HIV on the brain: is neurosignalling damage irreversible even on antiretroviral therapy?
Year: 2021
Type: article
Abstract: Even with successful antiretroviral therapies (ARTs), comorbidities in persons with HIV (PWH) remain high. Among these are a range of neurocognitive impairments presenting within the full spectrum under HIV-associated neurocognitive disorder (HAND), which can range from asymptomatic neurocognitive impairment to the severe neurological dysfunction affecting activities of daily living [1]. Multiple causes associated with HIV disease may exist and the underlying mechanisms remain poorly defined, but neurocognitive dysfunction is thought to be largely driven by neuroinflammation and dysregulation of neural and immune networks in the central nervous system (CNS) [2]. Also, alcohol abuse in addition to HIV infection has the potential to further decrease neurocognition, though study results can be conflicting: some found no correlation of days of intoxication to degree of neurocognitive impairment [3], but PWH users of alcohol also display lower than average neurocognition [4]. Although suppression of virus by ART can potentially dampen inciting factors driving neuroinflammation, it is unclear if treatment intercedes on all facets of neuroinflammation and restores neural connections. In this issue, a new study by Maxi et al.[5] uses a simian immunodeficiency virus (SIV)-infected rhesus macaque model wherein they study the effects of infection as well as binge alcohol use on measures of neuroinflammation. The investigators further evaluate the impact of ART in this model to reduce inflammation and restore neurosignals. Although ART reduced most measures of neuroinflammation, including IBA1, CX3CR1 and GFAP gene expression in the frontal cortex, and CD74 and CD11ß in the basal ganglia, brain-derived neurotrophic factor (BDNF) signalling was not restored in either anatomical location. BDNF, a member of the neurotrophin family, is one of the most abundant neurosynaptic factors in the brain and mediates CNS plasticity. Loss of BDNF is associated with memory and learning deficits, and has been associated with increased incidences of depression and Alzheimer's disease. Importantly, multiple studies have shown that loss of BDNF also correlates with severity of HAND [6], where cerebrospinal fluid BDNF levels were significantly lower in PWH with HIV-dementia when compared with PWH without dementia [7]. Serum BDNF levels also correlated directly with performance on neurocognitive tests of executive functions and memory [8]. In a cross-sectional study of 350 PWH and 50 HIV seronegative individuals, ART did not alter serum levels of BDNF in PWH, although CNS BDNF values were not assessed [9]. Furthermore, alcohol exposure, specifically beer and liquor, was also associated with decreased serum BDNF in PWH in that study. Although moderate alcohol ingestion can acutely trigger BDNF release, which prevents progression to compulsive alcohol consumption, chronic heavy alcohol consumption eventually disrupts the protective functions of BDNF [10,11]. Chronic alcohol exposure may further exacerbate the reduction of BDNF in the brain of PWH. Additional knowledge is lacking on BDNF regulation in terms of timing and duration of alcohol and HIV exposures. To determine specific neurocognitive or behavioural issues correlating to perturbations in BDNF signalling during lentivirus infection is admittedly challenging to address in humans and often not adequately measurable in macaque models. A recent cross-sectional study of 109 PWH aged 50 years and older showed significant inverse correlation of BDNF plasma levels with depression [12]. However, the exact dynamics of BDNF signal alterations in relation to HIV and ART exposures still need to be understood to inform therapeutics. Given the significant role played by BDNF in neurocognition, it is crucial to determine in PWH if ART can reverse HIV induced BDNF changes the brain, especially in those with chronic alcohol abuse. Given the difficulties of sampling the brain in humans, nonhuman primate (NHP) infected with lentivirus offers an opportunity to determine this. In this new study, Maxi et al.[5] started dosing NHP with alcohol 3 months prior to SIV infection and continued through the end of the study, while ART was given 2.5 months after infection and tissues obtain 11 months after infection. Although this study timeline modelled the most likely sequences of exposures in human, longitudinal studies with CNS samplings at multiple time points could further elaborate the findings. The reduction of BDNF in PWH who abuse alcohol is most likely a consequence of both viral infection induced neuroinflammation and alcohol-related neurosignal suppression. Due to this multifactorial causation, treatment of the virus alone may not be enough, as shown in the current study by Maxi et al.[5]. In addition to prescribing physical exercises to increase BDNF levels in the brain [13], there are a number of drugs that modulate BDNF signalling, including several antidepressants and small molecule mimetic of BDNF such 7,8-DHF and P021 [14,15]. Studies in rodents and in postmortem human brains demonstrated that antidepressants such as ketamine increased BDNF levels in the brain by activating the TrkB receptor [16–18]. Delivery of BDNF or mimetic or inducers into the brain could also be improved with new gene therapies. Thus, treatments to restore BDNF in the CNS could supplement therapies for PWH demonstrating neurocognitive impairment. Treatment of HIV infection with ART has altered HIV infection to a chronic disease, but complimentary treatments targeting comorbidities need to be considered and better studied to optimize complete health of PWH. Acknowledgements The authors were supported by National Institutes of Health grants R01 AI143457 (R.K.R.) and R33 MH112360 (C.S.T.) Conflicts of interest There are no conflicts of interest.
Source: AIDS
Authors: C. Sabrina Tan, R. Keith Reeves
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3175163955