Acquired Immunodeficiency Syndrome

81.1 Clinical Features

and Laboratory Investigations The acquired immunodeficiency syndrome (AIDS), as defined according to the criteria of the Centers of Disease Control, is a state characterized by one or more opportunistic diseases indicative of underlying cellular immunodeficiency, in the absence of underly- ing causes of cellular immunodeficiency other than human immunodeficiency virus type 1 infection and in the absence of all other causes of reduced resis- tance reported to be associated with opportunistic diseases. The opportunistic diseases in AIDS include opportunistic infections and neoplasms that can re- sult from immunodeficiency. AIDS is caused by a retrovirus named human immunodeficiency virus type 1 (HIV-1). This virus has previously been desig- nated human T cell lymphotropic virus type III (HTLV-III), lymphadenopathy-associated virus (LAV), and AIDS-related virus (ARV). High-risk groups in non-Third-World countries have been defined as homosexual or bisexual males, intravenous drug abusers, immigrants from Haiti and Central Africa, blood transfusion recipients, heterosexual partners of HIV-infected individuals, children of mothers in- fected with HIV, and hemophiliacs who have received factor VIII concentrate. About 72% of AIDS patients originate from the first of these risk groups and 17%

from the second group. The other risk groups consti- tute only minor percentages of the total AIDS patient population.

AIDS can manifest itself in many different ways.

Most patients present with malignant tumors and/or infections that are infrequently seen in immunocom- petent individuals. The most common tumors in AIDS are Kaposi sarcoma, primary CNS lymphoma, systemic non-Hodgkin lymphoma, and plasmocy- toma. The opportunistic infections most frequently include Pneumocystis carinii pneumonia, toxoplas- mosis, cryptococcal meningitis, candidiasis of the up- per gastrointestinal tract, and many infections with other viruses, fungi, mycobacteria, and parasites.

Nonspecific signs and symptoms of the disease are weight loss, fatigue, malaise, night sweats, fever, cysts in the parotid glands and generalized lymphadeno- pathy. Neurological signs and symptoms are frequent and are reported in 30–75% of patients. Malignant lymphoma and metastatic Kaposi sarcoma may affect the CNS. Opportunistic infections of the CNS include

herpes simplex encephalitis, herpes zoster encephali- tis and radiculitis, cytomegalovirus encephalitis, papovavirus infection with progressive multifocal leukoencephalopathy, infection with Aspergillus fu- migatus, Candida albicans, and Cryptococcus neofor- mans, nocardiosis, coccidioidomycosis, Mycobacteri- um tuberculosis infection, atypical mycobacterial in- fections, toxoplasmosis, and neurosyphilis. However, only a minority (about 30%) of the CNS affections can be attributed to opportunistic infections. A pri- mary HIV-1 infection is the most common cause of neurological dysfunction. Acute diffuse leukoen- cephalitis, subacute encephalitis, aseptic meningitis, vacuolar myelopathy, and inflammatory demyelinat- ing peripheral neuropathy are generally assumed to be caused by direct HIV-1 infection. It should be not- ed that the following clinical descriptions refer to untreated patients. With treatment the disease course will be halted or modified.

Acute diffuse leukoencephalitis has been de- scribed in a limited number of cases. Clinically this disease is characterized by rapid mental deteriora- tion, progressive tetraparesis, and in some cases death within a few days.A relapsing-remitting course of dis- ease has also been described, indistinguishable from multiple sclerosis.

Subacute HIV-1 encephalitis, also called AIDS en- cephalopathy or AIDS dementia complex, is the most frequent neurological manifestation of AIDS and eventually afflicts many AIDS patients. Subacute HIV- 1 encephalitis usually develops after other complica- tions of AIDS have appeared, but it may also be the first major or even the sole clinical manifestation of HIV-1 infection. In subacute HIV encephalitis cogni- tive, motor, and behavioral abnormalities are usually early features. Early cognitive abnormalities are im- paired memory, loss of concentration, confusion, and slowing of mentation and movement. The onset of de- mentia is usually insidious, but a rapid onset over a period of a few days and accelerations are not rare.

Behavioral abnormalities include apathy, social with- drawal, dysphoric mood, organic psychosis, and re- gressive behavior. Early motor symptoms are lack of balance, weakness of the legs, tremor, and loss of co- ordination. Neurological examination often reveals ataxia and pyramidal tract signs. The majority of pa- tients develop a severe and global dementia within 2 months after the onset of symptoms, but sometimes the initial course is more protracted, and a mild or

Acquired Immunodeficiency Syndrome

moderate impairment of intellectual functions is pre- sent for several months prior to the subsequent onset of a more severe global dementia. The dementia of subacute HIV-1 encephalitis has been described as subcortical because of the relative absence in many patients of seizures and other signs of focal cortical involvement. The affected patients usually remain alert. Neurological symptoms in the end stages are variable and include aphasia, ataxia, hypertonia, motor weakness with paraparesis, quadriparesis or hemiparesis, pseudobulbar palsy with dysphagia and dysarthria, tremor, blindness, extrapyramidal signs with rigidity, incontinence, myoclonus, epileptic seizures, and sometimes organic psychosis. Retinopa- thy is found in about one-third of the patients with subacute HIV-1 encephalitis. Cotton wool spots are the most frequently observed retinal abnormalities;

less frequently a hemorrhagic retinitis is seen. Optic neuritis is a rare finding. Death usually occurs within 1 year after the first signs of encephalopathy are noted.

