People living with human immunodeficiency virus (HIV) infection (PLWH) struggle with chronic health conditions, among which include neurocognitive impairment (NCI). A recent paper in Nature Reviews Neurology examines the mechanisms responsible for the increased risk of NCI among PLWH and explores potential treatments.
Study: Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management. Image Credit: New Africa / Shutterstock.com
Introduction
According to the United States Centers for Disease Control and Prevention, the most common route of HIV transmission in the U.S. is male-to-male sexual contact, which caused about 68% of all new HIV diagnoses in 2020. Comparatively, heterosexual contact was responsible for 22% of new HIV cases in 2020. The use of contaminated needles presents another significant route, while vertical transmission from the mother to the newborn accounts for a small proportion of new cases.
Worldwide, there are over 38 million PLWH, over half of whom reside in Africa, with a high prevalence of NCI. Currently, a large proportion of PLWH is on anti-retroviral therapy (ART), which are drugs that suppress viral replication, restore CD4+ T-cell numbers, improve immunity, reduce the rate of progression, and extend survival.
However, PLWH in low-income countries have less access to ART and other medical interventions.
HIV-associated neurocognitive impairment
HIV lives and multiplies in immune cells, particularly CD4+ T-cells that are severely depleted, as well as macrophages and microglia.
Despite ART, latent infection persists, especially in the brain, with the release of viral proteins. These may cause neuronal degeneration, thereby leading to NCI, which affects 30-50% of PLWH. HIV-associated NCI may reduce adherence to ART, impair attention, concentration, memory, and cognitive function, cause loss of independence, and shorten life.
Early ART initiation is linked to significant improvement in cognitive function. Nevertheless, lingering refractory NCI has been observed.
Risk factors for NCI
The highest risk of NCI among PLWH is in people aged 50 years or older, who also form the largest and fastest-growing percentage of PLWH, both in the U.S. and Europe.
People with the lowest CD4+ levels are at a higher NCI risk, with rapid aging in neurocognitive function. Some research suggests a higher risk of NCI among Black and Latino individuals, who have higher infection risks as well compared to Whites and comprise over 66% of all PLWH in the U.S.
NCI risk increases with age, lower CD4+ counts (Blacks), hepatitis C virus (HCV) infection (Latinos), comorbidities (PLWH of Mexican and Puerto Rican origin), lower nadir CD4+ counts (Mexican origin), and current ART (Puerto Rican origin).
Earlier research into NCI pathophysiology suggests the involvement of dysregulated immunity, mitochondrial perturbations due to metabolic dysfunction, impaired metal ion regulation, disrupted lysosomal function, and dysbiosis. A better understanding of the mechanisms responsible for this complication and the pathways involved could support the development of future therapeutics.
Mechanisms of HIV-associated NCI
Some of the contributors to HIV-associated NCI include direct and indirect injury due to latent infection in the brain and cerebrospinal fluid (CSF). Chronic HIV infection may cause neuronal damage prior to ART initiation, a phenomenon known as the “legacy effect.”
PLWH on ART may still exhibit viral ribonucleic acid (RNA) genetic material in the CSF but not in blood, or at higher levels in the CSF than in blood, in 5-15% of PLWH, even with suppressed viral replication. This rate is declining with effective and well-tolerated ART.
A related phenomenon is chronic immune activation, even with sustained ART. Viral RNA and proteins are found in exosomes from infected cells, which alter the function of uninfected immune cells to trigger pro-inflammatory pathways.
Conversely, exosomes from uninfected cells may enhance HIV transcription in infected cells, as may some substances of abuse, especially the benzodiazepine alprazolam.
Synaptodendritic pruning, which leads to the loss of neuronal connectivity, brain atrophy, and reduced white matter connections, are fundamental to HIV-associated NCI. Both neurons and their axons exhibit progressive breakdown, which is associated with higher levels of degenerative proteins such as neurofilament light, Tau, and phosphorylated Tau.
Mechanisms of direct neuronal injury
Neuronal damage could be the direct effect of the viral proteins produced by continued, albeit dampened, viral protein expression in the brain. These may cause oxidative stress, altered calcium ion signaling, impaired mitochondrial function, and apoptosis.
