AIDS DEMENTIA COMPLEX: PATHOGENESIS AND SYMPTOMS

Di Michele S, D’Aurizio C. AIDS dementia complex: Pathogenesis and symptoms. International Journal of Infection. 2022;6(3):80-85

Stefano Di Michele^1* and Carlo D’Aurizio²

¹ Division of Gynecology and Obstetrics, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy;
² Department of Neurorehabilitation, Popoli Hospital, Popoli, Italy.

*Correspondence to:
Stefano Di Michele,
Division of Gynecology and Obstetrics,
Department of Surgical Sciences,
University of Cagliari,
Cagliari, Italy.
e-mail: dr.dimichelestefano@gmail.com

ABSTRACT

AIDS Dementia Complex (ADC) is a frequent pathology caused by HIV infection that can affect cognitive, motor, and behavioral functions with a mechanism that is still unclear. HIV infection is often known before the onset of dementia, but ADC can sometimes appear before other clinical signs. The onset is usually abrupt in the more advanced stages of HIV infection and begins with apathy, psychomotor slowing, memory problems, and loss of interest in usual activities. ADC is characterized by disturbances in recent memory, the slowing down of mental processes, personality changes, headaches, aphasia, and hemiparesis. Antiretroviral therapy (ART) can reduce the incidence and severity of ADC by controlling viral replication. HIV infection is associated with inflammation and the production of reactive oxygen species (ROS), resulting in neuronal damage. It is likely that HIV causes damage to the central nervous system (CNS) through indirect mechanisms, such as inducing the production of inflammatory cytokines or neuropeptides. In fact, neuronal cells and oligodendrocytes incubated in vitro are damaged by exogenous TNF. In the brain, HIV can cause diffuse paleness of the white matter, reduction in the number of neurons, and atrophy in the frontotemporal regions. HIV can induce the chemokines and pro-inflammatory cytokines causing sympathetic damage and cell death.

KEYWORDS: HIV, infection, AIDS dementia complex, central nervous system

INTRODUCTION

Some pathologies affecting the central nervous system (CNS) are attributable to the primary action of the human immunodeficiency virus (HIV) and not to opportunistic infections (1). Broad neurological and cognitive impairments can occur in people with HIV, including a range of symptoms from mild cognitive issues to severe dementia. Acquired immunodeficiency syndrome (AIDS) Dementia Complex (ADC), also known as HIV-associated dementia (HAD), and sometimes referred to as subacute encephalitis, AIDS encephalopathy, or HIV encephalitis (2), is considered the most frequent neurological complication of HIV infections (3). This severe neurological pathology results in significant cognitive and motor dysfunction that interferes with daily life and functioning.

In most patients, HIV infection is already known before the onset of dementia, but ADC can sometimes appear before other signs or symptoms of the infection (2). In this last case, the onset of the disease is usually insidious and one of the first signs is psychomotor slowing which can be confused with depression (4). The onset is usually more abrupt in the more advanced stages of HIV infection.

ADC begins with apathy, psychomotor slowing, memory problems, and loss of interest in usual activities (2).  Sometimes, however, the onset can be characterized by psychomotor agitation. This is followed by disturbances in recent memory, the slowing down of mental processes, and personality changes. There may be headaches, alteration disorders, aphasia, hemiparesis, more rarely, compulsive seizures and ocular disorders such as nystagmus and gaze paralysis (5). As the disease progresses, there is a further slowing down of mental processes which can lead to a state of confusion, disorientation, hallucinations, stupor, and coma. Microcephaly and progressive psychomotor disorders may be present in children (6). In the absence of therapy, the decline is rapid, and an average survival period of less than 6 months is generally reported (7).

The therapeutic implications for ADC involve antiretroviral therapy (ART). Effective ART can reduce the incidence and severity of ADC by controlling viral replication (8). Anti-inflammatory treatments target neuroinflammation and may offer additional benefits (9). Neuroprotective agents that reduce oxidative stress and excitotoxicity are potential therapeutic avenues (10) (Table I).

Table I. Therapeutic Approaches to treating AIDS dementia complex (ADC).

DISCUSSION

ADC alone represents more than 15% of all neurological complications in HIV infection, and even in children, ADC is more frequent than opportunistic infections (11). ADC can be defined as a subcortical dementia that affects cognitive, motor, and behavioral functions and can be considered the direct result of the action of the HIV virus, although the mechanism of action is not yet perfectly known (12). HIV has been isolated in the brain and cerebrospinal fluid (CSF) of patients with ADC (13). In particular, the virus has been found in macrophage cells, astrocytes, and microglial cells, as well as in multinucleated giant cells within the CNS (14).  Oligodendrocytes and neurons have also been found infected, although on rare occasions (15). The pathogenesis of ADC involves multiple complex mechanisms at the molecular level (Table II).