Other neurological complications include cerebral hemorrhage and cerebral infarction. Thrombocy- topenia predisposes AIDS patients to cerebral hemor- rhage, while nonbacterial thrombotic endocarditis may lead to cerebral infarction.

The majority of children with AIDS are born to women who have AIDS or pre-AIDS themselves and who are intravenous drug abusers, sexual partners of male members of high-risk groups, or of Haitian ori- gin. In a smaller percentage of the affected children, transfusion-associated AIDS has been implicated.

Clinical characteristics of AIDS in children include failure to thrive, generalized lymphadenopathy, he- patosplenomegaly, recurrent bacterial infections, and infections with opportunistic agents. Neurological abnormalities are variable. The most consistent find- ings are acquired microcephaly and moderate to se- vere mental retardation. Motor deficits ranging in severity include pyramidal tract signs with spastic paraparesis or tetraparesis and pseudobulbar palsy.

Hypotonia with hyperreflexia is frequent in affected children, especially early in the course of disease. In some children, psychomotor retardation is stationary.

In others progressive mental and motor deterioration occurs with a remitting course. Subacute HIV-1 en- cephalitis can be found in this latter group of patients.

Vacuolar myelopathy is a common neurological complication in AIDS. It is frequently difficult to cor- relate spinal cord abnormalities with clinical symp- toms and signs in individual patients since many pa- tients have coexistent encephalopathy or peripheral neuropathy. Clinical features may be a spastic mono- paresis, paraparesis, or tetraparesis with hyperreflex- ia and extensor plantar reflexes, but sometimes re- flexes are absent. Incontinence and sexual distur- bances are frequent, as are sensory abnormalities with sensory ataxia. Neuropathologically, myelopathy

of grades I, II, and III can be distinguished. A steadily progressive spastic–ataxic paraparesis, which usually evolves over several weeks to months, is most charac- teristic of patients with grade III, severe myelopathy.

Signs and symptoms are similar but less severe in pa- tients with grade II myelopathy. Clear myelopathic signs are infrequent in patients with grade I myelopa- thy.

Patients with AIDS are susceptible to a number of PNS complications. Peripheral nerve affections occur in about half of the patients with subacute encephali- tis. Cranial nerve signs are less prominent.Apart from herpes zoster radiculitis, a distal symmetrical periph- eral polyneuropathy, chronic inflammatory demyeli- nating polyradiculoneuropathy, and mononeuritis multiplex have been described. Distal symmetrical peripheral neuropathy manifests itself by distal sen- sory disturbances and a mild degree of weakness in the distal muscles of the lower extremities. The symp- toms are predominantly sensory with burning, painful paresthesias and numbness. In more ad- vanced stages the muscular weakness may become more marked and spread to the arms. Chronic in- flammatory demyelinating polyradiculoneuropathy resembles the Guillain–Barré syndrome but the course is subacute or, more often, chronic. Weakness is most severe in distal muscles but also affects prox- imal muscles. Sensory abnormalities are usually less marked. In severe cases weakness becomes general- ized, and facial diplegia, bulbar weakness, and respi- ratory difficulties result. In mononeuritis multiplex, nerve dysfunction is relatively abrupt in onset. In the course of time, multiple nerves become involved, re- sulting in patchy weakness and sensory loss.

Diagnosis of HIV-1 infection cannot be made with standard serological tests in the early phase of the dis- ease. Recombinant enzyme-linked immunosorbent assays (ELISAs) are commonly negative in the early phase, as are tests for antibodies. Serological tests be- come positive after 3–4 weeks. Early diagnosis is pos- sible with the serum or plasma viral p24 antigen test, also used in blood donors to detect viral infection. Es- timation of plasma viral RNA levels is even more sen- sitive than the p24 antigen test. Counts of CD4+ lym- phocytes give important information of the immune status of the patient. Studies of T lymphocyte subpop- ulations in AIDS reveal a depletion of CD4+ T helper cells with an inversion of the CD4+ helper to CD8+

suppressor cell ratio. In active HIV-1 infections the count is low. The most specific diagnosis of HIV in- fection is by direct identification of the virus in tissue or blood of suspected patients or indirectly by demonstrating the presence of antibodies to the virus. Longitudinal studies have shown that in serum, HIV-1 antigens appear early and transiently after pri- mary HIV-1 infection. Antibody production follows, after which HIV antigens may disappear.

81.1 Clinical Features and Laboratory Investigations 617

Immunological investigations may include tests demonstrating cutaneous anergy to recall antigens, depressed response in lymphocyte transformation assays, and usually a decreased natural killer cell ac- tivity. Lymphopenia may be present. These immuno- logical abnormalities may be absent early in the dis- ease. Abnormalities in B cell function and humoral immunity have been reported. Immunoglobulin lev- els may be high due to nonspecific polyclonal B cell activation. Circulating immune complexes may be present. Serological studies for a number of infections are frequently positive, such as hepatitis A and B, her- pes group viruses, and toxoplasmosis. If indicated, cultures of body fluids for bacteria, mycobacteria, viruses, and fungi may be performed.

The CSF of patients with HIV infection of the CNS usually has slightly raised protein content and less of- ten a mononuclear pleocytosis with cell counts of up to 50 cells/mm

. The CSF of children with AIDS en- cephalopathy shows these abnormalities less often.