Indirect neurotoxicity
Brain macrophages and microglia with latent HIV release excitatory substances like quinolinic acid at toxic levels, thereby exciting neuronal glutamate receptors and resulting in memory loss. These immune cells also release inflammatory cytokines, which is exacerbated by ART-induced inflammation.
These infected cells and viral proteins, with the inflammatory milieu, cause a breakdown of the blood-brain barrier (BBB), thereby allowing the virus and infected immune cells to penetrate the brain.
Both HIV and ART cause profound and widespread changes in mitochondrial structure and function, subsequently altering energy pathways in neuronal and glial cells, possibly impairing brain health.
In addition to the neuronal toxicity of ART, these may interact adversely with other drugs to harm the brain. With aging, the brain is exposed to higher levels of the drugs, as pharmacodynamics change and the BBB weakens.
The activation of the NLRP3 inflammasome is documented in HIV, even with viral suppression. In response to danger signals like oxidative molecules and lysosomal disruption, this inflammasome releases inflammatory chemicals like interleukin 1β (IL-1β) and IL-18, which reduces synaptic neurotransmitters, impairs structural and functional growth of neurons, and triggers pyroptosis. Chronic neuroinflammation also exposes the brain to degenerative injury.
As PLWH age, their risk of Alzheimer's disease (AD) rises. In fact, the similarity of findings in AD- and HIV-associated NCI suggests that HIV increases the rate of brain aging; however, this remains unproven.
The role of comorbidities
Previous studies indicate that comorbidities like diabetes mellitus, hypertension, obesity, metabolic syndrome, or depression directly contribute to HIV-associated NCI. These conditions appear earlier, progress faster in PLWH, and require different treatment strategies as compared to people without HIV.
Coinfections with tuberculosis, hepatitis C virus (HCV), and cytomegalovirus may also increase the risk of NCI in PLWH. The gut microbiome could also be involved, as HIV is harbored and disseminated by the gut. Moreover, with gut dysbiosis, the gut-brain axis causes changes in neuronal structure and function.
Potential pharmacological interventions
There are no approved pharmacological treatments for NCI. Some potential drug interventions include human growth hormone-releasing hormone (hGHRH) analogs like tesamorelin and phosphatidylinositol-glycan-specific phospholipase D (GPLD1). Tesamorelin restores GH secretion, stimulates brain blood flow, blocks oxidative damage, and promotes neurogenesis and synapse growth through its stimulation of insulin-like growth factor 1 (IGF1).
GPLD1 is an exercise-induced enzyme that can modulate inflammatory pathways, improve mitochondrial function, and restore normal coagulation pathways. The administration of GPLD1 imitates the effects of exercise and may benefit NCI.
Trials are going on to evaluate the effects of treating viruses specific to PLWH in terms of NCI benefit. Drugs like rapamycin that act on the mTOR pathway could also be neuroprotective by restoring metabolic and immune homeostasis.
With available information on interferon (IFN) activity in the brain of PLWH, it is possible that human IFNβ and IFNα isoforms may be developed into a therapy for chronic HIV and the secondary prevention of NCI.
Non-drug approaches
Non-pharmacological interventions can affect metabolism and inflammatory processes in ways that drugs cannot.”
These include physical activity, better sleep, nutritional alterations, and cognitive exercises. Improved sleep, for example, enhances cognitive ability by improving learning, memory, and concentration capabilities, as well as robust immune function.
Similarly, healthy eating strategies synchronize with activity and sleep to restore metabolic normalcy, as well as stimulate neuronal growth and synaptogenesis. Physical exercise also improves mood and is associated with better general health.
Such approaches help treat the comorbidities and, as a result, the risk of NCI. Furthermore, these strategies do not increase the risk of introducing or aggravating adverse effects due to drug interactions.
What are the implications?
Despite advances in our understanding of HIV-associated NCI pathogenesis, the translation of findings into the clinical setting has been disappointing.”
While pharmacological approaches for the prevention or treatment of HIV-associated NCI remain at the experimental stage, non-pharmaceutical strategies can be easily incorporated into the daily routines of PLWH to improve their cognitive functioning and quality of life.
Journal reference:
- Ellis, R. J., Marquine, M. J., Kaul, M., et al. (2023). Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management. Nature Reviews. doi:10.1038/s41582-023-00879-y.
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