, and 34.5% had a history of IRIS. The prevalence of CH was high (27.4%), even in younger individuals, and CD8+ T cells and nadir CD4+ counts strongly associated with CH after controlling for age. A history of IRIS was associated with CH in a subgroup analysis of patients 35 years of age and older. Inflammatory biomarkers were higher in CH carriers compared with noncarriers, supporting a dysregulated immune state. These findings suggest PWH with low nadir CD4+ and/or inflammatory complications may be at high risk of CH regardless of age and represent a high-risk group that could benefit from risk reduction and potentially targeted immunomodulation.

Keywords: AIDS/HIV; Aging; Clonal selection; Macrophages; T cells.

Figure 1. Characteristics of clonal hematopoiesis in people with HIV analyzed according to a history of IRIS.

(A) Proportion of participants with any clonal hematopoiesis (CH) mutation. (B) Number of CH variants identified per individual stratified by history of immune reconstitution inflammatory syndrome (IRIS). (C) Variant allele frequency (VAF; log transformed) over increasing age stratified by history of IRIS. Median values are represented by linear regression lines, and the shaded area represents the upper and lower 95% CIs. R represents Spearman’s correlation coefficient from each group with P value. (D) Proportion of individuals with any CH mutation by age group and history of IRIS.

Figure 2. Adjusted logistic regression with 95% CIs of key variables and their impact on risk of clonal hematopoiesis in people with HIV.

(A) Each HIV-associated variable was independently evaluated with logistic regression models while controlling for known factors that could impact clonal hematopoiesis (CH) risk (age, sex, race/ethnicity, smoking history, lymphoma/chemotherapy history) (n = 197). Odds ratios (OR) with 95% CIs are depicted. CD4⁺ and CD8⁺ T cell counts are presented as an OR per 50 cells/μL change. CD4⁺ T cell nadir was evaluated as a categorical variable (CD4⁺ T cell nadir <200 cells/μL) and a continuous variable (per 50 cells/μL change). (B) Sensitivity analysis was performed due to enrichment of younger individuals with a history of IRIS (n = 158). Logistic regression models evaluating the same key variables and controlling for the same cofactors were repeated, including only individuals ≥35 years of age. IRIS, immune reconstitution inflammatory syndrome; HLH, hemophagocytic lymphohistiocytosis.

Figure 3. Comparison of biomarkers in people with HIV with or without clonal hematopoiesis at the follow-up time point.

Available biomarkers were compared by clonal hematopoiesis (CH) status (n = 89). Data are presented as box-and-whisker plots with medians (lines within boxes) and IQRs (box bounds). Groups were compared by Wilcoxon’s rank sum test and resultant P values are shown. sCD14, soluble CD14; IL-8, interleukin-8; TNF-α, tumor necrosis factor α; vWF, von Willebrand factor; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1; IFN-γ, interferon γ; MPO,myeloperoxidase.

Figure 4. Characteristics of clonal hematopoiesis in people with HIV at initiation of antiretroviral therapy and longitudinal changes after immune reconstitution.

(A) Proportion of participants with any clonal hematopoiesis (CH) mutation at the Acute time point (time of antiretroviral therapy initiation). (B) Number of CH variants identified at the Acute time point per individual stratified by development of immune reconstitution inflammatory syndrome (IRIS). (C) Longitudinal trend in variant allele frequency (VAF; log transformed) from Acute time point to Follow-up time point by inflammatory syndrome status (No IRIS, IRIS, HLH). HLH occurred in setting of, or prior to IRIS, in all individuals. Data are presented as box-and-whisker plots with medians (lines within boxes) and IQRs (box bounds). Groups were compared using pairwise Wilcoxon’s rank sum test. (D) Comparison of VAF between those without IRIS to those with IRIS with or without HLH at the Acute and Follow-up time points. Groups were compared using Wilcoxon’s rank sum test and resultant P values are shown. *P < 0.05.