The CSF of patients with AIDS encephalopathy often contains oligoclonal immunoglobulin bands, which have anti-HIV activity. CSF anti-HIV antibodies are present in most AIDS patients, irrespective of the presence of neurological complications. These anti- bodies occur early in the course of the disease, indica- tive of an early seeding of HIV to the CNS. A longitu- dinal study showed that HIV-1 antigen is present transiently in CSF before the occurrence of antibod- ies. HIV-1 antigen continues to be present in children and adults with progressive AIDS encephalopathy. As a rule, it is not found in the CSF of asymptomatic seropositive controls, some of whom have anti-HIV antibodies in the CSF. Persistence of HIV-1 antigens in the CSF most probably reflects ongoing CNS in- volvement. HIV-1 antigens in the CSF are not a result of leakage of viral proteins through the blood–brain barrier, as in some patients the quantity of HIV-1 antigens is larger in CSF than in serum, whereas oth- er patients have extremely high serum levels and no HIV-1 antigens in the CSF. The same arguments apply to anti-HIV antibodies, proving that the synthesis of these CSF antibodies occurs within the blood–brain barrier.

EEG often shows moderate, generalized slowing of the background pattern in subacute HIV-1 encephali- tis, occasionally with non-periodic high-voltage spik- ing. Even in patients with seizures or myoclonic jerks, paroxysmal discharges are not usually seen. In pa- tients with distal symmetrical peripheral neuropathy the nerve conduction velocity is normal or slightly re- duced. EMG shows some signs of denervation in dis- tal muscles. In chronic inflammatory demyelinating polyneuropathy a marked slowing of nerve conduc- tion is the rule. The abnormalities are frequently patchy. F responses are prolonged or absent, which is in conformity with a component of radiculopathy.

Conduction block is a common finding. EMG is either normal or shows signs of denervation and reinnerva- tion.

81.2 Pathology

It has been estimated that approximately 40% of pa- tients with AIDS have clinically apparent CNS dys- function. At autopsy, neuropathological abnormali- ties are found in about 80% of patients, and 20%

of patients have multiple coexisting CNS disease processes. Neuropathological signs of subacute HIV-1 encephalitis are found in about 50% of patients with AIDS, and it is accordingly the most common CNS illness associated with AIDS.

The brains of patients with subacute HIV-1 en- cephalitis, also called giant cell encephalitis or mi- croglial nodule encephalitis, usually show some de- gree of atrophy at postmortem examination. Mild to moderate ventricular dilatation is associated with an apparent reduction of cerebral white matter volume and shrunken cortical gyri. The most prominent microscopic abnormalities in the brain involve the white matter and deep gray matter. Subacute HIV-1 encephalitis is characterized by intraparenchymal and perivascular infiltrations of lymphocytes and macrophages, located in both gray and white matter.

The perivascular infiltrations occur typically around capillaries and venules and are most frequently de- tected in the centrum semiovale, basal ganglia, and pons. In mild cases the infiltrates are lymphocytic and scanty. In more severe cases, inflammatory infil- trates are composed mainly of foamy macrophages, in some instances intermixed with multinucleated giant cells. These multinucleated cells are thought to be de- rived from macrophages as they display macrophage markers, and are considered to be a histopathological hallmark of HIV-1 encephalitis.

The most common white matter abnormality is diffuse pallor, demonstrated by myelin staining. The borders of these large areas of pallor are ill defined.

The subcortical white matter is relatively spared.

There is some variability in the regional intensity of the pallor, which is most prominent in the centrum semiovale. The myelin loss is accompanied by a loss of axons, but the axons are relatively better preserved.

Diffuse reactive astrocytosis occurs and generally parallels the inflammatory and parenchymal changes.

In addition, most patients have small, poorly defined

foci of more complete demyelination. These usually

have a perivascular distribution. The lesions are

associated with inflammatory infiltrates, which are

composed of lymphocytes, lipid-laden foamy macro-

phages, reactive astrocytes, microglia, and sometimes

multinucleated cells. Another common finding is

vacuolation of the white matter, most frequently ob-

served in the centrum semiovale and less commonly in the internal capsule, brain stem, and cerebellum.

Electron microscopic examination shows intramye- linic vacuoles.

The cerebral cortex is relatively normal.Astrocyto- sis is usually found only in the deep cortical layers.

Considerable neuronal damage and loss is seen only in cases of severe white matter changes. Inflammato- ry infiltrations with presence of macrophages, lym- phocytes, multinucleated cells, and reactive astro- cytes are present in the basal ganglia and brain stem.

Sometimes focal areas of coagulation necrosis with cavitation are seen, principally in the basal ganglia.

Microglial nodules with multinucleated giant cells are found in both gray and white matter, in the latter case often accompanied by demyelinating lesions.

HIV-1 virus has been identified in these nodules. In a number of cases, however, the microglial nodules contain cells with the intranuclear and intracytoplas- mic inclusion material typical of cytomegalovirus in- fection. Microglial nodules may be the consequence of either HIV-1 infection or cytomegalovirus infec- tion. Cytomegalovirus-associated nodules are usually distinguished by their predominant localization within the cortical gray matter and by the presence of characteristic intranuclear inclusion bodies within or near the nodules.

Ultrastructural studies of the brain in subacute HIV-1 encephalitis reveal many virus-like particles in the cytoplasm of most macrophages and multinucle- ated giant cells and, less often, in astrocytes, but not in neurons and oligodendrocytes. These particles are double-membraned structures, which contain cylin- drical nucleoids, characteristic of the Lentivirus sub- family of the retrovirus group. These structures have been identified as HIV-1. In addition to complete in- fectious HIV-1 virions, HIV-1 RNA, HIV-1 DNA, and HIV-1 core proteins have been identified in the brains and also in the CSF of patients with subacute HIV-1 encephalitis. Macrophages and multinucleated cells of macrophage origin appear to be infected, but there is evidence that some other cells are also infected to a lesser extent.

