PATHOGENETIC MECHANISMS OF NEUROLOGICAL DAMAGE IN HIV-1 INFECTION

P. Tocco^*

UOC Emergency Neurology and Stroke Unit, Asl Pescara P.O., Pescara, Italy.

^*Correspondence to:
Pierluigi Tocco, MD,
UOC Emergency Neurology and Stroke Unit,
Asl Pescara P.O.,
Pescara, Italy.
e-mail: pxtocco@gmail.com

Received: 01 November, 2024 Accepted: 17 January, 2025

ISSN 2279-5855 print ISSN 2974-6345 online. Copyright © by BIOLIFE 2025 This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

ABSTRACT

Infection by Human Immunodeficiency Virus-1 (HIV-1) can affect the central nervous system (CNS) by triggering various neurological symptoms. HIV-associated neurocognitive disorders (HAND) is a term that refers to the varying neurological and cognitive impairments that can afflict HIV patients, and HIV-associated dementia (HAD) is one of the most severe forms. HIV-1 causes systemic infection through infected CD4⁺ cells and CD14⁺ monocytes. Entry of the virus into the CNS causes neuroinflammation mediated by CD8⁺ T cells that can act against virus-infected cells. HIV-1 induces a high level of trafficking of immune cells and a strong inflammatory environment in brain tissue, which results in the release of pro-inflammatory cytokines that can increase the inflammatory state and contribute to CNS disorders.

KEYWORDS: AIDS, HIV, CNS, neurological symptoms, infection, HIV-associated neurocognitive disorders, HIV-associated dementia

INTRODUCTION

The central nervous system (CNS) is often affected by human immunodeficiency virus-1 (HIV-1) (1). The varying neurological and cognitive impairments in HIV-1 patients are collectively referred to as HIV-associated neurocognitive disorders (HAND), which range from asymptomatic neurocognitive impairment to severe HIV-associated dementia (HAD). The new therapies to treat AIDS have reduced not only the pathogenesis of the disease, but also the neurological and neurocognitive disorders caused by HIV-1 (2). Commonly used diagnostic tests such as neuropsychological tests, magnetic resonance spectroscopy, and neuroimaging have made it possible to better study the pathogenesis of HAND. Numerous experimental and clinical evidence have highlighted the presence of neurological symptoms in over 40% of AIDS patients, in different stages (3). However, in the last 10 years, greater clarity has been gained on pathogenesis, diagnosis, and therapy, which has extended the life span of patients infected with HIV-1.

DISCUSSION

HAND includes a varied range of cognitive, behavioral, and motor impairments which can afflict HIV-1 infected patients. Neurological involvement is expressed by various pathologies such as HIV-induced encephalopathy, progressive multifocal leukoencephalopathy, vacuole myelopathy, and necrotizing myelitis (4). Among them, the most specific and frequent clinical syndrome is HAD, recurring in over a third of patients with neurological symptoms (5).

HAD is the expression of a complex neurological, behavioral, and psychiatric symptomatology in which the pathogenetic mechanisms are not yet completely clear. HAD can be related to a series of mechanisms in which the priority participation of monocyte/macrophage isotype cells of both peripheral origin and neuro resident immune cells such as microglia is likely (6). They would have the dual function of spreading the infection and producing toxic immune substances, such as cytokines and other mediators, directed against neurons and oligodendrocytes (7).

According to the accumulated experimental evidence, it is possible that in immunopathological determinism, a singular mechanism is created according to which the virus would have the function of catalyzing a series of interdependent events tending to damage neurons through the mediation of substances produced remotely by other cell types (paracrine effect). These mechanisms would determine a variety of histopathological expressions such as reactive gliosis, focal necrosis, nuclear atypia of oligodendrocytes, and dimerization, to which is added a typical hallmark such as the presence of giant multinucleated cells composed of macrophage antigens and antigens of the HIV-1 virus itself (8).

The precise mechanisms by which HIV-1 enters the CNS are not fully understood, although several hypotheses have been proposed. However, the virus is certainly present in the CNS already at the time of seroconversion (9). Simian immunodeficiency virus (SIV) inoculation experiments in rhesus macaques revealed that infected cells invade brain tissue within two weeks of primary infection at rates ranging from 20 to 65% (10). Among the hypotheses, it has been suggested that macrophages coming from the peripheral blood would transport HIV-1, and the virus could penetrate through anatomical damage to the blood-brain barrier (BBB) in the form of a virion or transported by T lymphocytes. Furthermore, in vitro studies have shown that the cells of the choroid plexus and the endothelial cells of the CNS are susceptible to direct HIV-1 infections (11).

