Cathepsin B and cystatin B in HIV-seropositive women are associated with infection and HIV-1-associated neurocognitive disorders

OBJECTIVE: HIV-1-associated neurocognitive disorders (HAND) is triggered by immune activation of brain cells and remain prevalent during progressive viral infection despite antiretroviral therapy. Cathepsins and cystatins are lysosomal proteins secreted by macrophages and microglia, and may play important roles in neuroregulatory responses. Our laboratory has shown increased secretion and neurotoxicity of cathepsin B from in-vitro HIV-infected monocyte-derived macrophages, and increased expression in postmortem brain tissue with HIV encephalitis and HAND. We hypothesized that cystatin B and cathepsin B could represent potential biomarkers for HAND. METHODS: Monocytes, plasma, and cerebrospinal fluid (CSF) from retrospective samples from 63 HIV-seropositive Hispanic women were selected for this study. These were stratified as 27 normal, 14 asymptomatic, and 22 HIV dementia, and as 14 progressors and 17 nonprogressors. Samples were evaluated for cystatins B and C and cathepsin B expression and activity. RESULTS: Increased cathepsin B and cystatins B and C were found in plasma of HIV-seropositive women. Higher intracellular expression of cathepsin B and cystatin B were found in monocytes from women with HIV-associated dementia (P<0.05). Significant increase in cystatin B concentration in CSF was found in women with dementia compared with HIV-seropositive asymptomatic women. CONCLUSION: These results demonstrate that dysregulation of cystatin B-cathepsin B system is operative in HIV-associated neurocognitive impairment and suggests that intracellular expression of cystatin B and cathepsin B in monocytes could be potential candidate biomarkers for HIV dementia, whereas increased cathepsin B and cystatins B and C in plasma are potential candidate markers of chronic HIV-1 activation.