PATHOGENETIC MECHANISMS OF NEUROLOGICAL DAMAGE IN HIV INFECTION

Mazzatenta A, Fortunato M, Carnevali G. Pathogenetic mechanisms of neurological damage in HIV infection. International Journal of Infection. 2023;7(1):27-31.

A. Mazzatenta^1*, M. Fortunato² and G. Carnevali³

¹ Section of Physiology and Physiopathology, Department of Neuroscience, Imaging and Clinical Science, ‘G. d’Annunzio’ University of Chieti–Pescara, Chieti, Italy;
² Unit of Clinical Pathology and Microbiology, Miulli General Hospital, Acquaviva delle Fonti (Bari), Italy;
³ Cranio-Maxillo-Facial Surgery, University of Ferrara, Ferrara, Italy.

*Correspondence to:
Andrea Mazzatenta,
Section of Physiology and Physiopathology,
Department of Neuroscience, Imaging and Clinical Science,
‘G. d’Annunzio’ University of Chieti–Pescara,
Chieti, Italy.
e-mail: andrea.mazzatenta@unich.it

ABSTRACT

It is known that the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) can attack the central nervous system (CNS) to cause neurological symptoms such as encephalopathy, progressive multifocal leukoencephalopathy, myelopathy, and necrotizing myelitis. HIV can induce subacute encephalopathy, also called AIDS dementia complex (ADC), which is quite common and found in 1 out of 3 patients. The mechanisms involved in ADC are not entirely clear, but it is believed that microglia and macrophage cells participate in pathological processes. Microglia producing toxic mediators, including cytokines, would damage neurons and oligodendrocytes. HIV is present in the CNS, where it is transported by peripheral blood macrophages or T lymphocytes. Alternatively, HIV could reach brain tissue through anatomical damage to the blood-brain barrier (BBB). In the brain, HIV can attack both choroid plexus cells and endothelial cells. T cells appear to be attacked by different viruses than those that attack macrophages and microglia, and only some HIVs can invade the CNS. Microglial cells are activated by different CNS diseases, including infections, and exhibit a series of phenotypic expressions that are not fully understood. Similar to macrophages, microglia appear to be more particularly infected in certain areas that have a high iron content and a high content of neurotransmitter peptides. In the CNS, HIV is able to elicit an efficient humoral response, as evidenced by the absence of IgG and complement, and the almost total absence of effector cells, such as CD4+ cells. HIV infection and cytokine production increases the expression of human leukocyte antigen (HLA) class I molecules on parenchymal cells and make them vulnerable to cytotoxic T lymphocytes (CTLs). HIV 1, and gp 120 alone, stimulate the production of cytokines such as IL-1, TNF, IL-6, IL-8, and granulocyte macrophage colony-stimulating factor (GM-CSF), as well as ferritin, arachidonic acid products, and reactive O2 metabolites. The cytokines IL-1 and TNF seem to be able to determine white matter lesions, astrogliosis, and vascular changes, with increased permeability and necrosis of the vessels.

KEYWORDS: HIV, AIDS dementia complex, neurological, CNS, HIV-induced encephalopathy

INTRODUCTION

The central nervous system (CNS) is an important target of the human immunodeficiency virus (HIV)-1, which causes acquired immunodeficiency syndrome (AIDS) (1). Numerous experimental and clinical evidence has highlighted the presence of neurological symptoms in over 50% of HIV patients at different stages (2).

Post-mortem neuropathological studies have even raised this percentage to over 80%. Various neurological diseases, including HIV-induced encephalopathy, progressive multifocal leukoencephalopathy, vacuole myelopathy, and necrotizing myelitis are caused by HIV (3). Among them, the most specific and frequent clinical syndrome is HIV-induced subacute encephalopathy, also called AIDS dementia complex (ADC). ADC occurs in more than one-third of HIV patients with neurological symptoms (4). This syndrome is the expression of a complex neurological, behavioural, and psychiatric symptomatology in which the pathogenetic mechanisms are not yet completely clear (5).

DISCUSSION

ADC is related to a series of mechanisms in which monocyte/macrophage isotype cells of both peripheral origin and neuro residents such as microglia participate (6). These cells 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 a singular immunopathological mechanism is created in which the virus would have the function of catalysing a series of interdependent events which damage neurons through the mediation of substances produced remotely by others cell types (paracrine effect). These mechanisms cause a variety of histopathological events such as reactive gliosis, focal necrosis, nuclear atypia of oligodendrocytes, and dimerization, in addition to the presence of giant multinucleated cells composed of macrophage antigens and antigens of the virus itself (8).

The precise mechanisms by which HIV enters the central nervous system (CNS) are not fully understood, although several hypotheses have been proposed (9). However, the virus is already certainly present in the CNS at the time of seroconversion. 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 could transport HIV (11), and that the virus could penetrate through anatomical damage to the blood-brain barrier (BBB) in the form of a virion or by T lymphocyte transportation (12). 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 infection (13).

