Vascular injury markers associated with cognitive impairment in people with HIV on suppressive antiretroviral therapy

Guha, Debjani; Misra, Vikas; Yin, Jun; Horiguchi, Miki; Uno, Hajime; Gabuzda, Dana

doi:10.1097/qad.0000000000003675

Cited by 7 publications

(8 citation statements)

References 59 publications

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“…We found that soluble plasma vascular injury markers (ICAM-1, VCAM-1, and CRP) were associated with HAND, similar to findings in our recent study [ 55 ]. However, EV-associated forms of these markers did not show significant associations with HAND.…”

Section: Discussionsupporting

confidence: 91%

“…In a recent study, we showed that soluble forms of vascular injury markers are increased in PWH with HAND compared with no HAND [ 55 ]. To determine if EV-associated forms of these markers have stronger associations with HAND compared to soluble forms, we examined the association of plasma EV-associated vascular injury markers (ICAM-1, VCAM-1, CRP) with HIV status, HAND, and vascular disease ( Supplemental Digital Content S4 ).…”

Section: Resultsmentioning

confidence: 99%

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CSF Extracellular Vesicle Aβ42 and Tau/Aβ42 Ratio Are Associated with Cognitive Impairment in Older People with HIV

Guha,

Misra,

Chettimada

et al. 2023

Viruses

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HIV-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Older people with HIV (PWH) are also at risk for amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). β-amyloid (Aβ) and Tau biomarkers are associated with aMCI/AD, but their relationship to HAND is unclear. Given the role of extracellular vesicles (EVs) in age-related neurological disorders, we investigated soluble and EV-associated Aβ42, total Tau, NFL, GFAP, ICAM-1, VCAM-1, and CRP in relation to cognitive impairment in PWH. Plasma and CSF EVs were isolated from 184 participants (98 PWH on ART and 86 HIV− controls). Biomarkers were measured using Meso Scale Discovery assays. The median age of PWH was 53 years, and 52% were diagnosed with mild forms of HAND. PWH had increased plasma NFL (p = 0.04) and CSF Aβ42 (p = 0.0003) compared with HIV− controls but no significant difference in Tau or EV-associated forms of these markers. CSF EV Aβ42 was decreased (p = 0.0002) and CSF EV Tau/Aβ42 ratio was increased (p = 0.001) in PWH with HAND vs. no HAND, while soluble forms of these markers showed no significant differences. Decreased CSF EV Aβ42 (p < 0.0001) and an increased CSF EV Tau/Aβ42 ratio (p = 0.0003) were associated with lower neurocognitive T scores in age-adjusted models; an optimal model included both CSF EV Aβ42 and plasma NFL. Levels of soluble, but not EV-associated, ICAM-1, VCAM-1, and CRP were increased in PWH with HAND vs. no HAND (p < 0.05). These findings suggest that decreased Aβ42 and an increased Tau/Aβ42 ratio in CSF EVs are associated with cognitive impairment in older PWH, and these EV-associated biomarkers may help to distinguish aMCI/AD from HIV-related cognitive disorders in future studies.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

CSF Extracellular Vesicle Aβ42 and Tau/Aβ42 Ratio Are Associated with Cognitive Impairment in Older People with HIV

Guha,

Misra,

Chettimada

et al. 2023

Viruses

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“…Although CSF NFL, GFAP, and YKL-40 levels were not significantly different between PWH with or without asymptomatic CSF viral escape, CSF YKL-40 correlated positively with CSF IL-1β, IFN-γ, IP-10, and NFL and negatively with neurocognitive T scores. Previous studies have suggested that CSF YKL-40 is associated with increased plasma and CSF HIV/SIV RNA, HIV/SIV encephalitis, and markers of axonal injury [ 19 , 21 , 22 , 48 , 51 , 52 ]. CSF YKL-40 is a biomarker of glial activation associated with neuroinflammation [ 19 , 21 , 53 ] that is produced by CNS macrophages, microglia, and astrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…CSF and plasma albumin levels were measured using the BCG albumin assay kit (Thermo Fisher Scientific, Waltham, MA, USA), as described [ 48 ]. The CSF-plasma albumin ratio was calculated as an indirect indicator of blood-brain barrier integrity.…”

Section: Methodsmentioning

confidence: 99%

CSF Inflammation Markers Associated with Asymptomatic Viral Escape in Cerebrospinal Fluid of HIV-Positive Individuals on Antiretroviral Therapy

