Abstract
Despite the widespread success of combined antiretroviral therapy (cART) in suppressing viremia, the prevalence of human immunodeficiency virus (HIV)-associated neurological disorders (HAND) and associated comorbidities such as Alzheimer’s disease (AD)-like symptomatology is higher among people living with HIV. The pathophysiology of observed deficits in HAND is well understood. However, it has been suggested that it is exacerbated by aging. Epidemiological studies have suggested comparable concentrations of the toxic amyloid protein, amyloid-β42 (Aβ42), in the cerebrospinal fluid (CSF) of HAND patients and in the brains of patients with dementia of the Alzheimer’s type. Apart from abnormal amyloid-β (Aβ) metabolism in AD, a better understanding of the role of similar pathophysiologic processes in HAND could be of substantial value. The pathogenesis of HAND involves either the direct effects of the virus or the effect of viral proteins, such as Tat, Gp120, or Nef, as well as the effects of antiretrovirals on amyloid metabolism and tauopathy, leading, in turn, to synaptodendritic alterations and neuroinflammatory milieu in the brain. Additionally, there is a lack of knowledge regarding the causative or bystander role of Alzheimer’s-like pathology in HAND, which is a barrier to the development of therapeutics for HAND. This review attempts to highlight the cause–effect relationship of Alzheimer’s-like pathology with HAND, attempting to dissect the role of HIV-1, HIV viral proteins, and antiretrovirals in patient samples, animal models, and cell culture model systems. Biomarkers associated with Alzheimer’s-like pathology can serve as a tool to assess the neuronal injury in the brain and the associated cognitive deficits. Understanding the factors contributing to the AD-like pathology associated with HAND could set the stage for the future development of therapeutics aimed at abrogating the disease process.
Highlights
Human immunodeficiency virus (HIV) is a retrovirus that has affected more than 40 million people worldwide
Several studies have demonstrated the accumulation of toxic amyloid isoforms in the brains of HIV-1 patients on combined antiretroviral therapy (cART), resulting in increased numbers of HIV-affected people living with HIV (PLWH) with the comorbidity of Alzheimer’s disease (AD) with increasing age
It has been shown that crossbreeding of these mice with amyloid precursor proteins (APP) overexpressing mice resulted in the accelerated accumulation of amyloid β (Aβ) accumulation, which was concomitant with increased tau pathology and cognitive impairment, two features usually lacking in APP transgenic mice
Summary
Human immunodeficiency virus (HIV) is a retrovirus that has affected more than 40 million people worldwide. Neurocognitive dysfunction is detected in almost 50% of HIV patients, despite the use of combined antiretroviral therapy (cART), with increased incidence in older people [1,2,3,4]. Several studies have demonstrated the accumulation of toxic amyloid isoforms in the brains of HIV-1 patients on cART, resulting in increased numbers of HIV-affected people living with HIV (PLWH) with the comorbidity of Alzheimer’s disease (AD) with increasing age. It has been shown that certain antiretroviral medications, reverse transcriptase inhibitors, could have additive amyloidogenic effects on macrophages These effects were observed at very high concentrations that are unattainable in the brains of HIV-affected individuals [12]. Several studies have reported the presence of these HIV proteins in the post-mortem brain samples of HIV-affected individuals. Despite extensive research on HAND pathology, the lack of key clinical biomarker (s) and/or specific treatment (s) for the disease underscore the necessity for detailed research in this field
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