Annals of Indian Academy of Neurology
REVIEW ARTICLE
Year
: 2007  |  Volume : 10  |  Issue : 2  |  Page : 69--80

Changing patterns of human immunodeficiency virus-associated neuropathology


Francoise Gray1, Francesco Scaravilli2, Robert F Miller3,  
1 Service Central d'Anatomie et Cytologie Pathologiques, AP-HP Hôpital Lariboisière, Université Paris VII, France
2 Institute of Neurology, UCL, London, United Kingdom
3 Center for Sexual Health and HIV Research, Department of Primary Care and Population Sciences, UCL and Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1, United Kingdom

Correspondence Address:
Francesco Scaravilli
Institute of Neurology, UCL, London
United Kingdom

Abstract

This paper describes the evolution of the pathogenic concepts associated with the infection by the human immunodeficiency virus (HIV), with emphasis to the pathology of the nervous system. Although the first description of damage to the nervous system in the acquired immunodeficiency syndrome (AIDS) only appeared in 1982, the dramatic diffusion of the epidemic worldwide, as well as the invariably rapidly fatal outcome of the disease before the introduction of efficient treatment, generated from the beginning an enormous amount of research and re-thinking on a number of pathogenetic concepts. Less than 25 years after the first autopsy series on AIDS patients were published and the virus responsible for AIDS was identified, satisfactory definition and classification of a number of neuropathological complications of HIV infection have been established. This has led to the establishment of accurate clinical and biological diagnosis of the main neurological complications of the disease, which remain a major cause of disability and death in patients. Clinical and experimental studies have provided essential insight into the pathogenesis of CNS lesions and the natural history of the disorder. The relatively recent introduction of effective antiretroviral therapy in 1995-6 dramatically improved the course of prognosis of HIV disease. However, there remain a number of unsolved pathogenetic issues, the most puzzling of which remains the precise mechanism of neuronal damage underlying the specific HIV-related cognitive disorder (HIV-dementia). In addition, although antiretroviral therapy has changed the course of neurological complications, new issues have emerged, such as the lack of improvement or even paradoxical deterioration of the neurological status in treated patients. Interpretation of these complications remains largely speculative, partly because of the small number of neuropathological studies related to the beneficial consequence of this treatment.



How to cite this article:
Gray F, Scaravilli F, Miller RF. Changing patterns of human immunodeficiency virus-associated neuropathology.Ann Indian Acad Neurol 2007;10:69-80


How to cite this URL:
Gray F, Scaravilli F, Miller RF. Changing patterns of human immunodeficiency virus-associated neuropathology. Ann Indian Acad Neurol [serial online] 2007 [cited 2020 Apr 1 ];10:69-80
Available from: http://www.annalsofian.org/text.asp?2007/10/2/69/33213


Full Text

 Introduction



Involvement of the central nervous system (CNS) in the acquired immunodeficiency syndrome (AIDS) is a relatively recent event, which has generated an enormous amount of clinical and experimental research because of the dramatic worldwide spread of the epidemic involving over 30 million individuals[1],[2],[3] and its dire consequences.

The early eighties saw the appearance, initially in the USA, of a new "epidemics" of Kaposi sarcomas and unusual opportunistic infections in the gay community and Haitians.[4] The new disorder, referred to as "acquired immunodeficiency syndrome" (AIDS) with T-cell depletion, was considered to be induced by a virus. Originally known as "lymphadenopathy associated virus" (LAV)[5] or "human T cell lymphotropic virus type III" (HTLV-III),[6] it was finally named by consensus "human immunodeficiency virus" (HIV).

As the nervous system takes a major part as a cause of disability and death in AIDS patients,[7] a huge amount of post-mortem work tried to establish the spectrum of HIV damage.[8],[9] Additional work led to define the pathogenesis of cerebral damage and the natural history of CNS involvement, particularly in the early stages of the infection.

Unfortunately, not all the issues could be solved; these include the stage of the infection at which HIV enters the central nervous system and the precise mechanism of neuronal damage underlying the specific HIV-related cognitive disorder (HIV dementia); in addition, complications have emerged recently, following the introduction of therapeutic drugs.