Table II. The molecular mechanisms and inflammatory responses involved in AIDS dementia complex (ADC).

In the early stages of infection, HIV can enter the CNS through infected monocytes and CD4 T cells by crossing the blood-brain barrier (BBB). Within the CNS, HIV primarily infects microglia and macrophages, while astrocytes can also be infected but generally do not produce new virions. The transactivator of transcription (Tat) protein can be secreted by infected cells and can be taken up by neurons, causing oxidative stress and mitochondrial dysfunction (16). The viral gp120 protein is an envelope protein that can bind to neurons and cause direct toxicity, leading to apoptosis (17).

Infected glial cells can release excess glutamate, leading to excitotoxicity through overactivation of NMDA receptors on neurons, with an increase in intracellular calcium, which can trigger cell death pathways (18). HIV infection associated with the inflammatory process causes an increase in the production of reactive oxygen species (ROS), leading to oxidative damage to neurons (19,20).

HIV and its proteins can disrupt synaptic signaling and plasticity, cause chronic inflammation and neurotoxic environments that promote neuronal apoptosis, and lead to cognitive deficits (21) (Table III). Therefore, opportunistic infections and other co-morbidities in HIV-infected individuals can further impair CNS function (22).

Table III. The immune response in AIDS dementia complex (ADC).

The presence of the virus in the CNS has been demonstrated with various techniques including direct isolation, morphological identification, and in situ hybridization. HIV probably penetrates the CNS through macrophages which must be considered primary targets of the infection (23). However, the mechanisms through which neurological complications arise are still uncertain. Perhaps HIV induces damage to the CNS through indirect mechanisms, one of which could be the release of substances, such as cytokines, which would be able to act on the functioning of nerve cells or on neuromodulators (24). Myelin damage has been demonstrated in oligodendrocyte in vitro in cultures incubated with TNF. Furthermore, mononuclear phagocytes infected by HIV can release toxic substances capable of destroying isolated rat or chicken neurons in vitro (25).  On the other hand, TNF can increase HIV replication. Another possible mechanism of damage is represented by the release of gp120, which could increase the quantity of free calcium within neurons with subsequent irreversible damage (26).

Macroscopically, cerebral atrophy is frequently noted primarily in the frontotemporal regions (27). A diffuse pallor of the white matter may also be present; this occurs mainly in frontal and temporal areas but sometimes the results of the clinical investigation are normal. Histologically, alterations of white matter can be observed such as demyelization, vaporization, and astrocytosis. Inflammatory elements consisting mainly of lymphocytic and mononuclear cells are observable in the vicinity of the cerebral vessels (28). The most characteristic picture is the presence of multinucleated giant cells with several elongated and basophilic nuclei generally arranged at the periphery of the cells (29). The cytoplasm of these cells appears eosinophilic, densely colored in the center, and vaporized. Giant cells are more frequent in vascular spaces (30). Microglial nodules, which are mainly composed of mononuclear cells, are not specific to infection with HIV as they are also observed during cytomegalovirus encephalitis or toxoplasmosis (31). Electron microscopic studies have demonstrated the presence of retroviral particles in the cytoplasm of giant cells, which could therefore represent the major reservoir of the virus (32). Morphometric analysis has noted a reduction in the number of neurons (particularly of cells in the frontal and temporal regions), the loss of dendritic arborizations, and synaptic simplifications (33). HIV proteins such as gp120, Tat, and Vpr, have neurotoxic effects (34). gp120 is an envelope protein that interacts with chemokine receptors (e.g., CCR5, CXCR4) on neurons and glial cells, inducing apoptosis and synaptic damage (35). Tat can be secreted by infected cells and taken up by neurons, where it disrupts cellular functions, promotes inflammation, and increases oxidative stress (36). This viral protein induces cell cycle arrest and apoptosis in neurons.

CONCLUSIONS

The molecular mechanisms underlying ADC are crucial for developing targeted therapies to prevent and treat this debilitating condition in HIV-infected individuals. With further research focusing on these molecular aspects, it is hoped that the cognitive and functional decline associated with ADC can be further mitigated.

Conflict of interest

The authors declare that they have no conflict of interest.

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