Histological examination of acute diffuse leukoen- cephalitis reveals demyelination, most pronounced in the centrum semiovale. There is also axonal loss, but axons are relatively better preserved than myelin.

Microglial nodules and multinucleated giant cells may be present but have also been reported as absent.

Inflammatory reaction is variable. The demyelinating lesion may extend into the frontal, occipital, and tem- poral area. The basal ganglia, thalamus, and brain stem may also be involved in the process. The lesions may be large and multifocal or highly confluent, sym- metrical or asymmetrical. Presence of HIV-1 genome in the brain has been shown. Tests for all other infec- tions, in particular cytomegalovirus, are negative.

In multiple sclerosis-like leukoencephalopathy, multiple, large, well-defined areas of demyelination can be shown, which may involve hemispheric white matter, internal capsule, basal ganglia, optic tracts, corpus callosum, brain stem, and cerebellum. These lesions are characterized by myelin loss with presence of lipid-laden macrophages and preservation of ax- ons and nerve cell bodies, associated with marked gliosis and presence of perivascular inflammatory infiltrates. Multinucleated giant cells and microglial nodules are reported as absent. Direct evidence of HIV-1 infection has not (yet) been provided, although increase in CSF HIV-1 antigen during exacerbations has been demonstrated in some cases.

In children with progressive HIV-1 encephalopathy, brain weight is below normal for age, and sometimes there is obvious atrophy. Most of the brains show evidence of white matter disease, including pallor, diffuse lack of myelin, and astrocytosis. Probably both hypomyelination and demyelination are respon- sible for the diffuse lack of myelin. The axons are rel- atively better preserved than in adults. Calcification often occurs within or adjacent to the walls of small vessels in the basal ganglia and central white matter of the cerebral hemispheres, especially in the frontal lobes. Inflammatory cell infiltrates which resemble classic microglial nodules but which are larger are commonly observed. They consist of microglia, astro- cytes, lymphocytes, a few plasma cells, and often multinucleated cells, some of which have the propor- tions of multinucleated giant cells. The inflammatory infiltrates are most often located in basal ganglia and pons, but are also found in other gray and white mat- ter structures of brain and spinal cord. In addition, vascular or perivascular inflammation may be pre- sent, involving small or medium-sized arteries or veins. The inflammation of intraparenchymal vessels is accompanied by intimal fibrosis of medium-sized vessels and endarteritis obliterans with focal throm- bosis of small vessels.

Spinal cord disease afflicts approximately 25% of AIDS patients. Pathological changes are most promi- nent in the lateral and posterior columns at the tho- racic level, less severe in the anterolateral and anteri- or columns. White matter changes are often asym- metrical and are not confined to specific anatomic tracts. Microscopically, the disease is characterized by intramyelinic vacuoles, similar to those seen in cere- bral and cerebellar white matter. Axons are intact ex- cept in the most severely affected areas. The white matter vacuolation is associated with few lipid-laden macrophages, usually located within the vacuoles. Re- active astrocytes are rare, and inflammation is not present as a rule.

81.2 Pathology 619

81.3 Pathogenetic Considerations

Human immunodeficiency virus type 1 (HIV-1) has been identified as the primary cause of AIDS. HIV-1 is the prototypical member of the Lentivirinae sub- family of retroviruses affecting humans. Lentiviruses characteristically cause indolent infections in their host. These infections are notable for involvement of the nervous system, long periods of clinical latency, and weak humoral immune responses complicated by persistent virus presence. One feature that distin- guishes the lentiviruses from other retroviruses is the remarkable complexity of their viral genomes. Most retroviruses capable of replication contain only three genes. HIV-1, however, contains in its RNA genome at least six additional genes. It is probable that the dis- tinct but concerted actions of these additional genes underlie the profound pathogenicity of HIV-1. From a therapeutic standpoint, this same genomic com- plexity may also be the Achilles heel of the virus.

A broad-based search for antagonists specific for these HIV-1 gene products has started. High-resolu- tion electron microscopy has revealed the HIV-1 viri- on as an icosahedral structure containing 72 external spikes. These spikes are formed by the two major vi- ral envelope proteins, gp120 and gp41. The HIV-1 lipid bilayer is also studded with various host pro- teins, including class I and class II major histocom- patibility (MHC) antigens, acquired during virion budding. HIV-1 has a selective tropism of CD4+

T helper-inducer lymphocytes. The human CD4+

T lymphocyte and monocyte are the major cellular targets for HIV-1 infection, because the CD4+ mem- brane antigen represents the principal, if not sole, high-affinity receptor for this retrovirus. After entry of the CD4+ T lymphocyte, the viral RNA is tran- scribed into DNA and subsequently integrated into the CD4+ T lymphocyte DNA during cell division. In inactive CD4+ T cells much of the viral DNA remains unintegrated in the cytoplasm. The HIV replication cycle is restricted until the CD4+ T cell is activated by other pathogens (for instance, hepatitis B virus, her- pes simplex virus, cytomegalovirus) or by allogeneic stimulation (for instance, exposure to allogeneic se- men, blood, or allografts). After activation, transcrip- tion occurs in RNA, followed by protein synthesis.

Viral proteins and viral RNA assemble. Mature virus- es are formed by budding from the cytoplasmic mem- brane. In the process of HIV replication the CD4+

T cell is killed. The mechanism of cell death is unclear.

