Intra-blood-brain-barrier synthesis of HTLV-III-specific IgG in patients with neurologic symptoms associated with AIDS or AIDS-related complex

Intra-blood-brain-barrier production of virus-specific antibody is good evidence of infection within the blood-brain barrier. Patients with the acquired immuno-deficiency syndrome (AIDS) have an increased incidence of neurologic abnormalities--i.e., unexplained, diffuse encephalopathy manifested clinically as chronic progressive dementia. To define the role of human T-cell lymphotropic virus Type III (HTLV-III), the etiologic agent of AIDS, in the pathogenesis of neurologic dysfunction, we compared cerebrospinal fluid and serum from patients with neurologic symptoms associated with AIDS and the AIDS-related complex for the presence of antibodies directed against HTLV-III. Antibodies directed against HTLV-III antigens were detected by four immunologic tests: a fixed-cell immunofluorescence assay, an enzyme-linked immunosorbent assay, immunoblots of viral lysates, and immunoprecipitation of cellular lysates. All patients were seropositive, and 22 of 23 (96 per cent) had HTLV-III-specific antibodies in their cerebrospinal fluid. Unique oligoclonal IgG bands were detected in the cerebrospinal fluid, and the rate of IgG synthesis within the blood-brain barrier was elevated. In eight of nine patients tested, the enzyme-linked immunosorbent assay showed that the percentage of HTLV-III-specific IgG in cerebrospinal fluid was higher than in serum, suggesting that HTLV-III infection of neurologic tissue occurs in the majority of patients with neurologic disease associated with AIDS or its related complex.     

Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome

We conducted virus-isolation studies on 56 specimens from the nervous system of 45 patients in order to determine whether human T-cell lymphotropic virus Type III (HTLV-III) is directly involved in the pathogenesis of the neurologic disorders frequently encountered in the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. We recovered HTLV-III from at least one specimen from 24 of 33 patients with AIDS-related neurologic syndromes. In one patient, HTLV-III was isolated from the cerebrospinal fluid during acute aseptic meningitis associated with HTLV-III seroconversion. HTLV-III was also isolated from cerebrospinal fluid from six of seven patients with AIDS or its related complex and unexplained chronic meningitis. In addition, of 16 patients with AIDS-related dementia, 10 had positive cultures for HTLV-III in cerebrospinal fluid, brain tissue, or both. Furthermore, we cultured HTLV-III from the spinal cord of a patient with myelopathy and from the sural nerve of a patient with peripheral neuropathy. These findings suggest that HTLV-III is neurotropic, is capable of causing acute meningitis, is responsible for AIDS-related chronic meningitis and dementia, and may be the cause of the spinal-cord degeneration and peripheral neuropathy in AIDS and AIDS-related complex.     

Interferon-related leukocyte inclusions in acquired immune deficiency syndrome: localization in T cells

Blood samples from a series of 12 patients with Kaposi's sarcoma or infectious complications of the acquired immunodeficiency syndrome (AIDS) and from 18 homosexual contacts of AIDS patients were screened for interferon-related tubuloreticular inclusions (TRI) in circulating leukocytes. In the AIDS patients, TRI were detected by transmission electron microscopy in 1.5 to 10% of mononuclear cell sections. They were most frequent in patients with a decreased fraction of T helper cells and T4/T8 ratios less than 0.2. Only rare TRI-positive sections were found in 3/12 homosexual contacts with lymphadenopathy and 1/6 asymptomatic contacts. Serum interferon was found to be elevated in each AIDS case tested, but was not a sufficient condition for detection of TRI in homosexual contacts. Active DNA virus infections, including cytomegalovirus, were common to the AIDS cases and possibly contributed to the TRI pathogenesis. Localization of TRI in T suppressor/cytotoxic cells was demonstrated with monoclonal anti-Leu 2a antibodies. The pathophysiologic significance of interferon stimulation with formation of TRI in immunocompetent cells requires further investigation.     

