Acquired Immunodeficiency Disease Research Articles

Soluble Factor of Transformed B Lymphocytes in Patients with HIV Infection Stimulates Monocytes to Produce PGE2

Prostaglandins of the E series (PGE) were measured in the culture supernatants of peripheral blood mononuclear cells (PBMC) obtained from patients with human immunodeficiency virus (HIV) infection. Cell culture supernatants from 6 patients with acquired immunodeficiency disease (AIDS) and 11 patients with AIDS-related complex contained significantly higher concentrations of PGE than those from a group of 6 healthy HIV-negative male homosexual control subjects. The PGE producer cells were among the population of plastic-adherent PBMC. Transformed B lymphocyte cell lines spontaneously derived from the blood of patients with AIDS secrete a factor that stimulates normal donor adherent PBMC to produce PGE. The HIV permissive H9 cell line stimulated a significantly lower level of PGE production, which was not associated with HIV infection.

Neuropathogenesis of simian immunodeficiency virus infection in macaque monkeys.

Patients infected with human immunodeficiency virus (HIV) develop immunologic dysfunction and multiorgan inflammatory diseases directly associated with HIV-1 infection. Of these inflammatory diseases, the most devastating to the HIV-infected patient is involvement of the central nervous system (CNS). The pathogenesis of the clinical syndrome observed in these patients, termed HIV-associated dementia, remains poorly understood. However, as most of the detectable virus in the CNS is in cells of monocyte/macrophage lineage, it is clear that penetration of the blood-brain barrier by HIV-1 and the subsequent influx of monocytes into the brain are crucial components in the neuropathogenesis of HIV-associated dementia. Using the SIV-infected macaque model of acquired immunodeficiency disease, much has been learned about viral neuroinvasion occurring soon after experimental infection. The aim of this review is to discuss these recent advances and provide insight into plausible mechanisms for monocyte entry into the CNS.

Allergic manifestations in AIDS.

Hypersensitivity reactions and allergic manifestations of human immunodeficiency virus (HIV) infection have been observed since the beginning of the acquired immunodeficiency disease syndrome (AIDS) epidemic. Drug hypersensitivity remains the most visible and frequent untoward reaction, but chronic nasal symptoms and pruritic cutaneous disorders are also commonly observed allergic manifestations of HIV infection (1–3). Furthermore, a number of immunological derangements have been identified, which suggest an association between HIV infection and atopy. In this article, we review proposed pathophysiological mechanisms, diagnosis and management of the different clinical allergic disorders affecting HIV patients, and discuss controversial issues regarding immunotherapy in HIV disease.

Abdominal lymphadenopathy in benign diseases: sonographic detection and clinical significance.

We prospectively evaluated the frequency of lymphadenopathy in the right upper abdominal quadrant as detected by sonography in 650 consecutive unselected patients, after excluding patients with a known lymphoma or abdominal carcinoma and patients with acquired immunodeficiency disease. Evidence of enlarged lymph nodes (few in number, with an elongated shape and isoechoic to the liver, 8 to 22 mm in size), found primarily in the gastrohepatic ligament and porta hepatis, was seen on sonographic scans in 106 patients (16.3%). Associated conditions in 69 of 106 patients (65%) were hepatobiliary or pancreatic diseases and, less frequently, other benign entities (12 patients; 11.3%); in 25 cases (23.5%) no significant abdominal or systemic disease was present. Comparison with CT or surgical findings, or both, was available in 36 cases. We conclude that lymphadenopathy in the right upper abdominal quadrant may be found in relation to different non-neoplastic conditions as well as in the absence of any significant intra-abdominal disease. The frequency of this finding on sonographic scans must be recognized to prevent misdiagnosis of lymphoma or metastatic disease as well as to avoid overstaging of local (hepatobiliary, pancreatic, gastric) neoplasms.

Cat scratch disease and acquired immunodeficiency disease: diagnosis by transmission electron microscopy.