The killing of CD4+ T lymphocytes leads to depletion of this type of cells. Faster depletion of CD4+ T cells may result from enhanced susceptibility to superin- fection by other pathogens, for example, by cyto- megalovirus. CD4+ T lymphocytes play a central role in the immune response, and their depletion leads to many immunological abnormalities. The cellular (T

cell) immune system essentially ceases to function, but there are also marked abnormalities in B cell acti- vation (humoral immune system) and immunoregu- lation. There is a state of polyclonal B cell activation with high immunoglobulin levels and a poor anti- body response to new antigens. The deficiency of cel- lular immunity leads to an extreme susceptibility to viruses, fungi, mycobacteria, and parasites – agents that require cell-mediated immunity for contain- ment. Neoplasms arising in a cellular immunodefi- ciency state include primarily lymphomas and Ka- posi sarcoma. The B cell dysregulation may explain the frequent occurrence of severe pyogenic infec- tions, in particular with Streptococcus pneumoniae and Haemophilus influenzae. The elevated produc- tion of nonspecific immunoglobulins may lead to autoimmune processes such as immune thrombo- cytopenia. In addition, CD4+ T antigens are also pre- sent on the cell surface of certain types of macro- phages and monocytes, which may therefore also be infected by HIV-1. The infection of these cells results in additional immunological deficits, especially in chemotaxis.

HIV-1 leads to a persisting infection. The viral ge- netic information is integrated in the DNA of the host cell and the virus can only be destroyed by killing the infected cells. It has been demonstrated that a small percentage of infected cells may survive and con- tribute to virus persistence. Infected monocytes and macrophages may contribute to the persistence of HIV-1 as they appear to be relatively resistant to the cytolytic effect of HIV-1.

HIV-1 appears to be transmitted predominantly by contact with infected blood or semen. However, the virus has also been isolated from cervicovaginal se- cretions, tears, urine, saliva, breast milk, and CSF.

These fluids could possibly also be involved in the transmission of AIDS. HIV may be transmitted to a child in utero, during birth, or postnatally through in- fected breast milk.

The clinical picture of patients with HIV-1 infec- tions can range from asymptomatic (carrier with viremia or antibody or both) through chronic gener- alized lymphadenopathy to a variable degree of clini- cally manifest immunodeficiency. Estimation of viral load and CD4+ lymphocytes may help to predict which patients are likely to have the full-blown dis- ease. The latency period between infection and full- blown AIDS ranges from several months to several years.

Substantial evidence supports a direct etiological

role for HIV-1 in subacute encephalitis, aseptic

meningitis, vacuolar myelopathy, and peripheral neu-

ropathy. The intra-blood-brain-barrier synthesis of

HIV-1-specific antibodies has been demonstrated in

the majority of AIDS patients with neurological

symptoms but also in patients without these. The

oligoclonal IgG bands in the CSF of AIDS patients have been demonstrated to contain anti-HIV activity.

The presence of HIV-1 antigens in CSF appears to be strongly associated with CNS involvement. HIV-1 has been isolated from CSF in patients with subacute en- cephalitis and aseptic meningitis. The fact that virus has been isolated from CSF cannot be attributed sole- ly to the presence of infected lymphocytes since many samples are free of cells. HIV DNA and RNA se- quences have been demonstrated in CNS tissue of pa- tients with subacute encephalitis. HIV-1 has been iso- lated from brain in subacute encephalitis, from the spinal cord in vacuolar myelopathy, and from the sur- al nerve in a patient with peripheral neuropathy. The multinucleated giant cells seen in subacute encephali- tis show a striking similarity to the multinucleated cells that develop from the fusion of T lymphocytes infected by HIV-1 in vitro. Ultrastructural examina- tion has identified intact retroviral particles within the multinucleated giant cells in some cases. The multinucleated cells are probably of macrophage origin, as they share morphological features and macrophage markers. Very similar multinucleated giant cells have been reported in lymph nodes in AIDS patients. There is evidence that the multinucle- ated giant cells are of hematogenous origin. It is pos- sible that the virus penetrates the CNS by migration of infected mononuclear cells from the blood, but a direct viral invasion of the CNS is not excluded. Im- munohistochemical identification of HIV antigen has shown that the most frequently infected cells include macrophages, microglia, and multinucleated giant cells; less frequently capillary endothelial cells, astro- cytes, and oligodendroglia are infected, and also neu- rons, but only rarely. The virus is concentrated in, although not limited to, the white matter.

The precise mechanisms underlying the structural cerebral damage remain to be determined. The low- level infection, sometimes seen in a few neurons, astrocytes, and oligodendrocytes, cannot be held responsible for the severe CNS damage that is often present. The functional and structural damage of the CNS is therefore probably related indirectly to the HIV-1 infection, which primarily affects monocytes and macrophages and to a lesser degree endothelial cells. Data indicate that the extent of endothelial and macrophage infection is more commensurate with the clinical findings than the extent of neuronal and glial infection. This observation led to the suggestion that the CNS dysfunction reflects an infection of the endothelial cells that impairs the blood–brain barrier and leads to fluctuations in fluid and electrolyte lev- els and to structural damage. Another possibility is that activated macrophages secrete a variety of mate- rials, such as tumor necrosis factor, interleukin, and proteolytic enzymes, that cause brain tissue damage and impairment of neurological function.An alterna-

tive is that the release of HIV-1 envelope glycopro- teins from infected macrophages may interfere di- rectly with neuronal function as these HIV-1 proteins may directly suppress neuronal responses to neu- rotropic factors and cause shortened neuronal sur- vival.

