Encephalitis with Infiltration by CD8+ Lymphocytes in HIV Patients Receiving Combination Antiretroviral Treatment

Abstract

We report the neuropathological findings in 10 HIV‐infected patients treated by combination antiretroviral therapy who developed subacute encephalopathy of rapidly progressive onset. Brain biopsy showed encephalitic lesions variably associated with myelin loss and slight axonal damage. There was inconstant, weak expression of HIV protein p24; tests for other pathogens were negative. The most striking feature was diffuse, perivascular and intraparenchymal infiltration by CD8+ T‐lymphocytes. Six patients improved after the treatment. Four had an unfavorable outcome and died within a year. Post‐mortem in one case confirmed HIV leukoencephalitis with p24‐positive multinucleated giant cells, associated with acute demyelinating encephalomyelitis (ADEM) in the cerebellum. There was diffuse infiltration by CD8+ lymphocytes; CD4+ cells were virtually absent. These cases may represent a specific clinicopathological entity, of which a few comparable cases have been already described. They can be included in the wide framework of immune reconstitution disease. Such syndromes have been described with opportunistic infections, but only seldom with HIV infection of the central nervous system (CNS). Our findings support the hypothesis that CD8+ cytotoxic lymphocytes can be harmful in immune reconstitution disease, particularly in the absence of CD4+ lymphocytes. CD8 cytotoxicity produces an acutization of a smoldering infection and/or an immunopathological reaction similar to ADEM.

Introduction

The introduction of combination antiretroviral treatment (cART) has dramatically improved the course and prognosis of human immunodeficiency virus (HIV) disease by reducing viral load (VL) and increasing CD4+ lymphocyte count 1, 29, 37, thereby protecting against opportunistic infections 32, 39. In most developed countries where treatment is widely available, it has significantly reduced morbidity and mortality in HIV‐infected patients and improved their quality of life. HIV infection has become a chronic disease and epidemiological surveys show that acquired immunodeficiency syndrome (AIDS)‐defining events are no longer the major causes of death in HIV‐infected patients 8. Neuropathological studies have confirmed this favorable development 16, 40.

However, the central nervous system (CNS) is still a major target of the infection 28 and new patterns of involvement have appeared 16. In a number of patients, cART‐induced partial restoration of specific immunity may unmask or worsen a preexisting disease. Unusual inflammatory syndromes, associated with underlying opportunistic infections after initiation of highly active antiretroviral therapy (HAART), have been reported increasingly in AIDS patients. This complication, referred to clinically as immune reconstitution inflammatory syndrome (IRIS), is defined as a “paradoxical deterioration in clinical status, attributable to the recovery of the immune system during cART 41.” In addition to a variety of systemic infections 5, 30, 41, CNS mycobacterial infection 7, 11, 38, Cytomegalovirus (CMV) retinitis 19, 20 and cryptococcal meningitis 21, 50 related to IRIS have been reported. In some patients with progressive multifocal leukoencephalopathy (PML) receiving cART, contrast enhancement suggested an unusually florid inflammatory reaction with blood–brain barrier breakdown 6, which was confirmed by cerebral biopsy 23, 35, 43. In most cases, this correlated with prolonged survival and was interpreted as a marker of both improved immune status and outcome 6, 18, 23; however, in rare instances 35, it resulted in clinical and radiological deterioration.

Although HIV encephalitis (HIVE) cannot be considered an opportunistic infection, there are a few neuropathological reports suggesting that immune reconstitution may play a role in the paradoxical aggravation of encephalopathy in patients receiving cART. A new type of severe leukoencephalopathy with intense perivascular infiltration by HIV‐gp41 immunoreactive monocytes/macrophages and lymphocytes, associated with widespread myelin loss, axonal injury, microgliosis and astrogliosis was described by Langford et al 24 in seven patients who failed HAART. Among a number of different potential mechanisms, the authors suggested that the tissue damage could be caused by an “overzealous” response of a newly reconstituted immune system to HIV antigens already present when therapy was initiated 25. Miller et al 34 reported two autopsy cases of patients with advanced HIV disease who developed an acute rapidly fatal encephalopathy or presented with worsening of preexisting encephalopathy, following cART‐induced increase of CD4 count and reduction in HIV VL. In both cases, magnetic resonance imaging (MRI) showed extensive diffuse or multifocal white matter signal abnormalities. At post‐mortem, both had widespread myelin loss with axonal damage, reactive astrocytosis and intense perivascular infiltration by macrophages. Unlike Langford's cases 24, only occasional HIV‐p24 positive macrophages were present in one case. They were not found in the other, but HIV‐DNA was identified in both brains by in situ polymerase chain reaction (PCR). The most striking feature in both cases was a massive diffuse perivascular and intraparenchymal infiltration by CD8+ lymphocytes in the absence of CD4‐ lymphocytes and it was suggested 34 that CD8+ cytotoxic lymphocytes may play a deleterious role in the syndrome of immune reconstitution.