A 33-year-old, homosexual, cat-owning, African-American man with human immunodeficiency virus infection by positive serologic tests and acquired immunodeficiency syndrome by CD4 lymphocyte count alone (39 cells/mL) presented with a one-year history of intermittent fever, weight loss, and generalized lymphadenopathy. A malignant lymphoma was suspected clinically. Light microscopic study of a left inguinal lymph node biopsy specimen revealed effacement of the lymph node architecture by a diffuse infiltrate of large, atypical reticulum cells, loose, patchy granulomatous inflammation, diffuse hyaline fibrosis, diffusely proliferated blood vessels, and multifocal degeneration and necrosis. Lymph follicles were absent and lymphocytes were moderately depleted. Microorganisms were not seen in lymph node sections stained with special histochemical stains (including the Warthin-Starry stain). These light microscopic changes were considered suggestive of a malignant lymphoma, especially Hodgkin's disease. The diagnosis of cat scratch disease (CSD) became apparent only after transmission electron microscopic study of the lymph node revealed clusters of small, pleomorphic bacteria in degenerated collagenous tissue and in blood vessel walls. This case illustrates the value of transmission electron microscopy in making the diagnosis of CSD, especially when light microscopic changes are superimposed on those of late human immunodeficiency virus infection of the lymph node.

Human immunodeficiency virus 1 envelope proteins induce interleukin 1, tumor necrosis factor alpha, and nitric oxide in glial cultures derived from fetal, neonatal, and adult human brain.

Although microglia are the only cells found to be productively infected in the central nervous system of acquired immunodeficiency disease syndrome (AIDS) patients, there is extensive white and gray matter disease nonetheless. This neuropathogenesis is believed to be due to indirect mechanisms other than infection with human immunodeficiency virus 1 (HIV-1). Cytokines and toxic small molecules have been implicated in the clinical and histopathological findings in CNS AIDS. Previously, we have demonstrated in rodent glial cultures the presence of biologically active epitopes of gp120 and gp41 that are capable of inducing interleukin 1 and tumor necrosis factor alpha. In this study, we map the HIV-1 envelope epitopes that induce nitric oxide, inducible nitric oxide synthase, interleukin 1, and tumor necrosis factor alpha in human glial cultures. Epitopes in the carboxy terminus of gp120 and the amino terminus of gp41 induce these proinflammatory entities. In addition, we compare HIV-1 infection and pathology in glial cells derived from human brain taken at different states of maturation (fetal, neonatal, and adult brain) in an effort to address some of the clinical and histological differences seen in vivo. This study demonstrates that, in the absence of virus infection and even in the absence of distinct viral tropism, human glia respond like rodent glia to non-CD4-binding epitopes of gp120/gp41 with cytokine and nitric oxide production. Differences among fetal, neonatal, and adult glial cells' infectivity and cytokine production indicate that, in addition to functional differences of glia at different stages of development, cofactors in vitro and in vivo may also be critical in facilitating the biological responses of these cells to HIV-1.

Pattern of arterial aneurysms in acquired immunodeficiency disease.

The ever-spreading incidence of infection with the human immunodeficiency virus (HIV) has introduced a spectrum of unusual, subtle, and often life-threatening lesions that can affect almost every organ and tissue in the body. With the introduction of laboratory serologic evidence of HIV infection, the spectrum of indicator diseases has extended beyond the classic opportunistic infections and Kaposi sarcoma. An analysis of 28 patients in Zimbabwe with focal areas of vascular disease treated during a 4-year period (1989-1993) defined 16 patients ranging in age from 12 to 46 years appropriate for special scrutiny as they evinced none of the usual causes of vascular disease. Twelve of the patients were HIV-positive; in two patients the serologic status was unknown; and two patients were HIV-negative at the time of their presentation. There were special clinical features in this group of patients selected for study: (1) They were young with a mean age of 31 years; (2) they were all indigenous Africans with no evidence of atherosclerosis; and there was (3) rapid development of focal necrotizing vasculitis with aneurysm formation and rupture or (4) slow, progressive development of granulomatous vasculitis. The sites of cardiovascular involvement included the left ventricle; aortic arch; thoracic, thoracoabdominal, and abdominal aorta; and iliac, femoral, gluteal, popliteal, and subclavian arteries. It is inferred that the association between HIV-positive status and arterial aneurysms or fibroproliferative aortic occlusion are causally related and that the principles of vascular surgery can be successfully applied to their treatment.