The frequent involvement of the CNS in AIDS is probably related to a number of factors. The brain is an immunologically privileged organ. HIV-1 within brain tissue may be hidden and protected from im- mune surveillance. In addition, the damage to the im- mune system caused by HIV infection promotes the persistence of viral infection. In infants the known susceptibility of the immature CNS to viral invasion plays a role and may explain the high incidence of AIDS encephalopathy in young children infected with HIV.

81.4 Therapy

Therapy for HIV-1 infection has been increasingly successful in considerably reducing morbidity and mortality. This has been achieved by a logical attack on targets provided by the life cycle of the HIV-1 virus and by using a combination of therapies in the so-called highly active anti-retroviral treatment (HAART). To understand the different approaches it is most illustrative to follow this life cycle of HIV-1 and indicate where interference with the cycle is pos- sible.

The HIV-1 virus consists of an outer envelope of protein, fat, and sugars wrapped around an inner core, the capsid, which contains genetic information in the form of two strands of RNA, and a number of special enzymes. Proteins of HIV-1 are strongly attracted to CD4+ surface receptors presented on dendritic cells, macrophages, monocytes, and, most abundantly, on T4 lymphocytes (helper cells). After binding to the CD4+ surface receptor, other proteins, such as glycoproteins gp120 and gp41, are activated, allowing the HIV cell to fuse with the outside of the cell. The therapeutic intervention at this point is ad- ministration of entry blockers. Attempts have been made to use CD4+ protein decoys, which have so far not been very successful. More promising as an entry inhibitor seems enfuvirtide (T20). Enfuvirtide is a complex peptide consisting of 36 amino acids. The compound binds to a subunit, gp41, of the glycopro- tein gp120, located on the viral envelope, blocking the entry of the virus in the cell. Data about side effects and long-term results are still scarce.

Once the viral capsid is inside the cell, the two strands of RNA are transcribed into DNA, the “provi- ral” DNA, by the enzyme reverse transcriptase. Inter- ventions at this step have been successful and several types of reverse transcriptase inhibitors have been

81.4 Therapy 621

developed and play an important role in combination therapies. The main groups are nucleoside reverse transcriptase inhibitors, nonnucleoside reverse tran- scriptase inhibitors, and nucleotide reverse transcrip- tase inhibitors.

Approved reverse transcriptase inhibitors include:

∑ Nucleoside analogues: zidovudine, didanosine, zalcitabine, stavudine, lamuvidine, abacavir

∑ Nucleotide analogues: tenofovir disoproxil fu- marate

∑ Non-nucleoside reverse transcriptase inhibitors:

delavirdine, efavirenz, nevirapine

The next step in the development of new virions is the entry of the proviral DNA into the cell’s nucleus, where the enzyme integrase connects the viral DNA with the host cell’s DNA. Integrase inhibitors are still under research, but may eventually open a therapeu- tic window at this level.

When the T lymphocyte is activated, special en- zymes transcribe DNA into messenger RNA. In this phase, transcription inhibitors could be expected to have therapeutic action, but so far they do not play an important role in HIV therapy.

Messenger RNA is now translated into new viral proteins, which are kept inside the cell. In the final part of the process these strings of proteins are cut up by the enzyme protease to form proteins that will handle the different functions of the new HIV virus.

The logical answer to this phase was the development of protease inhibitors, which has been successful. Pro- tease inhibitors now play a prominent role in HIV therapy.Approved protease inhibitors are: saquinavir, ritonavir, indinavir, nelfinavir, amprenavir.

This is not the place to give recommendations on combination therapy, which would be very soon outdated. Federal guidelines and recommendations are available on the Internet and updated regularly (http://www.projinf.org/fs/antiVirSrat.html). On this site generic names and brand names of the antiviral drugs are given, together with the names of the phar- maceutical companies. Federal guidelines are given for the circumstances in which therapy should start, how best to combine preparations, changes of thera- py, when indicated, and advice for treatment of preg- nant women. It is common policy now to prescribe a combination of a protease inhibitor with two nucleo- side analogues. Initially the combination therapy had the disadvantage that many pills had to be taken every day, some before meals, some after meals, three or four times a day. This hardly promoted therapy com- pliance, seriously contributing to the risk of drug re- sistance. There are attempts to replace these regimens by a once-a-day intake of drugs, and several drugs have already been approved for once-a-day use. The newer therapeutic regimens have been successful in restoring at least some immunocompetence in the

patients. Patients with progressive multifocal ence- phalopathy have shown temporary improvement. The improved CD4+ cell count is another sign of improve- ment.

Side effects of these multidrug regimens are com- mon, myopathy, neuropathy, gastrointestinal prob- lems, pancreatitis, bone marrow and hepatic toxicity, and fat redistribution being the most common. Both lipoatrophy and lipohypertrophy are possible, lipohy- pertrophy probably caused by the protease inhibitors and lipoatrophy caused by the reverse transcriptase inhibitors. Lipohypertrophy causes a protease paunch and buffalo hump. Lipoatrophy can disfigure the face and often requires cosmetic surgery. Bone marrow suppression is another possible side effect, leading to anemia and thrombopenia. Children born from mothers using antiretroviral drugs during pregnancy may present with severe mitochondrial disorders re- lated to depletion of mitochondrial DNA. The effects of HIV nucleoside analogue reverse transcriptase in- hibitors (NRTIs) on mitochondrial function have been known for some time. NRTIs are phosphory- lated intracellularly to dideoxynucleoside triphos- phates. These compounds compete with the natural substrates (deoxythymidine triphosphates) for HIV reverse transcriptase, but, since they lack a 3’ hydrox- yl group, the effect is termination rather than length- ening of the DNA chain. They are also substrates for DNA polymerase g, the enzyme required for replica- tion of mitochondrial DNA. Mitochondrial DNA en- codes crucial mitochondrial proteins and is present in multiple copies per cell. Decreased concentrations of mitochondrial DNA have been shown in muscles of patients with zidovudine-induced myopathy. NRTIs are widely used to diminish the rate of transmission of HIV across the placenta from infected mothers to children. In a series of 1784 children (Blanche et al.