In this paper, we describe the neuropathological findings in 10 biopsy cases and one autopsy case of encephalitis with heavy infiltration of CD8+ lymphocytes, in the absence of associated opportunistic infection of the brain, in HIV‐infected patients receiving cART, which have some similarities with the cases of Miller et al 34. The clinical data, more detailed in another paper 27, suggest that these CD8+ encephalitis represent a specific entity with characteristic clinical, radiological and neuropathological features requiring a specific treatment. We discuss the nosological situation of this entity in the wider framework of immune reconstitution disease and propose a pathogenic hypothesis.

Case Reports

Ten AIDS patients (five males and five females) receiving cART developed subacute encephalopathy of rapidly progressive onset, while on antiretroviral therapy. Three (cases 1–3) have been briefly described in a previous report 17. Imaging showed similar distinctive changes consisting of bilateral and diffuse or multifocal T2 and FLAIR high signal intensities involving both the white and the gray matter. On T1 weighted images, contrast enhancement showed very suggestive multiple punctate or linear gadolinium enhanced lesions. In case 3, the vascular changes were predominant, suggestive of vasculitis, both on MRI and arteriography, similar to that previously reported as “Cerebral vasculitis after initiation antiretroviral therapy 47.” Treatment included continuation of cART with added steroids. Six cases improved, and in three of these, their neurological status and levels of CD4+ and CD8+ lymphocytes returned to normal, coinciding with the disappearance of the radiological signs. Four cases had an unfavorable outcome, leading to death within 9–13 months after biopsy. A post‐mortem was performed in one case. The epidemiological clinical and radiological data are summarized in Table 1. The clinical, biological and radiological data are more extensively described in another paper 27.

Table 1.

Epidemiological clinical and radiological data in the 10 cases. Abbreviations: IVS = immunovirological status; VL = viral load; LE = leukoencephalopathy; MS = multiple sclerosis; SLE = systemic lupus erythematosus; tt = cART treatment

Case	Date of biopsy	Sex	Age at biopsy	Onset	Imaging	Course	Age at autopsy
1	2001	M	46	Stable IVS, resolutive episode ↗VL and ↘ CD4 Cause (?)	Diffuse LE	Death 8 months after biopsy	—
2	2002	M	41	Stable IVS, resolutive episode ↗VL and ↘ CD4 (Interruption tt)	Diffuse LE	Favorable, total recovery	—
3	2003	M	36	3 months after initiation tt Coinciding with ↗CD4	Focal changes Vasculitis	Favorable, total recovery	—
4	2005	F	47	Stable IVS, resolutive episode ↗VL and ↘ CD4 (Intercur. infect.)	Diffuse LE	Death 13 months after biopsy	49
5	2005	F	39	9 months after initiation tt Coinciding with ↗CD4	Diffuse LE	Death 9 months after onset	—
6	2005	F	25	2 years after initiation tt Coinciding with ↗CD4	pseudo‐ MS	Favorable, cognitive impairment	—
7	2007	F	37	stable IVS, ↗VL CSF ↗VL and ↘ CD4 (Interruption tt)	Diffuse LE 12 months after onset	Death	—
8	2007	F	54	stable IVS ↘ CD4 Cause (?), VL NA	Multifocal changes Pseudo‐MS	Favorable, total recovery	—
9	2007	M	33	stable IVS ↗VL and ↘ CD4 Cause (?)	Focal changes	Favorable cognitive impairment	—
10	2007	M	43	stable IVS ↗VL and ↘ CD4 ↗VL in CSF	Diffuse LE	Favorable cognitive impairment	—

