Accelerated Tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active anti-retroviral therapy

Abstract

This study aims to investigate the influence of human immunodeficiency virus (HIV) infection on the neurodegenerative processes normally associated with ageing. We have looked for evidence of beta amyloid and hyperphosphorylated Tau deposition in HIV-infected subjects before and after the advent of highly active anti-retroviral therapy (HAART). In addition we have looked for evidence of axonal damage. We have compared these HIV-positive cases with age-matched controls and with older non-demented controls. We find no evidence of significant premature beta amyloid deposition in HIV-infected cases; however, we do observe elevated levels of hyperphosphorylated Tau in the hippocampus of many HIV-infected subjects, compared with age-matched controls. The greatest levels of hyperphosphorylated Tau are noted in HAART-treated subjects. Axonal damage marked by expression of beta amyloid pre-cursor protein (BAPP) was highly variable in all groups including control subjects. We surmise that HIV infection and/or the use of anti-retroviral therapy may predispose to accelerated neuroageing in the form of hyperphosphorylated Tau deposition in the hippocampus. Within the age groups studied these significant neuropathological changes remained subclinical and were not yet associated with cognitive impairment.

Cognitively unimpaired HIV-positive subjects do not have increased 11 C-PiB

“…The lack of correlation between CSF 〈␤42 and 11 C-PiB MCBP in unimpaired HIVϩ participants could result from decreased A␤42 production, increased intraneuronal A␤42 deposition leading to reduced extracellular concentrations, or more extracellular A␤42 amyloid but in a diffuse, nonfibrillar A␤ form. 4,9,10 In each instance, relatively normal 11 C-PiB would occur. Future longitudinal examination, especially a larger sample of HIVϩ participants with low CSF A␤42 and normal 11 C-PiB, are required to understand whether observed low CSF A␤42 represents an aggregation of diffuse oligomeric forms ( 11 C-PiB-negative) that eventually become substantial fibrillar ( 11 C-PiB-positive) deposits, 1,5 or simply the low normal end of CSF A␤42 in HIVϩ participants.…”

“…Postmortem HIVϩ subjects have increased brain A␤42 and tau deposition compared to age-matched community controls. 4 Decreased CSF 〈␤42 is observed in subjects with AD and some unimpaired community controls with fibrillar A␤42. 3 Subjects with HAND have CSF A␤42 levels similar to participants with mild AD.…”

Antiretroviral Therapy and HIV-Associated Neurocognitive Disorders

“…However, longer life expectancy has brought new complications to the management of disease, one of which is the age-related metabolic and functional changes in the CNS. The neuroinflammation is still observed in the hippocampus of patients with suppressed CNS and peripheral VL, in addition to the accumulation of phosphorylated Tau, and intracellular and extracellular -amyloid (A) in the frontal cortex and the hippocampus (Brew, Pemberton et al 2005;Green, Masliah et al 2005;Anthony, Ramage et al 2006;Achim, Adame et al 2009). Interestingly, while increased accumulation of amyloid precursor protein (APP) was observed in the brains of HIV-infected individuals, the presence of phospho-Tau and A were not demonstrated before the implementation of cART.…”

Antiviral agents in Alzheimer’s disease: hope for the future?

“…Tau is a microtubuleassociated protein involved in intracellular transport and when it is phosphorylated, transport is impaired. Like Ab, several micro-organisms can cause tau phosphorylation or NFT formation: tau hyperphosphorylation occurs in cells infected with Borrelia burgdorferi spirochetes [Miklossy et al 2006]; hyperphosphorylated tau occurs in the brains and CSF of HIV-infected individuals [Anthony et al 2006]; and NFT occur in the brains of subacute sclerosing panencephalitis sufferers, years after the initial infection with measles virus [Bancher et al 1996;McQuaid et al 1994].…”