On cerebrospinal fluid biomarkers of HIV-1 infection

Abstract

HIV invades the central nervous system (CNS) shortly after transmission and is present throughout the course of infection, causing immune activation and neuroinflammation. If left untreated, more than 20% of patients with late-stage HIV/AIDS develop HIV-associated dementia (HAD). With combined antiretroviral treatment (cART), HAD is rare, but mild neurocognitive deficits are commonly noted and have been termed HIV-associated neurocognitive disorders (HAND). The diagnosis of HAND relies solely on neuropsychological testing, which might overestimate the prevalence of HAND. Analysis of biomarkers could enhance diagnostic precision. With an aging HIV-infected population, methods to distinguish HAND from other dementias, especially Alzheimer’s disease (AD), will increase in importance. This thesis evaluates biomarkers related to neuronal injury (neurofilament light chain protein [NFL] and total tau [t-tau]); immune activation (neopterin); and altered metabolism (soluble amyloid precursor protein α and β [sAPP], beta-amyloid1-42 [Aβ1-42], and phosphorylated tau [p-tau]) in cerebrospinal fluid (CSF) of HIV patients with and without cognitive deficits. For the purposes of differential diagnosis, AD patients and HIV-negative subjects with CNS infections were included. HAD patients exhibited a biomarker pattern with normal to low Aβ1-42, decreased sAPPs, normal p-tau, and increased t-tau, thus differentiating HAD from AD, neuroasymptomatic (NA) HIV-infected patients, and controls. Although CSF p-tau occurs physiologically with aging, p-tau levels were normal or decreased in HIV. HIV-related opportunistic infections (OI) and CNS infections in HIV-negatives were similar to HAD, indicating that neuroinflammation might induce a pathologic processing of amyloid that is separate from the metabolism in AD. Amyloid and tau metabolites could be useful biomarkers to distinguish HAD from AD. CSF NFL was highest in HAD patients, but NA patients, both with and without cART, also exhibited increases in NFL. This indicates ongoing axonal disruption at all stages of HIV, including some patients on cART. Most likely this is due to HIV-induced axonal disruption. CSF NFL levels increased in younger HIV-infected patients as compared to controls.