Provider-initiated HIV testing in rural Haiti: low rate of missed opportunities for diagnosis of HIV in a primary care clinic

A severely immune-suppressed AIDS patient was suspected of suffering from BK virus (BKV) meningoencephalitis, after being studied for common causes of neurological complications of co-infectious origin. Polymerase chain reaction (PCR) and sequence analysis of cerebrospinal fluid and brain samples, confirmed the presence of BKV. His clinical condition improved along with the regression of brain lesions, after modifications on his antiretroviral regime. Five months after discharge, the patient was readmitted because of frequent headaches, and a marked inflammatory reaction was evidenced by a new magnetic resonance imaging (MRI). The symptoms paralleled a rising CD4⁺ lymphocyte count, and immune reconstitution syndrome was suspected. This is the first non-postmortem report of BKV meningoencephalitis in an AIDS patient, showing clinical and radiographic improvement solely under HAART.     

Catastrophic minor head trauma.

The neurologic and neuropsychologic sequelae of Acquired Immune Deficiency Syndrome (AIDS) have received an increasing amount of attention recently. A variety of neurologic disorders are now associated with AIDS or AIDS-Related Complex (ARC). To date, however, there have been no detailed accounts of the behavioral sequelae or course of illness of AIDS/ARC victims who have suffered brain trauma. This paper describes the case of a 39 year old male patient who tested positive for the retrovirus now associated with AIDS/ARC (Human T-Lymphatropic Virus Type III or "HTLV-III") and suffered a closed head injury as a consequence of a physical assault. His course was rapid and his symptomatology more profound than would be expected on the basis of his injury alone. The assault is regarded as a second, catalytic injury and is presumed to derive its pronounced effect from the ongoing neurologic disorder resulting from or associated with the HTLV-III virus. The possible role of head injury in the exacerbation of diffuse and subclinical cortical dysfunction is discussed. Relevant contributions from sports medicine literature and Alzheimer's Disease research are reviewed.     

Guillain-Barré syndrome and other neurologic syndromes in hepatitis A, B, and non-A, non-B

Guillain-Barré syndrome and other neurologic syndromes occur rarely as complications of viral hepatitis, although a causal association has not been established. Seven cases of serologically documented hepatitis A have been reported with Guillain-Barré syndrome; all recovered, with mild neurologic residua in four. Eight cases of serologically documented acute hepatitis B have been reported with Guillain-Barré syndrome; all recovered, with mild neurologic residua in two. In one case, immune complexes of hepatitis B surface antigen and its antibody were present in the cerebrospinal fluid. Other neurologic syndromes have also been reported in patients with serologically defined viral hepatitis, including mononeuritis, auditory neuritis, and seizures. Chronic hepatitis B and mononeuritis multiplex are found together in 31-54% of patients with periarteritis nodosa. The mechanisms for these associations are unknown, but may include direct cytotoxicity of the virus or immune-mediated damage. Vasculitis of the vasa nervorum plays an intermediate role in at least some cases.     

The acquired immunodeficiency syndrome (AIDS): an update

The acquired immunodeficiency syndrome (AIDS) is a disease which is characterized by a profound defect in cell-mediated immunity leading to opportunistic infections and unusual neoplasms such as Kaposi's sarcoma. It is caused by a retrovirus of the human T cell leukemia/lymphoma virus family and has been termed HTLV-III/lymphadenopathy-associated virus. The virus selectively infects the T4 helper/inducer subset of T cells, accounting for the profound defects in immunity noted in AIDS patients. AIDS is transmitted sexually, and by blood and blood products, accounting for its relative confinement to specific risk groups. The disease is now seen worldwide, and as of September 1984, approximately 6,000 cases have been reported in the USA alone. There is no effective treatment for the disease at present, and the mortality of the full-blown syndrome approaches 100%. Hopefully, with the recent isolation of the causative agent of the syndrome, effective therapies and vaccinations will be forthcoming.     

The neuropathology of AIDS. UCLA experience and review.