The human immunodeficiency virus (HIV)

The discovery of the human immune deficiency virus - HIV-1[5],[10] was followed, a few years later, by that of a second virus, HIV-2, found in West Africa. Both are RNA viruses belonging to the lentivirus group of the retrovirus family.[11] HIV is a non transforming virus, which replicates through the generation of a proviral DNA intermediate by the action of a retroviral enzyme RNA-directed DNA polymerase (reverse transcriptase - RT). In vivo, a persistent infection follows integration of proviral DNA into the host genome.

As similar diseases affected macaques in primate centres in the USA and elsewhere,[12] it soon became apparent that these viruses had first been acquired, about a century ago, from non-human primates.[13],[14],[15]

To enter cells, retroviruses must bind to a specific cellular receptor located on the surface of CD4 cells;[16] they productively infect T-lymphocytes in vitro[17] as well as cells of the monocyte/macrophage lineage.[18],[19] Co-receptors too are involved in facilitating the infection; they include the chemokine receptors CXCR4[20] and CCR5.[21] Eventually, presence of HIV within a cell results in one of the following conditions: 1) productive infection; 2) latent infection, a situation in which the DNA provirus is blocked at the stage of transcription; 3) non-productive (or restricted) infection, in which the unintegrated or integrated viral DNA does not result in viral production.

The continuous evolution of HIV in vivo has important implications with regard to its replication[22] and its cytopathic effects.[22]

After the gay community, HIV infection soon spread to other groups, including intravenous drug users, patients receiving blood transfusion and organ transplants, women undergoing artificial insemination and children born to HIV-positive parents or breast fed by positive women. Although the heterosexual route of infection was well known from the outset, lately it has become the predominant form of infection, particularly in sub-Saharan regions.

Definition and classification of the multiple neuropathological complications of HIV infection

The severe deficit of cell-mediated immunity makes AIDS patients prone to infections of virtually any organ in the body by a wide range of opportunistic organisms including viruses, bacteria, fungi and protozoa. In addition, patients may develop tumours, the most common of which are non-Hodgkin's lymphomas and Kaposi's sarcoma.[23]

Among the viruses, cytomegalovirus was present in between 10%[24] and 30%[25] of the patients. Progressive multifocal leukoencephalopathy (PML), a previously rare viral encephalitis, due to a papovavirus, has an incidence varying between 2%,[26] 5%[27],[28] and 7%.[24] Cryptococcosis, the commonest mycosis in AIDS, presents predominantly as meningitis[29] and was identified in 3-8% of the cases.[26],[28] Toxoplasmosis became the commonest cause of intracerebral mass lesion, with a larger incidence in Europe[24],[30],[31] than in America.[26],[32],[33]

Lymphomas, either primary or secondary, are common in AIDS; they are usually high grade, non-Hodgkin and appear as multiple and partly necrotic masses. Histologically they consist of B-cell immunoblasts. A relationship with viruses, already found in patients undergoing transplants,[34] was confirmed in AIDS patients, all of whom proved serologically positive to Epstein-Barr virus.[35],[36]

An early paper[7] conveyed the impression that opportunistic organisms were also the cause of a subacute form of encephalitis, characterised by "subtle cognitive changes accompanied by malaise, lethargy….". However, its close relationship with HIV was confirmed by viral detection within the nerve tissue,[37] together with the finding of multinucleated giant cells (MGC)[38] [Figure 1]a, the hallmark of the syndrome.[39] These result from virus-induced fusion of infected macrophages, thus reflecting both productive infection and the pathogenic role for the virus. MGC [Figure 1]b, together with microglia, are seen to contain HIV protein. Further observations revealed 3 types of changes in HIV infected patients, in the absence of any other cause; these can be variably associated:

HIV encephalitis (HIVE) [Figure 2]a, characterised by disseminated foci or more diffuse lesions including myelin loss, astrogliosis and microglial activation with microglial nodules, macrophages and MGC. The viral load is high. HIV leukoencephalopathy (HIVL-lep) [Figure 2]b, shows diffuse myelin pallor, particularly severe in the centrum semiovale. It is frequently associated with HIVE. Both types may represent the extremes of a spectrum and may overlap in one third of cases.[40] Widespread axonal damage identified by immunocytochemistry of beta-amyloid protein precursor [Figure 3]a was also shown to be extremely frequent in AIDS.[41] Abnormality of the brain microvasculature[42],[43] leads to brain-blood-barrier (BBB) damage, in turn responsible for the diffuse myelin pallor.[44] This was recently confirmed by loss of tight junction protein, zonula occludens-1, in patients with HIV dementia.[45] This topic is reviewed by Petito and Cask.[46] A less obvious involvement of the grey matter is also frequent in AIDS. In its extreme form it has been defined as "diffuse poliodystrophy" [Figure 2]c, characterized by diffuse astrogliosis and microglial activation and observed in about half of AIDS patients.[27],[47] Neuronal loss, suspected at microscopy, was confirmed by several morphometric studies.[48] Later, neuronal damage in AIDS was correlated, at least in part, with apoptosis[49],[50],[51] [Figure 3]b.

HIV infection affects also children born to HIV-positive parents. Of the 3 million children infected, 50% have already died of AIDS. Sub-Saharan Africa is at present the area with the highest incidence, approximately 1000 new cases every day. Neurological complications in children, more common than in adults,[52],[53] consist of delayed or arrested development, microcephaly, progressive ataxia and cortico-spinal tract signs. Pathological changes[54] include vascular mineralization in 92%, white matter changes (78%) with inflammatory infiltrates (75%), MGC (36%) and vascular inflammation (30%). Recently, Gelbard et al[55] confirmed the presence of neuronal apoptosis. On the other hand, opportunistic infections have a lower incidence (14%).

Despite an overall similarity in the natural history of HIV infection in all the various risk groups (see above), some differences were observed: among the haemophiliacs, there is low prevalence of opportunistic infections and high rate of death from intracranial haemorrhage and liver cirrhosis.[56] Similarly, the incidence of opportunistic infections is lower in drug users than in homosexuals, despite similar CD4 counts.[57]

For a number of clinico-pathologic conditions in HIV infection, no plausible pathogenesis has been found. Among these, vacuolar myelopathy (VM) ,[7],[58] appears late in the course of the infection and represents the single most common spinal disorder in AIDS, with range from 1[27] to 55%.[59] It is rare in children.[60] Changes[61] include intramyelinic and periaxonal vacuoles, some containing macrophages, predominantly within the lateral and posterior columns, though not limited to any specific tract. In a clinical and pathological study, VM was noted[62] to start at mid-low thoracic level with rostral and caudal spreading with increasing severity.

Both the association of VM with HIVE and a number of pathological findings[63],[64] suggest a direct role by HIV. However, VM was found in non-AIDS immunocompromized patients.[65] Despite similarities with subacute combined degeneration (SCD), the role of vitamin B 12 deficiency was not substantiated. Another possibility is that persistent immune activation in the CNS may lead to local production of myelin or membrane damaging cytokines, such as TNF-α,[66] toxins or oxygen radicals. Degenerating myelin may attract macrophages; those expressing gp-120 may further cause a functional disorder of oligodendrocytes and thus could underlie the diffuse myelin loss seen in HIV encephalopathy.[67] Such macrophages may be activated to secrete cytokines or attempt to phagocytose myelin.

A further rare, complication of HIV infection is vasculitis, appearing as lymphocytic[68] or granulomatous[69] infiltration of the walls of cerebral vessels with or without accompanying necrosis and sometimes associated with meningitis.[70] Its exact relationship with HIV infection remains obscure.

Pathogenesis of CNS changes in HIV infection

Three issues appear relevant for the understanding of the pathogenesis of the CNS changes during HIV infection: 1) the types of cells harbouring HIV, 2) the pathogenesis of neuronal damage and 3) the time of arrival of HIV into the CNS.

