Human immunodeficiency virus (HIV)-induced disease of the central nervous system: pathology and implications for pathogenesis

Summary Significant contributions from many different groups during the last 2 or 3 years have characterized relatively uniform neuropathological changes of the CNS in AIDS patients. They feature human immunodeficiency virus (HIV)-induced multinucleated giant cells as a histopathological hallmark and HIV demonstrable by electron microscopy, immunocytochemistry, and in situ hyridization. Unfortunately, a varying and confusing terminology is used to designate these changes which have been reported in surprisingly different incidences. Focal lesions have a microgranulomatous appearance and were designated as multifocal giant cell encephalitis or subacute encephalitis, which may be confused with the nodular encephalitis caused by cytomegalovirus. For some authors, the latter designation also covers characteristic diffuse white matter changes which have been termed progressive diffuse leukoencephalopathy by others, and which may overlap with focal lesions. Pathological features of these HIV-induced syndromes and other data do not support a major cytopathic effect of HIV on neural cells; rather, they suggest secondary pathogenetic events involving the predominant cell type in the lesion, the monocyte/macrophage/microglia. However, low-level, latent, and persisting HIV infections of neural cells cannot be excluded at present; the CNS may then serve as an early infected virus reservoir. A detailed correlation of clinical symptoms and stage of the infection to neuropathological changes is currently lacking but urgently needed. The presence of the HIV-receptor (CD4) molecule on brain cells is controversial; similarly, a putative cross-reaction of HIV proteins with trophic substances and transmitters needs to be substantiated.Supported in part by the Medical-Scientific Fund of the Lord Mayor of the Federal Capital of Vienna, Austria     

Early central nervous system changes in human immunodeficiency virus (HIV)-infection

Early HIV infection of the CNS, as demonstrated by cerebrospinal fluid studies, seems relatively common. However most HIV carriers remain neurologically unimpaired during the incubation period. A few psychometric, radiological, and electrophysiological studies suggest that neurological abnormalities are present at early stages of HIV infection; the findings of these studies are controversial and until recently, they have not been supported by neuropathological data. Early brain changes, including leptomeningitis and vasculitis with myelin pallor and gliosis of the deep white matter are probably secondary to vascular inflammation and opening of the blood-brain barrier. Such conclusions are drawn from the examination of brains of asymptomatic HIV-positive individuals who died from unnatural causes, and of rare cases with acute fatal encephalopathy revealing HIV infection. In addition, early experimental simian immunodeficiency virus infection and feline immunodeficiency virus encephalopathy have demonstrated similar changes to those in man. Although small amounts of viral genome were detected by PCR in a few cases, the early changes in the human brain do not seem to result from a productive HIV infection of the CNS, as seen in HIV encephalitis. The occurrence of a usually asymptomatic and transient immunopathological reaction coinciding with early HIV infection of the nervous system appears to be more likely.     

Massive neuronal destruction in human immunodeficiency virus (HIV) encephalitis

Summary Human immunodeficiency virus (HIV) encephalitis in children with AIDS includes a diffuse white matter disease associated with an inflammatory cell infiltrate that features multinucleated giant cells. Cerebral cortex is relatively preserved and only focal loss of Purkinje cells in the cerebellum has been observed. We describe a case of encephalitis in a child with AIDS in which there was massive and diffuse destruction of the cerebral cortex with severe neuronal loss, marked inflammatory perivascular infiltrate with abundant multinucleated cells and large pleomorphic reactive astrocytes. Similar findings were present in the basal ganglia. Moreover, the cerebellum disclosed a complete loss of Purkinje and granule cells. These findings could not be related to an ischemic mechanism or to an associated opportunistic infection. Electron microscopy showed numerous HIV particles. This case illustrates a different pattern of CNS involvement by HIV and emphasizes the destructive capacity of this neurotropic virus for neural tissue.     