The central nervous system (CNS) has been examined at autopsy in 89 patients who died of the acquired immune deficiency syndrome (AIDS), including 14 patients who died primarily of neurologic complications of the disease. A total of 66 brains (74%) showed significant pathologic abnormalities, with opportunistic infections including cytomegalovirus (14) and cryptococcal (11) infections, progressive multifocal leukoencephalopathy (6), toxoplasmosis (6), and histoplasma microabscesses (1). Incidental Mycobacterium avium-intracellulare infection was found in 4 cases. Simultaneous CNS infection by more than one microorganism was encountered in 5 patients. Subacute (microglial nodule) encephalitis-related to cytomegalovirus infection or possibly brain infection by the causative agent of AIDS was present in 56 cases. Primary CNS lymphoma was noted in 3 patients. Secondary CNS deposits of lymphoma were found in 1 patient, and another patient had lymphomatoid granulomatosis. Vascular complications were not infrequently seen, and included infarcts secondary to vessel occlusion and disseminated intravascular coagulation in 4 patients and intracranial hemorrhage of variable severity in 13. White matter changes included vacuolar myelopathy (3 cases), central pontine myelinolysis (1 case), and foci of calcified, necrotizing leukoencephalopathy in pontocerebellar fibers of the basis pontis (2 cases). These findings highlight the variety of CNS complications in AIDS, some of which are not associated with clinical manifestations. Nevertheless, characterization of all lesions may be important in understanding the neurologic sequelae of AIDS.     

Gram-negative bacterial pneumonia with secondary aspergillosis in an AIDS patient

Summary A 40-year-old, HIV-infected female patient received antibiotic treatment for a urinary tract infection. After the initial success of therapy and a symptom-free period, she developed pneumonia with septic shock and adult respiratory distress syndrome (ARDS). In spite of intensive care and respirator therapy with positive end-expiratory pressure (PEEP), she died of infectious toxic shock. Autopsy findings showed relapsing, gramnegative, bacterial pneumonia (morphologically compatible with Klebsiella pneumonia) and secondary, invasive aspergillosis. The pathogenesis and epidemiology of these unusual complications of AIDS are discussed.Abbreviations AIDS acquired immunodeficiency syndrome - ARDS adult respiratory distress syndrome - CDC Centers for Disease Control - HIV human immunodeficiency virus - PEEP positive end-expiratory pressure     

Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)

Neurologic sequelae can be devastating complications of respiratory viral infections. We report the presence of virus in neural and capillary endothelial cells in frontal lobe tissue obtained at postmortem examination from a patient infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Our observations of virus in neural tissue, in conjunction with clinical correlates of worsening neurologic symptoms, pave the way to a closer understanding of the pathogenic mechanisms underlying central nervous system involvement by SARS-CoV-2.     

A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group.

BACKGROUND AND METHODS. Most strains of herpes simplex virus that are resistant to acyclovir are susceptible in vitro to both foscarnet and vidarabine. We conducted a randomized trial to compare foscarnet with vidarabine in 14 patients with the acquired immunodeficiency syndrome (AIDS) and mucocutaneous herpetic lesions that had been unresponsive to intravenous therapy with acyclovir for a minimum of 10 days. The patients were randomly assigned to receive either foscarnet (40 mg per kilogram of body weight intravenously every 8 hours) or vidarabine (15 mg per kilogram per day intravenously) for 10 to 42 days. In the isolates of herpes simplex virus we documented in vitro resistance to acyclovir and susceptibility to foscarnet and vidarabine. RESULTS. The lesions in all eight patients assigned to foscarnet healed completely after 10 to 24 days of therapy. In contrast, vidarabine was discontinued because of failure in all six patients assigned to receive it. The time to complete healing (P = 0.01), time to 50 percent reductions in the size of the lesions (P = 0.01) and the pain score (P = 0.004), and time to the end of viral shedding (P = 0.006) were all significantly shorter in the patients assigned to foscarnet. Three patients had new neurologic abnormalities while receiving vidarabine. No patient discontinued foscarnet because of toxicity. Although initial recurrences of herpes simplex infection after the index lesion had healed tended to be susceptible to acyclovir, acyclovir-resistant infection eventually recurred in every healed patient, a median of 42.5 days (range, 14 to 191) after foscarnet was discontinued. CONCLUSIONS. For the treatment of acyclovir-resistant herpes simplex infection in patients with AIDS, foscarnet has superior efficacy and less frequent serious toxicity than vidarabine. Once the treatment is stopped, however; there is a high frequency of relapse.     