Methods

In the autopsy case, post‐mortem examination was performed 24 h after death and was limited to the brain. The right cerebral hemisphere was frozen. Gross neuropathological examination was performed after 1 month of 10% buffered formalin fixation, on coronal sections of the left cerebral hemisphere and sections of the cerebellum and brain stem perpendicular to its axis. For light microscopy, large slices from many regions of the cerebral hemisphere, brainstem and cerebellum were embedded in paraffin and 15‐μm‐thick sections were stained by hematoxylin‐eosin (H&E) and cresyl violet combined with Luxol fast blue (Klüver–Barrerra stain). Smaller blocks were also taken from a number of brain regions of the cerebral and cerebellar hemispheres, including the deep gray nuclei, midbrain and brain stem, and embedded in paraffin wax. The same stains were used for the 10 cerebral biopsies and post‐mortem samples and included routine techniques (H&E, Masson's trichrome, Bodian silver impregnation combined with Luxol fast Blue, PAS) and immunohistochemistry performed in a Ventana automated stainer, using an avidin‐biotin complex, peroxidase‐based method with polyclonal antibodies (Ab): anti‐GFAP (1/1000, Dako, Glostrup, Denmark) and anti‐CD3 (1/100, Novocastra, Newcastle upon Tyne, UK), and monoclonal Ab: anti‐β‐APP (1/50, Millipore Corporation, Billerica, MA, USA), anti‐CD20 (1/200, Dako), anti‐CD138 (1/50, Dako), anti‐CD4 (1/200, Dako), anti‐CD25 (1/200, Novocastra), anti‐CD68 (1/100, Dako), anti‐HLADR (1/50, Dako), anti‐human neurofilament protein (1/50, Dako) and anti‐HIV protein p24 (1/5, Dako). The following organisms were looked for: Herpes simplex type 1 and 2, varicella zoster virus (VZV), CMV and Toxoplasma (by immunocytochemistry); JC and Epstein–Barr virus (EBV) (by in situ hybridization); Mycobacteria and fungi (by histochemistry).

Neuropathological Findings

Stereotactic brain biopsy in the 10 cases all showed encephalitic changes. Reactive astrocytosis (Figure 1A) and microglial activation (Figure 1B) were found in every case and were usually associated with myelin pallor. The latter was seen either as edema, sometimes vacuolar or true demyelination with macrophages containing myelin debris. Weak expression of HIV protein in macrophages and microglial cells was found in five cases (Figure 1C); multinucleated giant cells (MGCs) were not observed. Tests for other pathogens were negative. A constant and striking finding was diffuse infiltration by T‐lymphocytes, mostly CD8+ lymphocytes with a variable amount of CD4+ lymphocytes. CD8 infiltration was both parenchymal (Figure 1D) and perivascular, but it usually predominated in the perivascular regions. In most cases, the vessel wall was infiltrated by the lymphocytes, suggestive of lymphocytic vasculitis (Figure 1E,F). In four cases, vascular lymphocytic infiltration was massive “pseudolymphomatous” (Figure 1G–I). However, the lymphocytes were mostly T, CD3 positive lymphocytes and were morphologically normal. CD20 B‐cells and CD138 plasma cells were rare and mostly absent.

Figure 1.

Encephalitic changes and CD8+ lymphocytic infiltration in the brain biopsies. A. Reactive astrocytic gliosis. Case 7, GFAP immunostaining, ×200. B. Microglial activation. Case 1, HLADR immunostaining, ×200. C. Slight p24 expression in microglial cells and macrophages. Case 3, p24 immunostaining, ×800. D. Diffuse parenchymal infiltration by CD8+ lymphocytes. Case 7, CD8 immunostaining, ×200. E, F. Infiltration of the vessel wall by CD8+ lymphocytes suggestive of vasculitis. E. Case 3, H&E, ×400. F. Case 2, CD8 immunostaining, ×400. G, H, I. Massive perivascular and intramural “pseudolymphomatous” lymphocytic infiltration. The lymphocytes are predominantly CD8+ lymphocytes but there are also some CD4+ lymphocytes. Case 5: H&E (G), immunostaining CD8 (H), immunostaining CD4 (I), ×200.

In one case (case 9), the changes included marked microglial activation with frequent microglial nodules (Figure 2A) and a number of p24+ microglial cells (Figure 2B) reminiscent of HIV encephalitis. At the other end of the spectrum (case 8), the inflammation resembled an inflammatory demyelinating multiple sclerosis (MS)‐type or acute demyelinating encephalomyelitis (ADEM)‐type condition, including definite demyelinating foci (Figure 2C) with numerous intraparenchymal and perivascular macrophages (Figure 2D), relative sparing of axons (Figure 2E) and absence of CD25+ immunomodulatory T‐lymphocytes.