Brain pathology induced by infection with the human immunodeficiency virus (HIV)

Summary Neuropathological examination of brain tissue of 100 patients with infection by the human immunodeficiency virus (HIV), including 98 with clinically manifest acquired immune deficiency syndrome (AIDS), revealed distinct multifocal-disseminated and diffuse brain tissue lesions, which can be regarded as HIV-induced brain lessions: multifocal giant cell encephalitis (MGCE; 4) and progressive diffuse leukoencephalopathy (PDL; 25). These lesions were found in 38 brains, and in 17 in absence of infectious, necrotizing or inflammatory changes of other types. In 13 brains, a combination of MGCE with PDL was seen, suggesting a spectrum of HIV-induced brain lesions. MGCE is characterized by perivascular accumulations predominantly of rod cells, monohistiocytes and macrophages, all of which are strongly labeled with a monoclonal antibody to macrophages. Most conspicuous are multinucleated giant cells which are also labeled by anti-macrophage antibody, and which can be regarded as evidence of the local presence of HIV, as confirmed by electron microscopical detection of HIV particles in four MGCE brains, and by immunocytochemical detection of HIV proteins in two MGCE brains. PDL is characterized by a triad: diffuse myelin loss, astroglial proliferation, and infiltration by mono- and multinucleated macrophages. HIV-induced lesions can be morphologically differentiated from histopathological brain lesions known in immunosuppression, including what is called here nodular encephalitis [subacute encephalitis of the literature, in most cases attributable to cytomegalovirus (CMV) or toxoplasmosis], by their characteristic histopathology including the hallmark presence of multinucleated giant cells, by direct immunocytochemical and electron microscopical demonstration of HIV in the lesions, and by the absence of opportunistic agents (bacteria, fungi, Toxoplasma, CMV, HSV or papovaviruses). Diffuse poliodystrophy (diffuse proliferation of astroglia with swollen nuclei, occasionally minor neuronal loss and rod cell proliferation) was found in the cerebral cortex and other gray matter in half of all brains, including cases with gyral atrophy, and may be another correlate of HIV damage to the brain. Morphological delineation of HIV-induced brain lesions is a necessary prerequisite for a meaningful clinical definition of HIV-induced cerebral disease.Part of this study was presented at the International Scientific Meeting: Medical Brain Research — State and Perspectives, in Vienna, Austria, June 18–20, 1987     

Neuropathology of the acquired immune deficiency syndrome (AIDS): a report of 135 consecutive autopsy cases from Switzerland

Summary Neuropathological changes were studied in a consecutive autopsy series of 135 cases, comprising 73% of all patients who died of AIDS in Switzerland between April 1981 and December 1987. Central nervous system involvement was found in 119 patients (88%), 19 of which had multiple concomitant intracerebral lesions. Among the non-viral opportunistic infections, encephalitis due toToxoplasma gondii was most frequent and occurred in 35 patients (26%), followed by central nervous system infection withCryptococcus neoformans, which was found in five patients (4%). Cytomegalovirus (CMV) encephalitis was present in 14 patients (10%). Disseminated microglial nodules without morphological or immunocytochemical evidence of CMV was encountered in 18 patients (13%). However, in all but two of these patients there was evidence of extracerebral CMV infection, suggesting that CMV was responsible for these nodular encephalitides. Nine patients (7%) had progressive multifocal leukoencephalopathy (PML); in five of these, demyelination was associated with extensive tissue destruction and cyst formation. HIV-associated encephalopathy was observed in 21 patients (16%) and showed two characteristic morphological patterns: progressive diffuse leukoencephalopathy (PDL) and multifocal giant cell encephalitis (MGCE). PDL was observed in 13 cases and characterized by diffuse pallor and gliosis of the cerebral and cerebellar white matter with scattered multinucleated giant cells, but without significant inflammatory response. MGCE was found in eight patients and characterized by clusters of numerous multinucleated giant cells, rod cells, macrophages, lymphocytic infiltrates and occasional necroses. In our view, PDL and MGCE represent the two opposite variants of HIV-induced encephalopathies, with overlapping intermediate manifestations.     

The peripheral nerve complications of human immunodeficiency virus (HIV) infection

Peripheral nerve complications occurring in patients with human immunodeficiency virus (HIV) infection are frequent and challenging. This review discusses these various complications according to the degree of advancement of HIV disease. Particular emphasis is placed upon emerging causes of neuropathy found in the context of HIV disease, such as infection with hepatitis C and human T-lymphotropic virus type I, as well as neuropathies related to antiretroviral medications.     