1) Microglial cells and macrophages are the target for HIV[18],[19] and several studies suggest the role of 'Trojan horse' for HIV-infected monocytes in the dissemination of infectious particles. As for a possible role of neuroectodermal cells, various groups have found evidence of HIV infection in astrocytes[71],[72],[73],[74] and oligodendrocytes.[71] Moreover, demonstrable HIV-DNA and RNA in glial cells were found in all HIV-positive demented patients, but in only few non demented.[71] Cerebral endothelial cells too appear infected.[15],[71] As for nerve cells, HIV-1-DNA was detected by Nuovo et al[75] and Bagasra et al ,[76] but not by others.[71],[77] However, it appears that, in all cell types, HIV manages to establish a persistent, rather than productive, infection and that only in microglial cells and monocytes, it establishes a productive infection.[78]

Pathogenesis of neuronal damage

Therefore, an indirect mechanism of neuronal damage, as the basis of the cognitive disorder (see below), is considered more likely. This can be achieved via virus- and glial cell-derived proteins;[79] the following neurotoxic factors, possibly acting in combination,[80] have been incriminated: viral proteins, particularly gp120 , gp41 , tat , nef or substances produced by activated glial and microglial cells such as cytokines, prostaglandins, proteases, arachidonic acid or quinolinic acid metabolites.[48] In particular, viral proteins, such as tat , can cause neurotoxic damage at remote sites[81] by being transported along neural pathways. A glutamate-mediated excitotoxicity has been supported by in vitro studies,[82],[83],[84] as increased glutamate levels are found in the CSF and plasma of patients with HIV-related dementia.[85] Increased levels of quinolinic acid, a glutamate agonist, are present in the CSF of AIDS patients with cognitive and motor abnormalities.[86] In addition, activated microglial cells may express the high affinity glutamate transporter "excito-amino acid transporter -1" (EAAT-1), whilst its normal expression by astrocytes is inhibited.[87],[88]

It has been shown that a combination of toxins with cellular and viral factors induces a more severe degree of neuronal apoptosis that each of them in isolation.[89] This has led to the suggestion that neuronal damage in HIV infection may be multifactorial.[90] The mechanism of the irreversible neuronal DNA damage and eventual apoptosis appears to involve oxidative stress and glutamate-receptor-mediated toxicity.[80] In vitro studies have suggested that combined HIV protein and cytokine neurotoxicity may be mediated by oxidative stress[91] and cause neuronal apoptosis.[92] It was also shown, in vivo , that peroxinitrite activity resulting from the simultaneous production of super oxide anion and nitric oxide is significantly increased in demented, compared to non-demented, AIDS patients.[93] Finally, Nath et al[94] have suggested that neurotoxic proteins can initiate a cascade of events that self-perpetuate in a positive feedback manner. The topic is reviewed and discussed by Li et al .[95]

Time of arrival of HIV into the CNS

A late arrival of the virus into the CNS would allow early treatment to prevent infection entering the CNS, thus potentially avoiding late complications such as HIV encephalitis and dementia.

Unfortunately, early data seem to support the opposite hypothesis: the appearance of meningitis,[96] encephalopathy[97] or myelopathy[98] during seroconversion; intrathecal synthesis of HIV-1 antibody;[99] the recovery of HIV in the CSF[96] as well as a fulminating encephalitis in one patient accidentally injected with HIV, who died 15 days later.[100]

In keeping with the hypothesis of an early viral entry, Gray et al[101] described lymphocytic meningitis [Figure 4]a, perivascular mononuclear infiltrates, discrete myelin pallor, astrocytic gliosis and microgliosis. Additional findings were discrete neuronal loss via apoptosis[102] and diffuse axonal damage.[103] After the detection of HIV-DNA in the brain tissue of asymptomatic individuals,[104] An et al revealed a condition of immune activation of the cerebral tissue [Figure 4]b, with presence of toxic cytokines [Figure 4]c.[105] Finally, the same group[71] found that, at this stage, astrocytes and endothelial cells, in addition to microglia [Figure 4]d, are infected. However, viral replication remains very low during this stage.

The pathogenesis of HIV dementia

About 20 per cent of patients with AIDS develop a specific progressive cognitive/motor syndrome "HIV dementia" or AIDS-dementia complex (ADC), of which HIV-encephalitis was initially considered the pathological counterpart. Some groups still support this correlation,[106] whilst others were unable to confirm it,[90],[107],[108],[109] even applying morphometry[110] and PCR.[111],[112]

Other pathogenetic possibilities for the dementia were explored:

a) Microglial activation (MA),[110] although correlated by a number of observations,[71],[90],[113] remains a non specific finding.

