Preliminary Evidence for a Relationship between Elevated Plasma TNFα and Smaller Subcortical White Matter Volume in HCV Infection Irrespective of HIV or AUD Comorbidity

Abstract

Classical inflammation in response to bacterial, parasitic, or viral infections such as HIV includes local recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines. Proposed biomarkers of organ integrity in Alcohol Use Disorders (AUD) include elevations in peripheral plasma levels of proinflammatory proteins. In testing this proposal, previous work included a group of human immunodeficiency virus (HIV)-infected individuals as positive controls and identified elevations in the soluble proteins TNFα and IP10; these cytokines were only elevated in AUD individuals seropositive for hepatitis C infection (HCV). The current observational, cross-sectional study evaluated whether higher levels of these proinflammatory cytokines would be associated with compromised brain integrity. Soluble protein levels were quantified in 86 healthy controls, 132 individuals with AUD, 54 individuals seropositive for HIV, and 49 individuals with AUD and HIV. Among the patient groups, HCV was present in 24 of the individuals with AUD, 13 individuals with HIV, and 20 of the individuals in the comorbid AUD and HIV group. Soluble protein levels were correlated to regional brain volumes as quantified with structural magnetic resonance imaging (MRI). In addition to higher levels of TNFα and IP10 in the 2 HIV groups and the HCV-seropositive AUD group, this study identified lower levels of IL1β in the 3 patient groups relative to the control group. Only TNFα, however, showed a relationship with brain integrity: in HCV or HIV infection, higher peripheral levels of TNFα correlated with smaller subcortical white matter volume. These preliminary results highlight the privileged status of TNFα on brain integrity in the context of infection.

Keywords: IL1β; IP10; TNFα; alcoholism; brain; chemokines; comorbidity; complete blood count; cytokines; infection; liver; magnetic resonance imaging; metabolic panel; neuroimmune; neuroinflammation; soluble proteins; structural MRI.

Figure 1

Levels of soluble proteins by initial diagnoses. Relative to the control group, IL1β levels were low in the AUD (p = 0.02), HIV (p = 0.0004), and AUD+HIV (p = 0.0001) groups. Relative to the control group, IP10 and TNFα levels were high in the HIV and AUD+HIV groups (both p < 0.0001). IL1β: Interleukin (IL)1β; IP10: Interferon γ-induced Protein 10 (IP10); TNFα: Tumor Necrosis Factor α; black circles: healthy controls; open squares: Alcohol Use Disorder (AUD); open triangles: Human Immunodeficiency Virus (HIV); open diamonds: AUD+HIV.

Figure 2

Levels of soluble proteins by hepatitis C virus (HCV) serostatus among patient groups. IL1β: relative to controls, lower in AUD (p = 0.008), HIV (p = 0.001), HIV+HCV (p = 0.007), AUD+HIV (p = 0.001), AUD+HIV+HCV (p = 0.002). IP10: relative to controls, higher in AUD+HCV (p < 0.0001), HIV (p = 0.02), HIV+HCV (p < 0.0001), AUD+HIV (p = 0.5), AUD+HIV+HCV (p < 0.0001). Higher in AUD+HCV vs. AUD (p < 0.0001), HIV+HCV vs. HIV (p = 0.009), AUD+HIV+HCV vs. AUD+HIV (p = 0.0008). black circles: healthy controls; open squares: AUD; filled squares: AUD+HCV; open triangles: HIV; filled triangles: HIV+HCV; open diamonds: AUD+HIV; filled diamonds: AUD+HIV+HCV.

Figure 3

TNFα correlations with subcortical white matter volume. (a) In HCV seropositive AUD individuals and the 2 HIV groups (black circles, n = 127). (b) In the subset of HCV seropositive individuals collapsed across the 3 patient groups (black circles, n = 57). Inset: subcortical white matter volume.

Figure 4

Path analysis describing relationships between relevant variables, soluble protein levels, and subcortical white matter volume (WM). Path analysis includes 3 factors (reduced from 15 variables entered into principal component analysis (PCA)), 3 soluble proteins, and subcortical white matter in the HCV and HIV groups (n = 127). Factor 1 (6 variables) includes HCV viral load, fibrosis score (FIB4), aspartate aminotransferase/platelet count ratio (APRI), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transferase (GGT). Factor 2 (5 variables) includes injection drug use (IDU), VACS index, creatinine, estimated glomerular filtration rate (eGFR), and prealbumin. Factor 3 (3 variables) includes HIV viral load, total HIV conditions, and the albumin-to-globulin ratio (AGR).