Figure 2.

More specific changes observed in the brain biopsies. A, B. Changes suggestive of HIV encephalitis (HIVE): A. Microglial nodules. Case 5, H&E, ×250. B. Two microglial/macrophage cells clearly express p24. Case 9, immunostaining p24, ×400. C, D, E. Changes suggestive of inflammatory demyelinating encephalopathy. C. Clear‐cut demyelinated area with relative preservation of the axons. Case 8, Bodian silver impregnation combined with Luxol fast blue, ×200. D. Presence of numerous intraparenchymal and perivascular macrophages. Case 8, CD68 immunostaining, ×200. E. Axonal preservation in the demyelinated area; note marked perivascular lymphocytic infiltration. Case 8, Neurofilament immunostaining, ×200.

Post‐mortem examination was performed in case 4 and was limited to the brain. It showed two types of pathology. In the cerebral hemispheres, the changes were consistent with HIV encephalitis/leukoencephalopathy. There was widespread myelin pallor, sparing the U fibers, corpus callosum and internal capsule (Figure 3A) with slight axonal damage. It was associated with reactive astrocytosis, microglial activation and perivascular infiltration by macrophages, with occasional MGCs containing HIV proteins (Figure 3C). Interestingly, this patient had only questionable expression of HIV protein and no MGC on the biopsy performed 1 year before death. In the cerebellum, the changes were different consistent with ADEM (Figure 3B,F,G). There was perivascular demyelination and lymphocytic infiltration (Figure 3F,G). In these areas, MGCs were absent and HIV immunostains were negative. In both regions, infiltration by CD8 was massive, diffuse, intraparenchymal and perivascular (Figure 3D,H); CD4 were virtually absent (Figure 3E).

Figure 3.

Post‐mortem examination of case 4. A. Coronal section of the left cerebral hemisphere at the level of the head of the caudate nucleus. Widespread myelin pallor relatively sparing the U fibers, corpus callosum and initial part of the internal capsule. Klüver–Barrera stain. B. Horizontal section of the brainstem and cerebellum at the middle part of the pons. Multiple small demyelinated foci disseminated in both middle cerebellar peduncles. Klüver–Barrera stain. C. Left hemispheric white matter: Perivascular infiltration by lymphocytes and macrophages containing HIV proteins some of which are binucleated. P24 immunostaining, ×200. D, E. Left hemispheric white matter: Perivascular infiltration by lymphocytes which are mostly CD8+ lymphocytes. CD4+ lymphocytes are absent. D. CD8 immunostaining, ×200. E. CD4 immunostaining, ×200. F, G. Middle cerebellar peduncle: Multifocal perivenous demyelination with perivenous lymphocytic infiltration. Klüver–Barrera stain, 50. H. Middle cerebellar peduncle: Perivascular and intraparenchymal infiltration by lymphocytes which are mostly CD8+ lymphocytes. CD8 immunostaining, ×100.

The neuropathological findings in the 10 cases are summarized in Table 2.

Table 2.

Neuropathological findings in the 10 biopsies. Abbreviations: − = absent; ± = debatable; + = present; ++ = marked; +++ = severe; AL = axonal loss; PL = pseudo lymphomatous; MGC = multinucleated giant cell; WM = white matter

Case	Astrocytosis	Microglial activation	MGC	P24	WM changes	Vasculitis	CD8	CD4	CD25
1	++	++	−	+	Edema, myelin loss, AL	±	++	−	−
2	+	++	−	+	Edema±	±	++	+	+
3	++	+++	−	+	Edema	++	++	+	+
4	++	+	−	±	Edema	±	++	−	−
5	++	+++	−	−	Myelin loss, edema	+, PL++	+++	+	+
6	+	++	−	−	Edema, myelin loss	+	++	+	±
7	++	++	−	−	Edema, myelin loss	+	++	±	−
8	++	+ (macrophages)	−	−	Demyelination	+, PL	+++	++	−
9	+	+++	−	++	Edema, myelin loss	+, PL+	++	+	+
10	+	++	−	−	±Edema	+, PL++	+++	++	+

Discussion

Ten HIV‐infected patients, efficiently treated by cART, presenting with encephalopathy of rapidly progressive onset, had brain biopsies showing encephalitic signs with heavy infiltration by CD8 lymphocytes. This was variably associated with signs of productive HIV infection and signs of inflammatory demyelinating disease of MS or ADEM type. Both patterns were present in different areas, in the autopsy case.