b) Astrocytic abnormalities, including increased expression of adhesion molecules,[114] enhanced astrocyte activation[115] or loss of astrocytic function[72],[73],[116] could not be convincingly correlated.

c) The same was true for leukoencephalopathy[90],[110] and axonal damage, despite the consistent association of the latter with HIV encephalitis.[41]

d) Absence of correlation was also seen with poliodystrophy,[117],[118] as well as with cortical neuronal loss.[119]

As the various disorders associated with organic dementia have specific localisation for the cell loss, studies were carried out in the attempt at localising the cell loss also in HIV dementia. However, whereas Everall et al[120] found cell loss in the putamen, Bell et al[57] detected productive infection preferentially in the frontal cortex and Petito et al[121] reported reactive gliosis in the hippocampus.

The lack of exact correlation between the cognitive disorders and HIV-induced changes and recent reports of improvement of the cognitive disorders after HAART, suggest that HIVD might be the expression of a specific neuronal dysfunction resulting from the combined effects of several HIV-related neurotoxic factors, involving different aetiopathogenetic mechanisms some of which may be reversible.

If one accepts that HIVD reflects a specific neuronal dysfunction resulting from the combined action of HIV protein, glial and microglial activation, perhaps mediated by oxidative stress and glutamate-mediated excitotoxicity, its relationship with the different HIV-induced neuropathological changes is easier to understand.[122] Indeed, these changes may result from the same mechanisms: HIVE reflects productive HIV infection, HIVL is secondary to an alteration of the BBB resulting either from the effect of circulating factors or factors locally produced by activated macrophages. The same applies for axonal damage. Finally neuronal apoptosis and consequent DPD may result from the neurotoxicity of these combined factors or from axonal damage through retrograde degeneration. It is also possible that deafferentation of neurons may induce apoptosis in nerve cells. This hypothesis is in keeping with the description of synaptic and dendritic simplification in the brains of AIDS patients with severe HIVD[123] and in those with mild to moderate neurocognitive disorders.[124] The importance of the different factors may vary from one patient to another resulting in different histological features. This may explain why, although these lesions are more frequent in patients with HIVD, none can be strictly correlated to the cognitive impairment.

Modification of CNS complications of AIDS following the introduction of combination antiretroviral therapy (cART)

In 1981, reports of clusters of Pneumocystis pneumonia (PCP), Kaposi sarcoma and chronic mucocutaneous herpes simplex infection heralded the onset of the AIDS epidemic. Initially management of HIV disease was focused on treatment of opportunistic infections, such as PCP, cerebral toxoplasmosis and tumours, such as non-Hodgkin lymphoma. There was no specific HIV treatment available.

Later, in the late 1980s and early 1990s, with the introduction of prophylaxis against specific opportunistic infections (OIs) the incidence of AIDS-related OIs, such as PCP, began to fall.[125] Soon after, the introduction of nucleoside reverse-transcriptase inhibitor (NRTI) drugs coincided with a further reduction in both OIs and also HIV-associated dementia.[126]

In 1996 a new more powerful class of antiretroviral drugs, the protease inhibitors (PI) became available. Their introduction into clinical practice was associated with a dramatic reduction in incidence of AIDS-defining OIs and AIDS-associated deaths.[126],[127]

The term highly active antiretroviral therapy (HAART) was introduced to describe combinations of drugs used to treat HIV; HAART specifically refers to a combination of 2 NRTI class drugs, together with a PI class drug or a non-nucleoside reverse transcriptase inhibitor (NNRTI) class drug. Currently there are six classes of antiretroviral drugs available; NRTIs- such as zidovudine and lamivudine, nucleotide reverse transcriptase inhibitors (NtRTI) such as tenofovir, PIs such as ritonavir and amprenavir, NNRTIs such as efavirenz and nevirapine, fusion inhibitors such as enfuvirtide and integrase inhibitors such as raltegravir. The term combination antiretroviral therapy (cART) is now used to describe treatment of HIV infection using different classes of HIV drugs.

cART is successful in suppressing HIV replication;[128] improving cellular immunity[129] with protection against OIs.[130],[131],[132] Outside the nervous system, cART has decreased the incidence of tuberculosis[112],[133],[134] and of PCP;[135] prolonged survival in patients with tuberculosis and fungal infections[93] and prolongs survival in patients receiving chemotherapy for non-Hodgkin lymphoma.[136] In addition, several organ-specific disorders, including HIV-associated nephropathy, wasting syndrome and cardiomyopathy, all considered a direct consequence of HIV, benefit from cART. This review will deal only with the effects of cART on the nervous system.