Guha,

Misra,

Yin

et al. 2023

Viruses

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HIV establishes a viral reservoir in the CNS despite viral suppression in the blood on antiretroviral therapy (ART). In a minority of people with HIV (PWH), HIV RNA is detectable in CSF when HIV RNA in plasma is undetectable or HIV RNA levels are higher in CSF compared with plasma, an event termed CSF viral escape that can occur with or without neurological symptoms. Asymptomatic CSF viral escape occurs in 3–20% of PWH on ART, yet associated biomarkers are unclear. To identify biomarkers associated with asymptomatic CSF viral escape, we performed a matched group study of PWH on ART with vs. without CSF viral escape (n = 10 and n = 60, respectively, matched for age, duration of HIV infection, nadir CD4 count, and ART regimen) and 50 HIV-negative controls. PWH were on 3 or more ART drugs for >1 year, and the group with no CSF viral escape was suppressed below 50 copies/mL in plasma and CSF. Biomarkers of inflammation (IFN-γ, IL-1β, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF), cell adhesion (ICAM-1, VCAM-1), CNS injury (NFL), and glial activation (GFAP, YKL-40) were measured in paired plasma and CSF using the Meso Scale Discovery platform. PWH with vs. without CSF viral escape had more individuals (40%) with a plasma viral load (VL) > 50 copies/mL, higher CSF VL (median 156 vs. 40 copies/mL; p < 0.0001), lower CD4 count (318 vs. 512; p = 0.045), and higher CSF WBC (median [IQR] 4 [0–22] vs. 2 [0–4] cells/µL; p = 0.15) but similar proportions with HIV-associated neurocognitive disorders (HAND) (50% vs. 47%). CSF viral escape was associated with increased IL-1β, IFN-γ, IP-10, ICAM-1, and VCAM-1 in CSF but not plasma; IP-10 had the strongest association (p = 0.0008). CSF VL and WBC correlated with IFN-γ, IP-10, ICAM-1, and VCAM-1 (p < 0.05). Although markers of CNS injury showed no significant association with asymptomatic CSF viral escape, CSF YKL-40 correlated positively with CSF IL-1β (p = 0.003), IFN-γ (p = 0.0008), IP-10 (p < 0.0001), and NFL (p = 0.06) and negatively with neurocognitive T scores (p = 0.02). These findings identify CSF inflammation and glial activation markers that may serve as surrogate measures of HIV persistence in the CNS for future studies on therapeutics targeting the CNS reservoir.

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“…The decrease in mitochondrial DNA copy number in late-passage human aortic endothelial cells and the elevation of senescence-associated β-galactosidase accumulation have been observed in PLWH dysfunction and vascular injury; together with ICAM-1, it has been used in many clinical studies to estimate the risk of CVD [137]. It has been reported that the expression of adhesion molecules in PLWH is significantly higher than in the general population [138].…”

Section: Metabolic Effects Of Antiretroviral Therapymentioning

confidence: 99%

Human Immunodeficiency Virus as a Risk Factor for Cardiovascular Disease

Lembas,

Załęski,

Peller

et al. 2023

Cardiovasc Toxicol

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The developments in HIV treatments have increased the life expectancy of people living with HIV (PLWH), a situation that makes cardiovascular disease (CVD) in that population as relevant as ever. PLWH are at increased risk of CVD, and our understanding of the underlying mechanisms is continually increasing. HIV infection is associated with elevated levels of multiple proinflammatory molecules, including IL-6, IL-1β, VCAM-1, ICAM-1, TNF-α, TGF-β, osteopontin, sCD14, hs-CRP, and D-dimer. Other currently examined mechanisms include CD4 + lymphocyte depletion, increased intestinal permeability, microbial translocation, and altered cholesterol metabolism. Antiretroviral therapy (ART) leads to decreases in the concentrations of the majority of proinflammatory molecules, although most remain higher than in the general population. Moreover, adverse effects of ART also play an important role in increased CVD risk, especially in the era of rapid advancement of new therapeutical options. Nevertheless, it is currently believed that HIV plays a more significant role in the development of metabolic syndromes than treatment-associated factors. PLWH being more prone to develop CVD is also due to the higher prevalence of smoking and chronic coinfections with viruses such as HCV and HBV. For these reasons, it is crucial to consider HIV a possible causal factor in CVD occurrence, especially among young patients or individuals without common CVD risk factors.

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Vascular injury markers associated with cognitive impairment in people with HIV on suppressive antiretroviral therapy

Cited by 7 publications

References 59 publications

CSF Extracellular Vesicle Aβ42 and Tau/Aβ42 Ratio Are Associated with Cognitive Impairment in Older People with HIV

CSF Extracellular Vesicle Aβ42 and Tau/Aβ42 Ratio Are Associated with Cognitive Impairment in Older People with HIV

CSF Inflammation Markers Associated with Asymptomatic Viral Escape in Cerebrospinal Fluid of HIV-Positive Individuals on Antiretroviral Therapy

Human Immunodeficiency Virus as a Risk Factor for Cardiovascular Disease

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