Comparable CD8+ T‐cell encephalitis with variable expression of HIV, in the absence of opportunistic infection of the brain, has been reported previously in autopsy cases 24, 31, 34. A few reports of biopsy cases are also similar to ours: Rushing et al 38 reported six cases of IRIS of the brain; in one case, HIV p24 was expressed in rare cells and another case was interpreted as HIV encephalopathy associated with IRIS. Venkataramana et al 49 reported three cases of IRIS involving the CNS, the third one showed massive infiltration of CD8+ lymphocytes in the absence of any associated or triggering CNS infection.

There is no widely accepted standard definition of IRIS, but it can be considered a paradoxical deterioration in clinical status attributable to an excessive and dysregulated immune response to various infectious and non‐infectious pathogens, following modification of immune status 3. It has been described in various immune‐depression/reconstitution circumstances including reducing immune suppression in transplant, recovery from neutropenia after chemotherapy for cancer 3 or more recently withdrawal of natalizumab in MS 22, 33, but more frequently in HIV patients with cART‐induced immune reconstitution. Histopathologic criteria of IRIS have neither been defined, but it is usually dominated by CD8+ T‐lymphocyte inflammatory infiltration 38. Our patients had all been successfully treated by cART, recovering good HIV virological and immunological control indices. All presented with rapidly progressive neurological deterioration, in the absence of previously recognized or newly acquired infection or of side effects of therapy 41, and had predominant CD8+ lymphocyte inflammation on brain biopsy; they can be regarded as presenting with immune reconstitution disease in a wide extent. In three patients (cases 3, 5 and 6), onset of neurological signs coincided with treatment‐induced increased CD4 count; these can be considered as classical IRIS. In the other patients who had been successfully treated and had stable virological and immunological control indices, onset of neurological signs was associated with an episode of increased VL and decreased CD4 count that could be related to an intercurrent systemic infection (case 4), interruption of treatment (cases 2 and 7) or virological escape (case 10). No cause could be identified in the three cases (cases 1, 8 and 9). It is noteworthy that in such instances, there is usually associated activation and increased number of CD8+ lymphocytes in the blood (lympho‐homeostasia) 9.

The generally accepted pathogenic basis of IRIS is an unusually intense inflammatory reaction resulting from restoration of a pathogen‐specific immune response directed against antigens already present in the tissue when therapy was initiated 41. In our cases, and in the cases of Langford et al 24, Miller et al 34 and Lucas et al 31, HIV is the most likely responsible antigen. Six patients had elevated HIV VL in the cerebrospinal fluid (CSF), and in five cases, immunohistochemistry for HIV was positive in macrophage/microglial cells on brain biopsy, and no other infectious agent could be demonstrated either microbiogically or pathologically. The patient with productive HIV infection (case 9) also had the highest VL in CSF. In one case (case 10), viral HIV reactivation with elevated VL in CSF preceded the onset of encephalitis. However, virological data did not identify a particularly neurovirulent strain, or phenotypic differences between plasma and CSF strain in our cases.

The previously reported cases of IRIS are consistent with our findings and suggest that the undesirable effects of immune reconstitution may produce two types of response in the CNS: (i) an exaggerated inflammatory reaction to a smoldering active infection or (ii) a paradoxical immunopathological reaction to a latent antigen or inactive infectious agent, similar to acute perivenous encephalomyelitis 4. As examples in the CNS, symptomatic cryptococcal meningitis 50, intracranial cryptococcoma 4 and aseptic meningitis 50 can occur after cART initiation in patients with Cryptococcus neoformans infection. cART can unmask latent CMV retinitis 19 or cause immunopathological vitritis 20 in patients successfully treated for CMV retinitis. Both types of reaction were found in the autopsy case of fulminant inflammatory leukoencephalopathy associated with HAART‐induced immune restoration in AIDS‐related PML 48. The reactions are comparable in patients with HIVE. The lesions described by Langford et al 24 probably correspond to an accentuation of HIVE with massive perivascular infiltration by HIV‐gp41 positive macrophages. Both productive HIVE/HIVL in the cerebral hemispheres and ADEM‐type changes in the cerebellum were observed in our autopsy case 4.