1999), 8 children with probable mitochondrial dys- function were observed, without HIV infection, a much higher frequency than could be expected in the normal population (1 in 5,000–20,000). Quite a few uncertainties remain (Morris and Carr 1999). At this moment continuation of the policy of the treatment of HIV positive pregnant women with antiretroviral therapy is still recommended.

A more definite approach is the development of an

HIV-1 vaccine. The development of such a vaccine has

been complicated by the remarkable sequence het-

erogeneity of the HIV-1 envelope proteins. Hyperim-

munization of chimpanzees with HIV-1 envelope

protein did not protect them against HIV-1 infection

after injection of small quantities of the same strain

of bHIV-1. More recent vaccination studies in Asian

monkeys with a simian virus (SIV-1) infection, which

causes an AIDS-like disease, have generated more

positive results and suggest that an effective HIV-1

vaccine may be an achievable goal.

Preventive measures still prevail in the battle against AIDS, the universally propagated “safe sex”

being the major public prevention factor. Other pre- ventive measures are directed towards the avoidance of contact with infected blood, screening of blood donors for AIDS, and inactivation of virus in blood products such as factor VIII concentrate. Specific measures have also been advocated in the manage- ment of HIV-1-positive pregnant women, in order to reduce the risk of neonates acquiring the disease in the peri- or postnatal period.

In opportunistic infections and CNS tumors ap- propriate therapeutic measures have to be taken.

Identifying the causative agent in infections or the nature of the tumor is, therefore, important and the major role of MRI.

81.5 Magnetic Resonance Imaging

Neuroimaging studies are essential in the evaluation of AIDS patients with neurological symptoms. A high percentage of the patients infected with HIV-1 have CNS complications, including the AIDS dementia complex, opportunistic infections, and brain tumors.

The primary purpose of brain imaging is to detect potentially treatable opportunistic lesions.

Most patients with advanced subacute HIV-1 en- cephalitis have CT evidence of cerebral atrophy with enlargement of subarachnoid spaces and ventricles.

CT evidence of atrophy may precede clinical signs of encephalitis, whereas in other cases initial CT scans may be normal and the atrophy becomes evident on later scans. Marked hypodensities in the white matter of both cerebral hemispheres are sometimes noted.

An additional abnormality shown by CT scan in some children with HIV-1 infection of the CNS, and less frequently in adults, is calcification of basal ganglia and, less often, of the periventricular white matter and the frontal subcortical white matter. CT scans may also reveal abnormalities which are a conse-

quence of opportunistic infections, tumors, and vas- cular lesions of the brain. The presence of more than one type of lesion within one patient frequently com- plicates the interpretation of CT findings.

MRI has greater sensitivity than CT in identifying CNS lesions in this patient population, with the ex- ception of calcifications. HIV-1 infection of the brain leads to a number of patterns identifiable on MRI.

The most common pattern seen in AIDS dementia complex is generalized atrophy with widened ventri- cles and enlarged cortical sulci. Probably, however, at- rophy is a relatively late finding. MRS is more sensi- tive, already showing a decrease in the N-acetylaspar- tate (considered to be a neuronal marker) while im- ages are still normal.

The second pattern represents the subacute HIV-1 encephalitis and reflects the histological findings of diffuse, mild myelin pallor or demyelination with preference for the frontal and parietal lobes. MRI shows symmetrical periventricular areas of mildly in- creased signal intensity of the white matter, not in- volving the U fibers, with preferential involvement of the frontal and parietal lobes (Figs. 81.1 and 81.2).

There is no enhancement after contrast injection. The brain stem and cerebellum are not involved. In the course of the disease the white matter abnormalities progress, resulting in severe hemispheric involve- ment (Fig. 81.2).

In acute diffuse leukoencephalitis, large multifocal or more diffuse and extensive white matter abnor- malities are present. In the case of multifocal lesions, these are not necessarily symmetrical (Fig. 81.3).

Hemispheric white matter, internal capsule, thala- mus, and brain stem may be involved. In cases in which the disease course resembles multiple sclerosis, multifocal white matter involvement is seen (Fig.

81.3). Contrast enhancement of the lesions has not been reported.

The frequency of superimposed infections is rela- tively low, but double and multiple infections may oc- cur. Of the opportunistic infections, cerebral toxo-

81.5 Magnetic Resonance Imaging 623

Fig. 81.1. T

-weighted transverse images of 40-year-old male AIDS patient with an advanced stage of subacute HIV encephalitis. The MR images show widening of the ventri- cles and cortical atrophy. There are symmetrical signal abnormalities in the cerebral white matter, most promi- nently involving the frontal lobes.