In contrast to the reported success of prophylaxis and cART among HIV-infected patients in N America, Europe and Australasia, in parts of the world without access to these therapeutic interventions, because of financial constraints, such as southern Africa, HIV infection continues to spread relentlessly and patients continue to present with AIDS-defining OIs and malignancy, with attendant high rates of mortality.

While cART has unequivocally reduced rates of OIs and AIDS-related deaths in many cohort studies, it has many treatment-limiting side effects, notably those associated with NRTI-induced mitochondrial dysfunction, such as zidovudine-associated myopathy and stavudine-associated peripheral neuropathy and with PI-induced metabolic dysfunction, including dyslipidaemia and diabetes mellitus. Additionally many patients are intolerant of cART, as they experience nausea, anorexia, rash, biochemical hepatitis and neuropsychiatric side affects and in others development of genotypic and phenotypic resistance in HIV renders cART less or ineffective.

Unfortunately not all of the available antiretroviral drugs attain effective therapeutic levels in the CNS. Penetration of drugs across the blood-brain barrier (BBB) is dependant on several factors.[137] First, the integrity of the BBB; in advanced HIV there may be inflammation, facilitating diffusion of drugs. Second, cerebral blood flow may be influenced by HIV-associated nitric oxide production, permitting increased diffusion of drugs across the BBB. Third, endothelial cell-associated multidrug transporter proteins (MRP) act as unidirectional efflux pumps which may limit the ability of PIs to permeate brain tissue.[138] Fourth, the size, ionisation and lipophilicity of the drug molecule will influence the ease with which it will cross the BBB. Of currently available antiretroviral drugs, zidovudine penetrates the CNS most readily. The NNRI efavirenz also appears to penetrate the BBB and the boosted PI lopinavir/ritonavir (that is use of lopinavir together with a small dose of ritonavir) appears to suppress CSF HIV replication, despite the absence of measurable drug in CSF.[137],[139]

With regard to the CNS, despite a decrease in the number of AIDS-related post-mortems, brain disease remains a major cause of death. In the early stages, when HAART was administered to patients with severe immunodeficiency, the incidence of progressive multifocal leukoencephalopathy (PML) and primary non-Hodgkin lymphomas remained unchanged, whilst toxoplasmosis and CMV and HIV encephalitis decreased. On the other hand, when it was given at an early stage of immunosuppression, PML, CMV and primary lymphomas decreased, whereas infections occurring in mildly immunodeficient patients (VZV and HSV encephalitis) became more frequent. These data are reviewed and summarised by.[140]

But it soon became clear that these were not the only differences observed in this new era as other patients develop what has become known as 'burnt-out' lesions;[140] these result from treated forms of VZV encephalitis,[141] toxoplasmosis, HIVE and PML and are remarkable for the absence of both inflammation and infectious agents. These 'scar' lesions may be found in clinically and biologically cured patients who die from other causes as previously reported for toxoplasmosis.[142] In other instances, despite efficient treatment, the neurological condition of the patient may continue to deteriorate. In those patients with multifocal extensive toxoplasmosis or late treated HIVE or PML, it seems that, despite successful eradication of productive infection in the CNS, treatment was too late to prevent irreversible destructive lesions with, in some cases, secondary progressing Wallerian degeneration.[140]

In addition, in a minority of patients, HAART- and cATR-induced partial restoration of specific immunity may unmask or worsen a pre-existing disease. This complication, referred to as immune reconstruction inflammatory syndrome (IRIS) , is defined as a 'paradoxical deterioration in clinical status, attributable to the recovery of the immune system during HAART'.[143] Mycobacterial infection,[144],[145] CMV retinitis[146] and cryptococcal meningitis[147],[148] related to IRIS have been reported. In some patients with PML and receiving HAART, contrast enhancement revealed a florid inflammatory reaction, usually discrete in untreated individuals, which was confirmed by cerebral biopsy.[149],[150] In most cases, this correlated with prolonged survival and was interpreted as a marker of both improved immune status and outcome;[151],[152],[153] however in rare instances,[149] it coincided with clinical and radiological deterioration.

