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.
Highlights
25% of individuals infected with human immunodeficiency virus (HIV) are coinfected with hepatitis C virus (HCV) in the US and Western Europe and 95% of injection drug users with HIV are coinfected with HCV [1]
In this study we examined both monocyte and T cell populations to understand the impact of HIV/HCV coinfection on peripheral immune cells and how that may relate to cognition
We selected CD14 monocytes for gene expression analysis based on their immune response characteristics, including sensitivity to LPS, and because they could be isolated rapidly at high purity from whole blood thereby preserving their in vivo phenotype
Summary
25% of individuals infected with human immunodeficiency virus (HIV) are coinfected with hepatitis C virus (HCV) in the US and Western Europe and 95% of injection drug users with HIV are coinfected with HCV [1]. Coinfection is associated with rapid progression of liver fibrosis, poor response to pegylated interferon (peg-IFN) and ribavirin, and increased incidence of cognitive impairment [2,3,4]. HIV monoinfection has long been associated with severe cognitive impairment and dementia toward the end stage of the illness. Following the introduction of antiretroviral therapy (ART), severity of neuropsychological impairment diminished dramatically but a substantial portion of patients continued to suffer from mild cognitive problems (for review [5]). HCV infection has been found to affect brain metabolites with monoinfected patients displaying a decrease in the N-acetylaspartate/creatine ratio in the cerebral cortex [7]. Even in the context of HIV and HCV monoinfection, coinfection results in a statistically significant increase in cognitive compromise compared to each virus separately [8,9,10]
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