Applications and Limitations of Inflammatory Biomarkers for Studies on Neurocognitive Impairment in HIV Infection

Abstract

Despite reduced prevalence of severe forms of HIV-associated neurocognitive disorders (HAND) on current antiretroviral therapy (ART) regimens, milder forms of neurocognitive impairment (NCI) remain prevalent in HIV-infected populations. These mild forms of HAND consist of subtypes, probably reflecting distinct, though possibly overlapping, pathophysiological mechanisms. Factors associated with HAND in HIV patients with prolonged viral suppression on ART include older age, low nadir CD4, active HCV co-infection, and cardiovascular risk factors, but underlying mechanisms and their relationship to innate immune activation, chronic inflammation, and other features of systemic disease are poorly understood. In this article, we discuss applications and limitations of plasma inflammatory biomarkers for studies on HAND in HIV patients on ART and describe an analysis pipeline to reduce common sources of noise and increase likelihood of identifying relevant inflammatory biomarkers. Clinical covariates and comorbidities that influence inflammatory biomarkers, such as aging, obesity, metabolic abnormalities, HCV co-infection, and substance abuse, are also reviewed. As an example for using this analytic pipeline, we present an exploratory study of 22 plasma inflammatory biomarkers (IFN-α 2b and -γ, 16 cytokines/chemokines, sIL-2R, sCD14, HA, and YKL-40) in a cohort of HIV-infected individuals with advanced disease, frequent HCV co-infection, and viral suppression on ART. The identification of inflammatory biomarkers associated with HAND in HIV+ patients on ART may be useful to distinguish between HAND subtypes with distinct pathophysiology, and is important for achieving a systems-level understanding of the biology of these disorders, developing effective therapies, and evaluating therapeutic outcomes.Electronic supplementary materialThe online version of this article (doi:10.1007/s11481-013-9512-2) contains supplementary material, which is available to authorized users.

Abdominal Obesity Contributes to Neurocognitive Impairment in HIV-Infected Patients With Increased Inflammation and Immune Activation

“…Third, we did not measure sCD40L in plasma and thus its origin in CSF is uncertain. Fourth, the lack of relationship of GDS to other CSF inflammatory biomarkers was surprising but consistent with differences reported in prior studies 56 . We suspect that this variability may relate to differences in study populations, concurrent cardiometabolic variables, neurocognitive test instruments, or laboratory methods (multiplex versus single platform assays).…”

Soluble CD14, CD163, and CD27 biomarkers distinguish ART-suppressed youth living with HIV from healthy controls

“…In contrast, associations among biomarker networks involved in chronic macrophage activation and vascular injury were seen among YLWH. sCD163 was associated with higher levels of sCD25, a known biomarker of macrophage, activation syndrome, and was also associated with sVCAM and CRP in conditions associated with vascular injury in both HIV and non-HIV associated conditions such as autoimmune disease [13, 23, 26, 37–40]. While both sCD14 and sCD163 are associated with macrophage activation, the markers represent distinct pathways impacted by HIV; therefore, the lack of associations between these two biomarkers is not surprising but indicate complex effects by HIV infection on multiple innate immunity pathways [41, 42].…”

Neonatal intrahippocampal HIV‐1 protein Tat1–86 injection: neurobehavioral alterations in the absence of increased inflammatory cytokine activation

“…Cytokines and other inflammatory biomarkers have been clearly associated with HIV‐1‐associated dementia (HAD) in the pre‐cART era (Gartner and Liu, 2002; Glass et al, 1993; Perrella et al, 1992), but they may also play a role in the development of less severe forms of HAND despite viral suppression due to cART. A recent longitudinal study reported significantly higher levels of Interferon‐α‐2b, IL‐6, and sIL‐2R in HIV‐1+ individuals that became neurocognitively impaired, remained impaired, or worsened 1 year after the baseline study, compared to HIV‐1+ individuals who had either no impairment or improved neurocognitive status (Cassol et al, 2013). Neurocognitive impairment has also been associated with elevated levels of cytokines in perinatally HIV‐1‐infected children (Foster et al, 2012).…”