Fatal cases, possibly representing this syndrome, are those described by Langford et al[154] in 7 HAART-treated patients. In these, post-mortem revealed myelin loss, lympho-monocytic perivascular exudates, axonal injury and astrogliosis. All these changes were considered more severe than in the pre-HAART era. A pathologic and immunohistochemical account of the syndrome in the CNS was subsequently provided by Miller et al ;[155] they reported 2 patients who, despite HAART and a subsequent improved CD4 count and decreased HIV load in the CSF, developed fatal encephalopathy and diffuse myelin pallor [Figure 5]a. In both, the brain tissue showed presence of HIV-DNA by PCR; the salient pathology consisted of diffuse microglial hyperplasia and massive perivascular [Figure 5]b and intra-parenchymal [Figure 5]c infiltration by CD8+/CD4- lymphocytes. It was suggested that the rapid immune reconstruction induced by the treatment led to a redistribution of lymphocytes into the peripheral blood. This was followed by recruitment of CD8+ cells into the brain, resulting in diffuse infiltration and consequent tissue damage. The latter could take place in two ways: either by ligating TNF receptor-like molecules by their corresponding ligands, triggering the apoptosis pathway or by secreting the content of cytoplasmic vesicles.[156] More recently Venkatarama et al[157] reported three patients with neurological manifestations of IRIS. In their patient 3 a brain biopsy confirmed the presence of HIV encephalitis and a severe infiltration by CD8 and fewer CD4 lymphocytes.

A fatal case in a patient with PML revealed, at neuropathological examination, two co-existing and equally undesirable, effects of this therapy: on the one hand an active inflammatory PML with abundant JCV together with massive intraparenchymal and perivascular infiltration by CD8+ lymphocytes in the absence of CD4+ lymphocytes [Figure 5]d; this is a possible reaction to a smouldering active infection; on the other, an acute perivenous leukoencephalitis, similar to acute perivenous encephalomyelitis [Figure 5]e, devoid of JCV[158] and considered a possible reaction to a latent antigen or inactive infectious agent.[159] It is suggested that both patterns may relate to CD8+lymphocyte cytotoxicity.[160]

Finally, as HAART and cART have effectively lengthened the life expectancy of HIV-infected individuals, additional chronic patterns of HIV encephalitis have arisen that may explain the shift of the clinical manifestations from severe dementia to more subtle minor cognitive impairment.[161] A recent post mortem study in AIDS patients well treated by HAART, revealed high level of microglia/macrophage activation, particularly in the hippocampus where the degree of inflammation was higher than in control cases, pre-HAART AIDS and presymptomatic brains. This is consistent with reports of clinical examination and neuroimaging in HAART-treated individuals, suggesting that alterations in the hippocampus are more pronounced than was observed pre-HAART.[162] Although no evidence of dementia was observed the patients, the persistence of an ongoing neuroinflammation and the shift in its distribution to the hippocampus may pose a threat for the future health of individuals maintained long-term on HAART.[163]

Also, there is a concern that additional factors including aging and the secondary effects of treatment may worsen the course of the cognitive disorders. Increased cerebrovascular risk may result from metabolic changes (dyslipidemia, insulin resistance and changes in body fat) associated with chronic antiretroviral therapy.[164] Finally brain deposition of beta-amyloid has been shown to be a common pathologic feature in HIV positive patients[165] consistent with experimental demonstration that HIV protein tat inhibits beta-amyloid degradation by neprelysin[166] and with clinical observation of significantly decreased CSF beta-amyloid and increased tau concentrations similar to Alzheimer disease in HIV dementia.[167]

 Conclusion



It now appears that introduction of HAART has dramatically modified the course and prognosis of HIV infection. However these encouraging results are restricted to the developed world where treatment is widely available; in addition, their impact on the HIV-associated cognitive disorders, which represent the most disabling complications of the disease, is not clearly established; finally new HAART -related neurological complications have appeared. Therefore it is crucial that further research continue both for a better understanding of the mechanisms of neurodegeneration and for wider prevention and treatment of HIV infection.

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