The dysregulated immune response following a change in immune status in patients receiving cART may also have some bearing with the inappropriate immunopathological reactions seen in early HIV infection, in non‐AIDS patients with incomplete, on‐going involvement of the immune system. The diffuse infiltrative lymphocytosis syndrome (DILS) represents a systemic host‐determined antigen response to HIV. It is characterized by massive CD8+ lymphocyte infiltration associated with expression of HIV protein and HIV genome in tissues and frequently involves the peripheral nerve 14, 36. This syndrome has been described in early HIV infection in patients in whom the immune system was only partially affected. On the other hand, fulminating MS‐like leukoencephalopathy revealing HIV infection 15, MS inflammatory demyelinating changes ADEM‐type 44, 45 or MS‐type 2, 46 has been observed in patients with early, non‐AIDS, HIV infection.

The key change in our cases is a marked infiltration by CD8 + lymphocytes and many studies 34, 35, 48 support a role for CD8+ cytotoxic cells at the origin of the undesirable immunopathological reactions occurring in immune reconstitution syndromes, particularly in those with a fatal outcome.

CD8+ T‐lymphocytes form the majority of cytotoxic cells and are present only in small numbers within the normal CNS. In AIDS patients, cART‐induced immune reconstitution usually produces a strong cellular immune response, which, in some cases, is mediated by pathogen‐specific CD8+ cytotoxic T‐lymphocytes (CTLs) that are instrumental in preventing disease progression 10. In pathological circumstances, CD8+ CTL response in the tissues may be so intense that CD8+ outnumber CD4+ T‐lymphocytes and may be harmful. In the fatal cases of PML 35, 48 and HIVE 34, most lymphocytes were CD8+, whereas CD4+ lymphocytes were virtually absent in the brain. Although these patients had an increase of CD4+ cells in the blood, it seems that CD4+ T‐cells did not penetrate the CNS, whereas CD8+ T‐cells did. The weak or absent CD4+ response in the brain may explain the reactivation of a slowly progressive infection and increased viral replication. Indeed, help from CD4 T‐cells is critical for sustaining macrophage and effective CD8+ CTL responses during viral infection 12. CD8+ cytotoxicity may also contribute to the ADEM‐like disorder. This could occur by promoting myelin phagocytosis by monocytes/macrophages or triggering oligodendrocyte apoptosis through ligating tumor necrosis factor (TNF) receptor‐like molecules by their corresponding ligands. An imbalance of intraparenchymal CD8+/CD4+ T‐cells is observed in the early stages of MS and ADEM 13, 26.

Our findings tend to support this hypothesis. In the cases with favorable outcome, biopsy showed less severe and a more mixed inflammatory reaction including abundant CD8+ lymphocytes but also numerous activated macrophages and a number of CD4+ lymphocytes. In contrast, all patients who died had severe inflammation mostly composed of CD8+ CTL but weak or absent CD4 response in brain tissue (cases 1, 4 and 7) or had a few CD4+ lymphocytes but a low CD4+/CD8+ ratio (case 5). The autopsy case 4 had almost no CD4 lymphocyte on his biopsy performed 1 year before death and no CD4+ lymphocyte at post‐mortem examination of the brain. In this case, productive HIV infection of the brain was questionable on the biopsy but was obvious at post‐mortem examination; the patient also had ADEM changes in the cerebellum. Patient 8 who had MS‐ADEM‐like lesions at brain biopsy had a relatively high number of CD4+ lymphocytes and a favorable outcome. However, unlike the other cases who had CD4 lymphocytes on brain biopsy (cases 2, 3 and 6–8), he had virtually no immunomodulatory CD4 CD25 lymphocytes, which are involved in the prevention of autoimmune disease and are also essential to the regulation of immune response in allergy, transplantation cancers and infectious diseases 42.

In conclusion, our findings support the hypothesis that restoration of T‐cell function induced by cART allows an influx of memory T‐cells that recognized the infectious antigens. In patients with latent or inactive HIV infection of the brain, this may result in an acute or subacute encephalopathy caused by an unusually intense inflammatory reaction with influx of CD8+ lymphocytes. The latter may be beneficial, causing macrophage activation and control of the viral infection; it may also be harmful, particularly when there is an imbalance of intraparenchymal CD8+/CD4+ T‐cell ratios, CD8 cytotoxicity producing two types of undesirable effects: a worsening of HIVE and/or a paradoxical immunopathological reaction, MS or ADEM type.