Varicella-Zoster virus infections of the nervous system: clinical and pathologic correlates

BACKGROUND: Diseases that present with protean manifestations are the diseases most likely to pose diagnostic challenges for both clinicians and pathologists. Among the most diverse disorders caused by a single known toxic, metabolic, neoplastic, or infectious agent are the central and peripheral nervous system complications of varicella-zoster virus (VZV). METHODS: The pathologic correlates of the neurologic complications of VZV infection, as well as current methods for detecting viral infections, are discussed and presented in pictorial format for the practicing pathologist. RESULTS: Varicella-zoster virus causes chickenpox (varicella), usually in childhood; most children manifest only mild neurologic sequelae. After chickenpox resolves, the virus becomes latent in neurons of cranial and spinal ganglia of nearly all individuals. In elderly and immunocompromised individuals, the virus may reactivate to produce shingles (zoster). After zoster resolves, many elderly patients experience postherpetic neuralgia. Uncommonly, VZV can spread to large cerebral arteries to cause a spectrum of large-vessel vascular damage, ranging from vasculopathy to vasculitis, with stroke. In immunocompromised individuals, especially those with cancer or acquired immunodeficiency syndrome, deeper tissue penetration of the virus may occur (as compared with immunocompetent individuals), with resultant myelitis, small-vessel vasculopathy, ventriculitis, and meningoencephalitis. Detection of the virus in neurons, oligodendrocytes, meningeal cells, ependymal cells, or the blood vessel wall often requires a combination of morphologic, immunohistochemical, in situ hybridization, and polymerase chain reaction (PCR) methods. The PCR analysis of cerebrospinal fluid remains the mainstay for diagnosing the neurologic complications of VZV during life. CONCLUSIONS: Varicella-zoster virus infects a wide variety of cell types in the central and peripheral nervous system, explaining the diversity of clinical disorders associated with the virus.     

Present status of vaccination against HIV-1 infection

The development of an effective vaccine against the acquired immunodeficiency syndrome (AIDS) is a formidable task. The absence of any documented case of natural recovery from the disease raises the question of whether any vaccine against human immunodeficiency virus (HIV) could possibly be effective in preventing natural transmission of the virus. It also raises the issue of which type of immune response a vaccine should elicit to be protective. Many obstacles have to be overcome, including the considerable antigenic variability of the virus, its intracellular mode of transmission, its mucosal port of entry, and the persistent nature of the infection. The only animal model available for the development of prototype HIV-1 vaccines is the chimpanzee model. Chimpanzees infected with HIV-1 do not develop AIDS but remain persistently infected. This model, therefore, allows one to test for protection from infection, but not for protection from disease.     

Role of human immunodeficiency virus and cytomegalovirus in AIDS encephalitis.

Approximately half of patients with advanced acquired immune deficiency syndrome (AIDS) develop a subcortical dementia. The brains of all autopsies on AIDS patients performed at UCSD between 1982 and 1986 (N = 93) were studied. Neuropathologic changes consistent with a viral encephalitis were present in 54 brains (58%). Human immunodeficiency virus (HIV) antigens were detected in 37 of the brains (40%), most frequently in macrophages, multinucleated giant cells, and endothelial cells. Cytomegalovirus (CMV) was detected in 31 of the brains (33%), 22 of which also contained HIV. Cellular localization of CMV antigens suggests that CMV disseminates to the central nervous system hematogenously where the virus can infect endothelial cells, glia, and neurons. While the temporal course of the appearance of these two viruses within the CNS is not clear, the common simultaneous occurrence of both viruses within the brains of AIDS patients suggests that in vivo interaction between them may play a role in the pathogenesis of AIDS-associated encephalitis. Given the significant neurologic symptoms described in AIDS patients, the paucity of viral antigens suggests a pathogenic mechanism of indirect CNS damage rather than direct viral infection.     