Use and misuse of biomarker tests in “environmental conditions”

Use and misuse of biomarker tests in “environmental conditions”

Cytopathologic and neurochemical correlates of progression to motor/cognitive impairment in SIV-infected rhesus monkeys.

Neurochemical, pathologic, virologic, and histochemical correlates of simian immunodeficiency virus (SIV)-associated central nervous system (CNS) dysfunction were assessed serially or at necropsy in rhesus monkeys that exhibited motor and cognitive deficits after SIV infection. Some infected monkeys presented with signs of acquired immunodeficiency disease (AIDS) at the time of sacrifice. Seven of eight animals exhibited motor skill impairment which was associated with elevated quinolinic acid in cerebrospinal fluid (CSF). Examination of the brains revealed diffuse increases in glial fibrillary acidic protein immunoreactivity in cerebral cortex in all animals, regardless of evidence of immunodeficiency disease. Reactive astrogliosis preceded or was coincident with the onset of neuropsychological impairments. Virus rescue from CSF of six of eight infected animals showed that one of three animals with AIDS and none of three animals without AIDS at necropsy had virus rescue-positive CSF. Multinucleated giant cells were seen in the brain of only one animal with end-stage AIDS and high systemic virus burden at death. Neither systemic nor CNS virus burden was associated with the onset of CNS dysfunction. SIV-associated motor/cognitive impairment is associated with subtle, widespread changes in CNS cytology and neurochemistry, rather than with large increases in brain virus burden or widespread virus-associated brain lesions.

Does preferential Th subset activation contribute to the murine acquired immunodeficiency disease (MAIDS) ?

Does preferential Th subset activation contribute to the murine acquired immunodeficiency disease (MAIDS) ?

High Dose L-Carnitine Improves Immunologic and Metabolic Parameters in Aids Patients

Several reports indicate that systemic carnitine deficiency could occur in acquired immunodeficiency disease syndrome (AIDS), and that primary and secondary carnitine deficiency leads to critical metabolic dysfunctions. L-carnitine supplementation to peripheral blood mononuclear cells (PBMCs) of AIDS patients resulted in significant enhancement of the phytohemagglutinin (PHA)-driven proliferative response. High dose L-carnitine administration (6 gr per day for two weeks) to AIDS patients treated with zidovudine also led to increased PBMCs proliferation and reduced blood levels of triglycerides. In addition, a reduction of beta 2-microglobulin serum levels as well as circulating tumor necrosis factor (TNF)-alpha, mostly in patients exhibiting highly elevated levels, were found at the end of the treatment period. Our data suggest that in vivo L-carnitine could prove useful in ameliorating both the immune response and lipid metabolism in patients with AIDS, irrespective of initial serum carnitines levels. The mechanism(s) accounting for the observed results are currently not clear. Further studies are needed to confirm the hypothesis that L-carnitine affects the expression of HIV-induced cytokine.

Neuroimmunomodulation by opiates: relationship to HIV-1 infection and AIDS

Opiate addiction is a major risk factor for acquired immunodeficiency disease syndrome (AIDS). Since alkaloid opiates and endogenous opioid peptides have been shown to affect immune function, there is considerable interest in understanding whether opioids themselves play any direct or indirect role in modulating expression of HIV-1 and the development of AIDS in heroin addicts. This issue is difficult to address for two main reasons. The addictive liabilities of opiates prohibit direct controlled assessments of their effects in humans and epidemiological assessments of heroin addiction are compromised by the association of addiction with a variety of interdependent milieu cofactors, aside from opiates themselves, that have the independent potential to modulate immune function and viral expression. Accordingly, experimental evidence attained through in vitro and in vivo studies with animal models and human blood cells must supplement clinical observations to obtain the best possible estimate of the potential of opiates to modify host responses to HIV-1 infection and the development of AIDS. Reviewing current evidence from this perspective indicates that there is substantial support for the notion that opiates can affect both immunological and virological processes that dictate the pathogenesis of HIV-1 infections. However, the influence exerted by opiates appears to be conditionally dependent on the stage of opiate dependency. Thus, a well-maintained opiate dependency can be beneficial to host defense systems while poorly maintained dependencies can be quite disruptive. Such information has relevance, not only to the AIDS situation per se , but, also, to therapy of drug addiction and to the field of neuroimmunomodulation in general.