Distribution of human immunodeficiency virus (HIV) in the CNS of children with severe HIV encephalomyelopathy

Summary The presence and distribution of human immunodeficiency virus (HIV) were examined in the CNS of two children with severe HIV encephalitis and myelitis. Using polymerase chain reaction-mediated DNA amplification and subsequent Southern analysis, proviral HIV gag sequences were identified in brain tissue of both patients. In situ hybridization using antisense oligonucleotide probes revealed abundant HIV gag and env/nef RNAs selectively in areas with histopathological evidence for HIV-induced tissue damage. The spinal cord of one patient exhibited a striking subpial accumulation of HIV RNAs strongly suggestive of a liquorigenic spread of the infection. HIV RNAs were typically associated with cells of the monocyte/macrophage lineage, as shown by a combined immunohistochemical and in situ hybridization procedure. The present study supports the view that the pattern and distribution of HIV-induced brain lesions is largely determined by the extent of focal HIV replication within the CNS.Supported by the Swiss National Foundation for AIDS Research     

Why does the human immunodeficiency virus (HIV) invade the nervous system?

Human Immunodeficiency Virus (HIV) has neurotropic effects that are independent of the well-known lymphotropism. They have been proved by various techniques, but their pathogenesis is not clear. It is remarkable that the neuropathological features do not correlate with the degree of the clinical symptomatology. HIV antigens and antibodies are demonstrable within the central nervous system by immunological tests. The macrophages transport the virus across the blood-brain barrier and are responsible for its persistence in that location. Different cell types, especially of the subcortical areas, have HIV-receptive CD4 molecules. These markers may be identical with the receptors for endogenous neuropeptides and it is likely that viral proteins are causing a competitive inhibition of these mostly neurotrophic factors. This interference is discussed as one of the main reasons of HIV dementia.     

Alterations of nocturnal sleep in patients with HIV infection

Nocturnal sleep of 14 patients with HIV infection was characterized by longer sleep onset latency, shorter total sleep time, reduced sleep efficiency, more time spent awake and in Stage 1. There was significantly less sleep Stage 2 than in healthy controls. REM latency was slightly reduced and correlated negatively with depressive symptomatology, while percentages of REM and slow wave sleep were normal. Patients without complaints at the time of the investigation exhibited similar sleep abnormalities. The results stress the usefulness of polysomnography as a sensitive methodology for detection and monitoring of CNS affection in HIV positive patients.     

Recurrent stroke as a manifestation of primary angiitis of the central nervous system in a patient infected with human immunodeficiency virus

CONTEXT: Cerebral vasculitis in patients infected with human immunodeficiency virus (HIV) is usually related to additional or secondary infectious agents other than neoplastic diseases or HIV itself. OBJECTIVE: To describe a 31-year-old patient infected with HIV who presented with 2 recurrent, acute episodes of neurologic impairment in a 5-month period. DESIGN: Comparison of clinical and histologic data between the present case and previously published cases. SETTING: Community hospital. PATIENT: A 31-year-old, HIV-infected patient with recurrent strokes and chronic lymphocytic meningitis. INTERVENTION: After ruling out cardiac embolisms and coagulation disorders, the presence of central nervous system vasculitis, probably secondary to an infectious process, was suspected based on the clinical examination and cerebrospinal fluid abnormalities. RESULTS: Necropsy findings suggest the diagnosis of primary angiitis of the central nervous system, and the only infectious agent that could be found was HIV. CONCLUSIONS: Histologic studies were compatible with a diagnosis of primary angiitis of the central nervous system, but the pathogenic role of HIV in the genesis of the vasculitic process cannot be elucidated.     

Distribution of measles virus in the central nervous system of HIV-seropositive children

In an autopsy study the distribution of measles virus (MV) in the central nervous system (CNS) of 18 measles-infected children (13 HIV seropositive, 5 HIV seronegative), in Abidjan, Ivory Coast was examined using immunocytochemistry and in situ hybridization. Of these children 17 died from measles giant cell pneumonia. In 3 of the 13 HIV-seropositive patients MV antigens and genomic RNA was detected in the CNS. One of these positive patients had an MV encephalitis with abundant virus throughout most of the CNS. MV was not detected in the CNS of any of the 5 HIV-seronegative patients. These findings, albeit in a small number of cases, would suggest there may be an increased susceptibility to infection of the CNS with MV in HIV-positive children. In this respect entry and growth of MV in the CNS in HIV-seropositive individuals may be similar to the occurrence of measles inclusion body encephalitis in immunocompromised individuals. Furthermore, comparison of the HIV-MV encephalitis patient with two patients with subacute sclerosing panencephalitis (SSPE) demonstrated a paucity of virus in neuronal processes in the HIV-MV encephalitis. Unlike in SSPE, MV maturation by budding through the plasma membrane may occur, thereby minimizing build up of and intracellular movement of incomplete virus. Received: 6 March 1998 / Revised, accepted: 2 June 1998     