Human immunodeficiency virus type 2 infection associated with AIDS in West Africa

We recently reported the isolation of a new retrovirus, termed human immunodeficiency virus type 2 (HIV-2), from two West African patients with the acquired immunodeficiency syndrome (AIDS). This virus is related to but distinct from the well-characterized AIDS retrovirus, human immunodeficiency virus type 1 (HIV-1). We report here evidence of infection with HIV-2 in 30 patients, almost all from West Africa. Seventeen of them had a clinical syndrome indistinguishable from AIDS (7 of these 17 died). Others had either the AIDS-related complex or no HIV-related symptoms. All patients had serum antibodies reacting with HIV-2 in an indirect immunofluorescence assay. All serum tested contained antibodies reacting with the envelope glycoprotein of the virus in an immunoprecipitation assay. Cross-reactivity of serum antibodies with HIV-1 was detected in a minority of patients and varied according to the assay used. Retroviral isolates were obtained from the blood lymphocytes of 11 patients and were all identified as HIV-2 by nucleic acid hybridization; none hybridized with an HIV-1 probe. These findings indicate that some cases of AIDS in West Africa may be caused by HIV-2, but the extent of the spread of this virus and its clinical correlates will require careful epidemiologic investigation.     

The possible role of fungal infections in AIDS

The acquired immunodefficiency syndrome (AIDS) is characterized by a gross defect in the cell-mediated immune response. However, infection with human immunodeficiency virus (HIV), which is the generally accepted etiological factor of AIDS, cannot explain by itself the following problems: why do not some of the seropositive subjects develop AIDS or AIDS-related complex; why are some of the patients with AIDS seronegative for HIV and its corresponding antibodies; what is the reason why some of the healthy seronegative subjects from groups at a high risk for AIDS (homosexuals, hemophiliacs and drug abusers) have low T-helper to T-suppressor ratios. We suggest that some additional factor is necessary for the development of AIDS. We propose that the factor needed is a 'partial functional thymectomy'. We suspect that slow fungal infections, producing thymotoxic metabolites, may be a major cause for the latter.     

HTLV-III antibodies in hemodialysis patients — A consequence of blood transfusions?

Summary An investigation for HTLV-III antibodies in chronic hemodialysis patients revealed in four out of 276 patients a positive result using the ELISA and western blot techniques. All HTLV-III positive patients had received blood transfusions. As it has been shown that a needle stick could transmit the HTLV-III, it is suggested that hemodialysis patients who have received frequent blood transfusions should be screened.Abbreviations AIDS acquired immune deficiency syndrome - ELISA enzyme linked immunosorbent assay - HbSAg hepatitis surface antigen - HD hemodialysis - HTLV-III human T-cell lymphotropic virus type III     

Human herpesvirus latency

Herpesviruses are among the most successful human pathogens. In healthy individuals, primary infection is most often inapparent. After primary infection, the virus becomes latent in ganglia or blood mononuclear cells. Three major subfamilies of herpesviruses have been identified based on similar growth characteristics, genomic structure, and tissue predilection. Each herpesvirus has evolved its own unique ecological niche within the host that allows the maintenance of latency over the life of the individual (e.g. the adaptation to specific cell types in establishing latent infection and the mechanisms, including expression of different sets of genes, by which the virus remains latent). Neurotropic alphaherpesviruses become latent in dorsal root ganglia and reactivate to produce epidermal ulceration, either localized (herpes simplex types 1 and 2) or spread over several dermatomes (varicalla-zoster virus). Human cytomegalovirus, the prototype betaherpesvirus, establishes latency in bone marrow-derived myeloid progenitor cells. Reactivation of latent virus is especially serious in transplant recipients and AIDS patients. Lymphotropic gammaherpesviruses (Epstein-Barr virus) reside latent in resting B cells and reactivate to produce various neurologic complications. This review highlights the alphaherpesvirus, specifically herpes simplex virus type 1 and varicella-zoster virus, and describes the characteristics of latent infection.     

Seroepidemiology of HTLV-III (LAV) in the Federal Republic of Germany

Summary In 1984 10,281 sera were collected in the FRG and examined for antibodies to HTLV-III (LAV) with an enzyme-linked immunosorbent assay and confirmative tests. Of the German AIDS patients 81% have antibodies. Individuals belonging to AIDS risk groups, homosexuals, haemophiliacs and i.v. drug abusers, have antibody frequencies between 25%–72%. The detection of HTLV-III antibodies in blood donours indicates that the virus is being transmitted by blood transfusions.Abbreviations AIDS acquired immunodeficiency syndrome - LAS lymphadenopathy syndrome - ARC AIDS related complex - LAV lymphadenopathy associated virus - HTLV-III human T-lymphotropic virus type III - HBV hepatitis B virus