In the posterior regions, the signal

abnormalities are more subtle and

the U fibers are spared

plasmosis is the most common. It is the presenting opportunistic infection in at least 5% of the AIDS pa- tient population. The lesions of toxoplasmosis are multifocal and unequal in size (Fig. 81.4). Sometimes the lesions show the so-called “target” sign, with a rim of high signal intensity on T

-weighted images and a core that is isointense with normal white matter. Le- sions occur in all areas including the subcortical re- gion, basal ganglia, brain stem, and, less frequently, the cerebellar hemispheres (Fig. 81.4). The lesions can be very large, have contact with the ventricles, and mimic a lymphoma. After contrast injection the le- sions usually enhance. In about 5% of the cases, how- ever, no or only slight enhancement is seen. This may be due to the absence of inflammation as a conse- quence of the defective immune system of the patient, resulting in little or no capsule formation around the toxoplasmosis abscess. Possibly, this finding predicts a poor prognosis. Pragmatically one could consider

anti-toxoplasmosis treatment when multiple focal le- sions with ring enhancement are seen. If toxoplasmo- sis is present, the lesions will improve within a few weeks of therapy. Differentiation of larger single le- sions is from lymphoma. Progressive multifocal leukoencephalitis is discussed in Chap. 82. In this dis- ease, the lesions are confined to the white matter and extend into the arcuate fibers. There is a typically sharp border between gray matter and demyelinated white matter, leading to a characteristic pattern. Usu- ally the lesions do not enhance, but there are excep- tions. Cryptococcus neoformans infection is the most frequent intracranial fungal infection (2–7.5% of AIDS patients). The infection is preferentially located in the basal ganglia spreading along the Virchow–

Robin spaces. This pattern of spread may produce a typical appearance, suggestive of this type of infec- tion. Cytomegalovirus encephalitis resembles in many aspects the subacute AIDS encephalitis and

Fig. 81.2. A 48-year-old man presenting with AIDS presented with headaches, loss of concentration, mild cognitive impair- ment, and changes in behavior. The transverse FLAIR images show symmetrical involvement of the periventricular and deep cerebral white matter, sparing the U fibers. The posterior limbs of the internal capsules are involved, continued in the

corticospinal tracts of the midbrain and the white matter of

the temporal lobes. There is slight cerebral atrophy. This pat-

tern is characteristic of subacute HIV infection. Courtesy of

Dr. M. Heitbrink and Dr. B. Wiarda, Department of Radiology,

Medical Center Alkmaar, The Netherlands

may present with the same clinical symptoms. Pa- tients may also be asymptomatic. On MRI, diffuse, symmetrical, periventricular high-signal-intensity changes are seen on T

-weighted images, indistin- guishable from subacute HIV encephalitis. In some

cases a ventriculitis will develop. After contrast injec- tion this appears as an enhanced subependymal rim around the ventricles.

Of the CNS tumors complicating AIDS, primary lymphoma is the most frequently observed (about

81.5 Magnetic Resonance Imaging 625

Fig. 81.3. A 24-year-old man, suffering from AIDS, presented with a rapidly progressive neurological syndrome and mental and emotional deterioration. The T

-weighted sagittal image (first row, left) shows a high-signal-intensity lesion in the basal ganglia on the left side, probably a hemorrhage. The trans- verse proton density (first row) and T

-weighted images (sec-

ond and third rows) show lesions consistent with acute diffuse

leukoencephalitis. There is mildly increased signal intensity in

the centrum semiovale and around the ventricles, also involv-

ing the posterior limb of the internal capsule and the white

matter tracts in the pons. The lesions are asymmetrical at the

level of pons, midbrain, and periventricular area

5% of AIDS patients). In AIDS, lymphomas may be multifocal, which is rare in other patients. Also, the enhancement of lymphoma in AIDS patients may be less homogeneous. Differentiation from toxoplasmo- sis on MRI may be difficult. Both can present as single or multifocal lesions with mass effect; both can be

connected with the ventricular wall and enhance after contrast administration. Thallium-201 SPECT may offer a solution in distinguishing between infection and lymphoma. Leptomeningeal lymphoma can be diagnosed by the presence of pericerebral tissue that enhances with contrast. Metastases of Kaposi sarco-

Fig. 81.4. A 48-year-old male AIDS patient was admitted to the hospital with general malaise and left-sided hemiparesis, cerebellar ataxia, and diplopia. He also showed intellectual deterioration. The MR images show two types of lesions. The first type consists of multiple smaller, isolated lesions in the

cerebellum, pons, and basal ganglia.The second type of lesion

consists of a more symmetrical involvement of the periventric-

ular and deep cerebral white matter. The latter type of lesion

represents subacute HIV encephalitis; the dispersed, smaller

lesions were demonstrated to be toxoplasmosis

ma have been observed in the CNS and in the skull base, but are extremely rare.

In HIV-1 encephalitis in children, apart from the ventriculomegaly and atrophy also found in adults, there is often symmetrical bilateral calcification of the basal ganglia and the white matter adjacent to the frontal horns. Contrast enhancement of the basal ganglia may also occur, sometimes starting unilater- ally, becoming bilateral later on. Calcifications may also be related to a concurrent cytomegalovirus infec- tion. White matter disease is not a prominent feature

of HIV-1 encephalitis in children, although white matter changes may be present. Opportunistic infec- tions are less frequent in children than in adults. Cen- tral mass lesions are usually caused by primary lym- phoma.

In the spinal cord lesions have been described in AIDS patients. On MRI these lesions are not distin- guishable from lesions as seen in transverse myelitis in multiple sclerosis. Swelling of the cord is seen ini- tially with moderate enhancement, eventually fol- lowed by atrophy.

81.5 Magnetic Resonance Imaging 627