Immune Aging and HIV

Editors

Ujjwal Neogi

Department of Laboratory Medicine, Karolinska Institutet (KI)

Luke Elizabeth Hanna

National Institute of Research in Tuberculosis (ICMR)

Impact

(A) Typically, gut-associated bacteria, Firmicutes, produces butyrate which inhibits HDAC1. With normal aging or HIV-infection, Firmicutes is replaced causing reduced production of butyrate and consequently increased expression of HDAC1, which acts to increase HIV transcription. (B) Pannex-1 channels, usually closed, open upon binding of HIV to receptors CD4 and co-receptor CCR5, which causes release of ATP, an inflammatory signal. Increased levels of ATP in circulation were correlated with cognitive impairment and thus predictive of CNS compromise. (C) During HIV-infection plasma levels of monocyte activation markers sCD163 and sCD14, as well as pro-inflammatory marker IP-10 are elevated and inversely related with CD4+ T-cell depletion. Over-expression of these markers in the periphery leads to accelerated aging of T cells and senescence. (D) Upon HIV-infection, secretion of exosomes increases along with oxidative stress markers, and HIV-induced chronic activation alters the contents of exosomes. Notch-4 exosomal levels are elevated and correlated with other activation markers, HLA-DR. (E) HIV-infection reduces expression of circulating TRAIL, an apoptosis-inducing protein, which theoretically in turn limits apoptosis of CD4+ T-cell reservoirs allowing for persistent immune activation and inflammation. (F) Telomeres undergo attrition after HIV-infection due to reduced T-cell proliferation and this is associated with cellular senescence markers CD8+, HLA-DR, and CD38+.

Mini Review

09 October 2020

Biomarkers of Activation and Inflammation to Track Disparity in Chronological and Physiological Age of People Living With HIV on Combination Antiretroviral Therapy

Michellie Thurman

, 4 more and

Siddappa N. Byrareddy

With advancement, prompt use, and increasing accessibility of antiretroviral therapy, people with HIV are living longer and have comparable lifespans to those negative for HIV. However, people living with HIV experience tradeoffs with quality of life often developing age-associated co-morbid conditions such as cancers, cardiovascular diseases, or neurodegeneration due to chronic immune activation and inflammation. This creates a discrepancy in chronological and physiological age, with HIV-infected individuals appearing older than they are, and in some contexts ART-associated toxicity exacerbates this gap. The complexity of the accelerated aging process in the context of HIV-infection highlights the need for greater understanding of biomarkers involved. In this review, we discuss markers identified in different anatomical sites of the body including periphery, brain, and gut, as well as markers related to DNA that may serve as reliable predictors of accelerated aging in HIV infected individuals as it relates to inflammatory state and immune activation.

7,515 views

22 citations

Original Research

30 September 2020

Impact of Age and HIV Status on Immune Activation, Senescence and Apoptosis

Malene Hove-Skovsgaard

, 10 more and

Susanne Dam Nielsen

Gating strategy. (A) Activated T-cells (HLA-DR+ CD38+). (B) Senescent T-cells (CD28-CD57+). (C) Apoptotic T-cells (CD28-CD95+).

Introduction: Residual immune dysfunctions, resembling those that occur during normal aging, may persist even in well-treated people with HIV (PWH), and accelerated aging has been proposed. We aimed to determine if HIV infection is an independent risk factor for T-cell immune dysfunctions including increased immune activation, senescence and apoptosis. Moreover, in PWH we aimed to identify the associations between age and immune activation, senescence and apoptosis.

Materials and Methods: We included 780 PWH with suppressed viral replication (<50 copies/mL) and absence of hepatitis B and hepatitis C co-infection and 65 uninfected controls from the Copenhagen Co-morbidity in HIV Infection (COCOMO) Study. Flow cytometry was used to determine T-cell activation (CD38+HLA-DR+), senescence (CD28-CD57+), and apoptosis (CD28-CD95+). T-cell subsets are reported as proportions of CD4+ and CD8+ T-cells. We defined an elevated proportion of a given T-cell subset as above the 75th percentile. Regression models were used to determine the association between HIV status and T-cell subset and in PWH to determine the association between age or HIV-specific risk factors and T-cell subsets. Furthermore, an interaction between HIV status and age on T-cell subsets was investigated with an interaction term in models including both PWH and controls. Models were adjusted for age, sex, BMI, and smoking status.