An ultrasensitive human immunodeficiency virus type 1 protease radioimmuno rate assay with a potential for monitoring blood levels of protease inhibitors in acquired immunodeficiency disease syndrome patients

The angiotensin I-based peptide Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Glu-Glu-Ser yields angiotensin I (AngI) and Leu-Glu-Glu-Ser upon hydrolysis by the human immunodeficiency virus type 1 (HIV-1) protease, but not by human renin. N-terminal sequencing of the reaction products showed that the HIV-1 protease cleaved exclusively at the Leu-Leu bond. The rate of Ang I formation can be measured by a radioimmunoassay, since the parent peptide has minimal cross reactivity in this assay. The rate of enzymatic hydrolysis is maximal at pH 4.5–5.0 and at an ionic strength of 1 m. At 37°C, 0.1 m Na acetate buffer, pH 5.0, 1 m NaCl, 10% glycerol, 5% ethylene glycol, 1 mg/ml bovine serum albumin, and 3 m m EDTA, the reaction obeys Michaelis-Menten type kinetics with K m = 17.2 ± 3.5 μm and k cat = 2.30 ± 0.33 min −1. The activity assay readily quantitates as little as 0.25 n m of HIV-1 protease. The production of Ang I by the HIV-1 protease is inhibited in the presence of a HIV-1 protease inhibitor. The newly discovered substrate is relatively insensitive to human or monkey serum. Therefore, the effect of sera from 20 patients with advanced acquired immunodeficiency disease syndrome (AIDS) on Ang I production in the above assay system was examined. Results of this study indicate that it may be possible to adapt the above Ang I-based system to determine blood levels of HIV-1 protease inhibitors in AIDS patients during clinical trials.

Primary immunodeficiency diseases and Epstein-Barr virus-induced lymphoproliferative disorders.

Increased incidence of malignant disorders is noted in patients with both primary and acquired immunodeficiency diseases. The pathogenetic mechanism(s) for these disorders remain unclear. Defective immunosurveillance of these patients, however, is mainly postulated to be responsible for the increased risk of these malignant disorders. Of the malignant disorders, Epstein-Barr virus (EBV)-induced lymphoproliferative disorders (LPD) have been increasingly reported, possibly due to improved therapeutic management techniques such as bone marrow transplantation, which results in prolonged survival periods for the primary immunodeficiency; the dramatic development of immunosuppressive treatments for transplant recipients; and the growing numbers of acquired immunodeficiency syndrome (AIDS) patients. This review focuses on the primary immunodeficiency diseases and EBV-induced LPD, and discusses pathogenetic mechanism(s) for the increased incidence of these malignant disorders.

Extraintestinal rotavirus infections in children with immunodeficiency

Some rotavirus strains, including vaccine candidates, have been demonstrated to cause hepatitis in immunodeficient and malnourished mice and to grow in human liver cells. To determine whether rotavirus spreads outside the intestine in naturally infected children, we examined tissues from four immunodeficient children affected with severe combined immunodeficiency disease, acquired immunodeficiency disease syndrome, or DiGeorge syndrome. Chronic rotavirus-related diarrhea, which persisted until death, had also developed in each child. Using indirect immunoperoxidase techniques, we identified rotavirus antigen in the liver and kidney with a hyperimmune guinea pig antiserum prepared to double-shelled rotavirus particles. Similar immunostaining with an antiserum to a rotavirus nonstructural protein (NS26) provided evidence of active virus replication. The observed reactivity was eliminated specifically when serial sections were immunostained with the same antiserum that had been absorbed with either double-shelled rotavirus particles or NS26. Immunostaining was not observed in the liver of children with other diseases (alpha 1-antitrypsin deficiency, inspissated bile syndrome, and acute rejection of a transplanted liver). These findings demonstrate that rotavirus infections in children can extend beyond the intestinal tract. Further studies are warranted to determine whether extraintestinal rotavirus replication occurs in children without severe immunodeficiency, such as malnourished children.