Subacute sclerosing panencephalitis in a child with human immunodeficiency virus (HIV) infection on antiretroviral therapy

Subacute Sclerosing Panencephalitis (SSPE) in HIV-infected children is a scarcely reported entity with previous reports describing fulminant course. The impact of highly active antiretroviral therapy (HAART) in altering its course remains unknown. We describe a child with HIV infection, who developed measles at 5 months of age and later developed SSPE at 14 years of age, remaining stable at 7 month follow-up, while on HAART for WHO (World Health Organisation) stage IV disease. The dynamics of HIV-related immunosuppression has an impact on the clinical course of SSPE. Contrary to reported cases of fulminant progression, a classic presentation with slow progression can be expected in children on HAART. We reemphasize the recommendation of “early measles vaccination” to prevent measles infection and subsequent SSPE in these children with an increasingly good life expectancy in the era of HAART.     

Myelin basic protein in the cerebrospinal fluid of patients infected with HIV

Summary The major pathological abnormalities of HIV encephalopathy are infiltrates of macrophages, multinucleated giant cells, microglial nodules and demyelination. Elevated myelin basic protein (MBP) levels in the cerebrospinal fluid (CSF) provide a marker for central nervous system demyelination. The purpose of this study was to investigate the possible role of CSF MBP as a useful and early marker for HIV encephalopathy. The CSF of 40 consecutive patients with HIV infection of various clinical stages was investigated, including 13 patients with clinical signs of HIV encephalopathy. CSF MBP was elevated in 2 patients (5.0 and 5.3 ng/ml), both of whom had moderate to severe HIV encephalopathy. The course of the disease was rapid in both patients. In the remaining 38 patients, CSF MBP levels were marginally elevated (n=12) or normal (n=26). Our results suggest that CSF MBP is not a sensitive marker for the diagnosis and evaluation of HIV encephalopathy, but may be an indicator of prognosis for the course of the disease. There were only few findings of elevated CSF MBP levels in patients with HIV encephalopathy in the current study, and this may be because the disorder progressed slowly in most patients. It is possible that CSF MBP levels in HIV encephalopathy may only be elevated with acute clinical deterioration but are normal in slowly progressive forms of demyelination, as seen in multiple sclerosis.     

Human immunodeficiency virus (HIV) envelope and core proteins in CNS tissues of patients with the acquired immune deficiency syndrome (AIDS)

Summary Frequency, cellular tropism and relation to pathology of productive infection with human immunodeficiency virus (HIV) in human central nervous system (CNS) were studied. Serial sections of formolfixed and paraffin-embedded CNS tissues from 70 patients (69 with acquired immune deficiency syndrome, AIDS) were immunolabeled with monoclonal antibodies against HIV antigens (Ags) p17, p24, and gp41. Additional and double (immuno)stains were used to identify cell types and opportunistic infectious agents. HIV Ags were detected in 52 cases; they were restricted to cells with characteristics of microglia or macrophages. Anti-gp41, anti-p24, and anti-p17 labeled 50, 33, and 15 cases, respectively. Immunoreactivity for core proteins predominated in mature macrophages and microglia of fully developed lesions; additional immunoreactivity for gp41 was seen in microglia adjacent to, or unassociated with, histopathological lesions. Multifocal and/or diffuse lesions previously suggested as HIV induced because of characteristic histopathology, consistently contained large numbers of cells with HIV Ags (33 cases), confirming their HIV specificity. Isolated labeled microglia without associated pathology, found in seven brains, presumably represent the earliest stage of productive CNS infection by HIV. Lesions of opportunistic infections contained no (34 cases), few (16 cases), or many (4 cases) cells with HIV Ags. These data do not suggest transactivation of local HIV production by opportunistic agents as a frequent event in vivo. Development of specific HIV histopathology appears correlated with the number of productively infected cells.Supported by the Austrian Fund for the Advancement of Scientific Research (P 7154-MED). Major parts of this study were presented at the Vth International Conference on AIDS, June 4–9, 1989, in Montreal, Canada (Th. B. P. 248)     