Results: In adjusted models a positive HIV status was associated with elevated proportions of CD8+ activated (p = 0.009), CD4+ senescent (p = 0.004), CD4+ apoptotic (p = 0.002), and CD8+ apoptotic (p = 0.003) T-cells. In PWH a 10-year increase in age was associated with higher proportions of CD4+ and CD8+ senescent (p = 0.001 and p < 0.001) and CD4+ and CD8+ apoptotic T-cells (p < 0.001 and p < 0.001). However, no interaction between HIV status and age was found. Furthermore, in PWH a CD4+/CD8+ ratio < 1 was associated with elevated proportions of T-cell activation, senescence, and apoptosis.

Discussion: We found evidence of residual T-cell immune dysfunction in well-treated PWH without HBV or HCV co-infection, and age was associated with T-cell senescence and apoptosis. Our data supports that HIV infection has similar effects as aging on T-cell subsets. However, since no interaction between HIV status and age was found on these parameters, we found no evidence to support accelerated immunological aging in PWH.

5,305 views

19 citations

Original Research

06 October 2020

Monocyte and T Cell Immune Phenotypic Profiles Associated With Age Advancement Differ Between People With HIV, Lifestyle-Comparable Controls and Blood Donors

Davide De Francesco

, 2 more and

Neeltje A. Kootstra

2,617 views

7 citations

Original Research

30 June 2020

Associations Between Plasma Immunomodulatory and Inflammatory Mediators With VACS Index Scores Among Older HIV-Infected Adults on Antiretroviral Therapy

Thomas A. Premeaux

, 7 more and

Lishomwa C. Ndhlovu

The prevalence of age-related comorbidities is increased in people living with HIV, even in those well-controlled on combination antiretroviral therapy (ART). Persistent immune activation and inflammation may play pivotal roles in the pathogenesis; however, the burden of morbidities in the older HIV infected population may be exacerbated and driven by distinct mechanisms. In a cross sectional study of 45 HIV-infected participants 60 years or older, we examined the relationships between 14 immunomodulatory and inflammatory factors and the Veterans Aging Cohort Study (VACS) Index, a metric of multimorbidity and mortality comprised of age, CD4 count, hemoglobin, Fibrosis-4 [FIB-4], and estimated glomerular filtration rate [eGFR], by linear regression analysis. All participants were virally suppressed (<50 HIV RNA copies/mL), on ART, and primarily Caucasian (86.7%), and male (91.1%). Plasma levels of monocyte/macrophage-associated (neopterin, IP-10, sCD163, sCD14, and MCP-1) and glycan-binding immunomodulatory factors (galectin (Gal)-1, Gal-3, and Gal-9) were assessed, as well as inflammatory biomarkers previously linked to the VACS Index (i.e., CRP, cystatin C, TNF-α, TNFRI, IL-6, and D-dimer) for comparison. In regression analysis, higher VACS index scores were associated with higher levels of neopterin, cystatin C, TNFRI, and Gal-9 (all p < 0.05), potentially driven by correlations found with individual VACS components, including age, CD4 count, FIB-4, and eGFR. Gal-9, cystatin C, and TNFRI directly correlated with the extent of multimorbidity. Multiple correlations among markers were observed, suggesting an interplay of overlapping, but distinct, pathways. Collectively, in addition to cystatin C and TNFRI, both galectin-9 and neopterin, independently emerged as novel fluid markers of the VACS Index and burden of comorbidity and may further guide in understanding pathogenic mechanisms of age-related disorders in older HIV-infected individuals on suppressive ART.

4,437 views

17 citations

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