Monocyte Activation in HIV/HCV Coinfection Correlates with Cognitive Impairment

Abstract

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) effectively prolongs life and significantly improves immune function. HIV/HCV coinfected individuals have peripheral immune activation despite effective ART control of HIV viral load. Here we examined freshly isolated CD14 monocytes for gene expression using high-density cDNA microarrays and analyzed T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV and HIV, and HIV-suppressed coinfected subjects. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological performance, which were summarized as a global deficit score (GDS). Monocyte gene expression analysis in HIV-suppressed coinfected subjects identified 43 genes that were elevated greater than 2.5 fold. Correlative analysis of subjects’ GDS and gene expression found eight genes with significance after adjusting for multiple comparisons. Correlative expression of six genes was confirmed by qPCR, five of which were categorized as type 1 IFN response genes. Global deficit scores were not related to plasma lipopolysaccharide levels. In the T cell compartment, coinfection significantly increased expression of activation markers CD38 and HLADR on both CD4 and CD8 T cells but did not correlate with GDS. These findings indicate that coinfection is associated with a type 1 IFN monocyte activation profile which was further found to correlate with cognitive impairment, even in subjects with controlled HIV infection. HIV-suppressed coinfected subjects with controlled HIV viral load experiencing immune activation could benefit significantly from successful anti-HCV therapy and may be considered as preferential candidates.

Cognitive impairment in HIV and HCV co-infected patients: a systematic review and meta-analysis

“…Among the studies that measured the GDS Rempel et al, 2013;Sun et al, 2013), the meta-analysis revealed statistically significant differences between groups (SMD = 0.56, 95% CI: 0.36, 0.75, The co-infected group showed poorer visual memory and motor functioning than the HIV mono-infected group prior to antiretroviral therapy Before cART, a greater percentage of coinfected patients performed poorly on the neuropsychology summary score (HIV/HCV: 50%; HIV: 20%). After being exposed for six months to antiretroviral therapy, no differences were found between groups HIV/HCV > HIV before cART HIV/HCV ≅ HIV after cART Perry et al p < .00001).…”

“…Overall, most studies reported that the HIV/HCV co-infected patients were generally more impaired than HIV and HCV monoinfected patients and controls Ciccarelli et al, 2013;Clifford, Evans, Yang, & Gulick, 2005;Devlin et al, 2012;von Giesen et al, 2004;Hinkin et al, 2008;Letendre et al, 2005;Martin et al, 2004;Parsons et al, 2006;Rempel et al, 2013;Ryan, Morgello, Isaacs, Naseer, & Gerits, 2004;Sun et al, 2013;Vivithanaporn et al, 2012). Other studies found no differences on cognitive performance between HIV/ HCV and HIV mono-infected groups (Aronow, Weston, Pezeshki, & Lazarus, 2008;Thiyagarajan et al, 2010), between HIV/HCV and HCV mono-infected groups (Clifford et al, 2009;Perry et al, 2005), and between HIV/HCV and both HIV and HCV mono-infected groups (Thein et al, 2007).…”

“…For the meta-analysis, the global deficit score (GDS) was also extracted, which was defined as a unitary global score representing overall neuropsychological tests performances. Each individual cognitive test score was converted to T-scores demographically corrected (for education, age and gender) Rempel et al, 2013;. The meta-analyses were performed for: (a) the studies that provided a GDS score and (b) the studies that reported specific neurocognitive domains.…”

“…The majority of studies included both male and female participants and two studies included only female participants (Crystal et al, 2012;Richardson et al, 2005). The proportion of male participants ranged from 56.2% (von Giesen et al, 2004) to 100% (Martin et al, 2004;Rempel et al, 2013;Sun et al, 2013;Winston et al, 2010). Regarding the clinical stage, 22 studies included participants in HCV chronic stage.…”

“…In the meta-analysis, two studies were included (Devlin et al, 2012;Rempel et al, 2013). The forest plots of the Regarding verbal fluency, significant heterogeneity in the meta-analysis was detected (I 2 = 61%; p = .11).…”