Varicella-zoster virus encephalitis in acquired immunodeficiency syndrome: Report of four cases

Four patients with acquired immunodeficiency syndrome, a 27-year-old female intravenous drug abuser and three males (two drug addicts aged 27 and 33 years and a 40-year-old homosexual) presented with a rapidly progressive encephalopathy. Two had generalized varicella-zoster virus skin infection, one had had a regressive thoracic zoster rash 7 months previously and one had no history of cutaneous eruption. Neuropathological examination revealed, in each case, multifocal necrotic changes with numerous, intranuclear Cowdry type A inclusion bodies in glial cells, endothelial cells, macrophages and neurons, within and around the lesions. These inclusion bodies were stained positively for varicella-zoster virus by immunocytochemistry and contained herpes virus nucleocapsids by electron microscopy. Molecular biology using the polymerase-chain-reaction method demonstrated viral genome. In one case, zoster-induced non-inflammatory vasculopathy involved medium sized leptomeningeal vessels and was associated with circumscribed areas of cortico-subcortical infarction. In another case, varicella-zoster virus encephalitis was associated with human immunodeficiency virus encephalitis and a secondary cerebral lymphoma. Multinucleated giant cells expressing human immunodeficiency virus proteins in their cytoplasm, were found in the lymphomatous deposits and in the varicella-zoster virus necrotic lesions. In these latter lesions, Cowdry type A inclusion bodies could be seen in the nuclei of some multinucleated giant cells confirming previous observations of MGCs co-infected by HIV and CMV, and supporting the hypothesis that DNA viruses interact with HIV, thus increasing its effect.     

Serologic evidence of human immunodeficiency virus infection of the central nervous system in African patients with acquired immunodeficiency syndrome

The intrathecal synthesis of antibodies to human immunodeficiency virus (HIV) was determined by 3 different immunoassays in 15 African patients with pre-acquired immunodeficiency syndrome (AIDS) and AIDS. Isoelectric focusing together with affinity-mediated immunoblot were found to be superior to enzyme-linked immunosorbent assay and Western blot in providing information not only about the antigen specificity of locally produced antibodies but also about their clonal distribution. In 9 of the subjects, HIV-specific oligoclonal bands were demonstrable with higher frequency or intensity in the cerebrospinal fluid than in the autologous serum, indicating autochthonous synthesis of HIV-related antibodies.     

Psychological problems of families and health workers dealing with people infected with human immunodeficiency virus 1

The psychological problems of the families of human immunodeficiency virus 1 (HIV-1)-infected people, and of the health workers taking care of them, have been addressed in a few empirical studies and in several anecdotal reports and theoretical contributions. Apparently, HIV-1 infection and acquired immunodeficiency syndrome (AIDS) are able to elicit a wide range of emotional reactions, from rejection and refusal to provide care to immersion in the infected person's needs and burnout. Since irrational fears and attitudes play an important role in conditioning these reactions, education may not be sufficient to change behaviour. Counselling sessions and mutual support groups are often the most appropriate contexts where fears and concerns can receive an individually tailored response, and where formal and informal caregivers can be helped to manage stress.     

Indole amine deficiency in blood and cerebrospinal fluid from patients with human immunodeficiency virus infection

Twenty-four patients with human immunodeficiency virus (HIV) infection were investigated for possible changes in certain indole amine constituents in blood and cerebrospinal fluid (CSF). Albumin in serum was determined and used as a rough nutritional marker. Six of the 24 patients had acquired immunodeficiency syndrome AIDS, four had other clinical symptoms of HIV infection, and 14 had no apparent symptoms. The HIV-seropositive patients had significantly decreased tryptophan values; their blood concentrations were 28% lower and their CSF concentrations 30% lower than corresponding values in 14 healthy controls. The blood concentrations of 5-hydroxytryptamine (5-HT) were 50% lower, and the platelet content of 5-HT was 36% lower in HIV-infected individuals than in the control group. The most pronounced changes were invariably seen in the six cases with AIDS and in patients with a low number of CD4+ cells. No significant difference between controls and HIV-seropositive patients was detected in the mean CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), although these levels were markedly reduced in four of the HIV patients. Neither was any significant difference seen between patients and controls in the serum concentrations of albumin.