Other studies have underlined that HIV, similar to other lentiviruses, requires macrophage strains endowed with neurotropism. This macrophage neurotropism is 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 CNS (14). Viruses with this important mutated determinant would be different from those that infect T lymphocyte lines. However, in this context there is still much that 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.

Numerous studies have identified the brain as a reservoir of large quantities of HIV provirus and non-integrated DNA, even in the presence of minimal brain damage (15).  Post-mortem neuropathological studies have also highlighted a selective localization of HIV in macrophages and microglia, while cells such as neurons, oligodendrocytes, and astrocytes were spared. However, the same number of affected macrophages and microglial cells does not appear to correlate with the extent of neurological damage (16). Such evidence suggests that brain damage is likely caused by indirect mechanisms. It is also necessary to clarify the role of microglia, which share a series of antigenic markers and other properties with macrophages (which are part 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 antigen (HLA) antigens, and cytokines, such as TNF and IL-1b, fall into this category (17). This secretory ability of cells has been recognized in the culture of both rodent and human cells.

When microglial cells are activated by various pathologies of the CNS (in particular infections), they present a series of phenotypic expressions that are not entirely understood. A powerful marker of microglial activation is represented by HLA class II antigens (DR), which are also found in AIDS (18). This marker can also be induced by some cytokines and, in particular, by interferon gamma (IFNg) (19). During HIV infection, the microglia appear to be more particularly infected in some areas with common characteristics such as a high iron content and a high content of neurotransmitter peptides (20). Ultimately, the cell population of the CNS most affected by HIV infection is represented by macrophages and their brain equivalents, microglia. Monocytes are generally infected via the CD4 receptor, not only by the virus but also by contact with the gp 120 glycoprotein (21).

Regarding the direct infection of microglia, there is conflicting data in the literature, as these cells are not always infected in cultures and the differentiated state makes them resistant to infection. The presence of the virus in the CNS does not elicit an efficient humoral response such as the absence of sufficient levels of immunoglobulins and complement. Furthermore, some effector cells of the immune response are almost completely missing in the CNS. The cell-mediated response is fundamental for viral clearance but CD4+ T lymphocytes are lacking in AIDS, except in opportunistic infections such as cytomegalovirus.

As is known, the initiation of a specific immune response requires the presence of HLA antigens, the entry of immune cells through the veins of the CNS, and the presence of adhesion molecules such as lymphocyte function-associated antigen-1 (LAF-1) and intercellular adhesion molecule-1 (ICAM-1) (22). Viral antigens must be presented within class I and class II HLA molecules to elicit the activity of CD8+ and CD4+ lymphocytes, respectively. In the absence of CNS infection, the expression of HLA molecules is mostly restricted to endothelial cells. Viral infections or exposure to certain cytokines increase the expression of HLA class I molecules on parenchymal cells and make them targets of cytotoxic T lymphocytes (CTLs) (23). In patients with ADC, the expression of HLA class I molecules is present on endothelial cells and parenchymal cells located in the myelin areas, as confirmed by the high levels of beta-2-microglobulin in the cerebral spinal fluid (CSF) of almost all subjects with ADC (24). HLA class II molecules are exposed on activated immune cells and antigen-presenting cells such as APC cells (25). In ADC, class II HLA molecules are found on macrophages, microglia and multinucleated giant cells. On astrocytes, contrary to what happens in autoimmune forms such as experimental allergic encephalitis, such molecules have not been found.

The limited immune response to the virus is justified by a deficiency in the cellular mediated response due to the loss of CTLs and their failure to pass through the blood-brain barrier despite the presence of HLA molecules. Many studies have shown that HIV, or even gp 120 alone, can induce macrophages to produce cytokines such as IL-1, TNF, IL-6, IL-8, and granulocyte macrophage colony-stimulating factor (GM-CSF), as well as other substances of a different nature such as ferritin, arachidonic acid products, and reactive metabolites of O2 (26).

The mechanisms through which cytokines contribute to neurological damage are multiple. IL-1 and TNF, in particular, determine white matter lesions, astrogliosis, and vascular changes such as increased permeability and necrosis of the vessels (27). Furthermore, these cytokines, in vitro, have also demonstrated a potential ability to destroy oligodendrocytes and myelin. IL-1 and TNF can influence the normal physiological conditions of the CNS by determining the regulation of body temperature, including fever through the stimulation of PGE2 in the anterior hypothalamus (28).

CONCLUSIONS

Patients infected with HIV often demonstrate CNS involvement as well, with subacute encephalopathy, also known as ADC. The mechanisms of this syndrome are not yet fully understood, although there is much evidence that monocytic cells and other immune cells that produce pro-inflammatory cytokines are involved. Macrophages and microglia cells activated by the virus release immune proteins that damage CNS endothelial cells, neurons, oligodendrocytes and the surrounding tissue. Further studies are needed to discover the real biochemical and molecular reactions of this pathology.

Conflict of interest

The authors declare that they have no conflict of interest.

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