Other studies have underlined that HIV-1, similarly to other lentiviruses, requires macrophage strains endowed with neurotropism (12). This neurotrophic macrophage would be determined by the V3 domain (V3 region) of the gp 120 glycoprotein, but only some viral subsets are endowed with these properties and the ability to invade the CNS. Viruses with this important mutated determinant would be different from those that infect T lymphocyte lines (13). In this context, however, much still needs to be clarified, and above all, it is necessary to clone and study the amino acid sequences of many viral strains isolated from the CNS to confirm this possibility.

During the early stages of HIV-1 infection, CD4⁺ T cells that have bound HIV-1 transport it into the brain tissue (14). In healthy individuals, CD4⁺ T cells are present in the cerebrospinal fluid (CSF) where they represent approximately 300,000 cells per 150 ml of CSF and are very vulnerable cells to HIV-1 infection (15). The cerebral lymphatic vessels drain the CSF transporting CD4⁺ T cells and, in smaller quantities, CD8⁺ cells (16).

Numerous studies have identified the brain as a reservoir of large quantities of HIV-1 provirus and non-integrated DNA, even in the presence of minimal brain damage (17). Post-mortem neuropathological studies also have highlighted a selective localization of the HIV-1 virus in macrophages and microglia, while cells such as neurons, oligodendrocytes, and astrocytes were spared (18).

However, the same number of affected macrophages and microglial cells does not appear to be correlated with the extent of neurological damage. Such evidence would suggest that brain damage should be caused by indirect mechanisms (19). In this context, it is also necessary to clarify the role of microglia.

Microglia share a series of antigenic markers and other properties with the macrophage cells of the phagocytic system and secrete a series of substances that have the role of determining the development, differentiation, inflammation, and immunization of the CNS. Some proteases, human leukocyte antigens (HLAs), and cytokines such as TNF and IL-1b fall into this list (20). This secretory ability has been recognized in the culture of both rodent and human cells. During various pathologies or infections of the CNS, microglial cells undergoing activation present a series of phenotypic expressions that are not entirely known.

A powerful marker of microglial activation is represented by HLA class II antigens (DR) which are also found in AIDS (21). Furthermore, this marker can also be induced by some cytokines and by gamma interferon (IFN-g) (22).

During HIV infection, microglia appear to be more particularly infected in some areas that present some common characteristics such as a high iron content and a high content of neurotransmitter peptides (23). Ultimately, the population of macrophages and their brain equivalents, i.e. microglia, of the CNS is mostly, although not uniformly, affected by HIV-1 infection. Monocytes are generally infected via the CD4 receptor, not only by the virus but also by contact with the gp120 glycoprotein (24). A severe infection drastically reduces the presence of CD4⁺ T lymphocytes with much higher risks of developing neurological disorders. However, in HIV-positive individuals, antiretroviral therapy (ART) treatments at the beginning of the infection induce a benefit after 6 months by reducing the levels of inflammatory markers in the brain, including CD163 (25).

In AIDS, CD14⁺ monocytes represent a reservoir of HIV-1. They accumulate in the CNS and infect brain tissue, causing neuronal damage and mediating viral neuro-invasion (26). Monocytes in the peripheral blood of healthy individuals constitute 6-10% of all white cells, but these percentages can increase up to 40% in individuals suffering from chronic AIDS (27). Monocytes have the chemokine receptors CXCR5, CX3CR1, CXCR7, and CCR2 on their surface, which helps them cross the BBB and transport viruses into the brain (28). Treatment with ART inhibits viral replication in AIDS and reduces the pathological effects exerted by HIV-1.

CONCLUSIONS

HIV-1 causes systemic infection, including brain invasion, via infected CD4⁺ cells and CD14⁺ monocytes. Entry of the virus into the CNS causes neuroinflammation mediated by CD8⁺ T cells that can act against virus-infected cells. In addition, the high trafficking of immune cells and the inflammatory environment in brain tissue induced by HIV-1 infection, leads to the release of pro-inflammatory cytokines which can increase the inflammatory state leading to CNS disorders.

Conflict of interest

The author declares that they have no conflict of interest.

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