Methyl inosine monophosphate: A potential immunotherapeutic for early human immunodeficiency virus (HIV) infection

MIMP is a new thymomimetic purine under development for immunorestorative therapy. Lymphocytes were obtained from eight patients with acquired immunodeficiency disease (AIDS), eight with symptomatic pre-AIDS (ARC), and 22 normal controls and were stimulated in vitro with phytohemagglutinin (PHA). AIDS patients (mean CD4 counts of 40) showed PHA responses <10% of control while ARC patients (mean CD4 counts of 544) showed responses approximately 50% of the control responses. MIMP (0.1, 1, 10 and 100 μg/ml) progressively augmented the PHA responses in all these groups. The augmentation of the responses of the leukocytes of AIDS patients while statistically significant was minimal. The augmentation of the responses of ARC patients was significant and their maximal responses approached control levels. The effect of 1 μg/ml MIMP was comparable with that observed with indomethacin (10 −6 M) and interleukin-2 (IL2 – 4 units/ml) and was additive with each of these stimulants. In a parallel manner, MIMP restored the suppression of control lymphocytes induced by the immunosuppressive 17 amino acid fragment of the P41 peptide of HIV. In vivo experiments showed that MIMP significantly delayed death in a murine FLV AIDS model at a dose of 1 mg/kg by the oral or parenteral route. MIMP is under preclinical development for early HIV disease to forestall progression to AIDS by attenuating virus-induced immunosuppression.

The expanding challenge of HIV-associated malignancies.

The expanding challenge of HIV-associated malignancies.

Molluscum Contagiosum

• Background and Design.— Molluscum contagiosum in acquired immunodeficiency disease, although not life threatening, is often a marker of late-stage disease and may lead to disfiguring cutaneous lesions. Although most current therapy results in at least temporary clearing of individual lesions, lesions frequently recur and new lesions arise. Examination of hematoxylin-eosin-stained histologic sections in two patients showed changes suggestive of viral infection in the epidermis 0.5 cm and 1 cm lateral to obvious clinical lesions. These areas were clinically free of any lesions. Both routine histopathologic examination and ultrastructural examination were performed in two patients infected with human immunodeficiency virus type 1 (HIV-1) and three non-HIV-1-infected patients. Results.— All patients showed histologic changes diagnostic of molluscum contagiosum. In addition, the sections from HIV-1-infected patients showed areas of acanthosis, hyperkeratosis, and nuclear atypia. Electron microscopy of these areas revealed rare viral organisms in these areas. Similar acanthotic, hyperkeratotic areas were not seen in the biopsy specimens from the non-HIV-1-infected patients and no viral particles were found in the epidermis around the lesions. Conclusion.— Viral structures consistent with molluscum contagiosum are present within the clinically normal epidermis around lesions of molluscum contagiosum in some HIV-1-infected patients. This may explain the large number of lesions seen in these patients and the difficulty in controlling the spread and recurrence of molluscum contagiosum in HIV-1-infected patients. (Arch Dermatol.1992;128:223-227)

Molluscum contagiosum. Ultrastructural evidence for its presence in skin adjacent to clinical lesions in patients infected with human immunodeficiency virus type 1. Military Medical Consortium for Applied Retroviral Research

Molluscum contagiosum in acquired immunodeficiency disease, although not life threatening, is often a marker of late-stage disease and may lead to disfiguring cutaneous lesions. Although most current therapy results in at least temporary clearing of individual lesions, lesions frequently recur and new lesions arise. Examination of hematoxylin-eosin-stained histologic sections in two patients showed changes suggestive of viral infection in the epidermis 0.5 cm and 1 cm lateral to obvious clinical lesions. These areas were clinically free of any lesions. Both routine histopathologic examination and ultrastructural examination were performed in two patients infected with human immunodeficiency virus type 1 (HIV-1) and three non-HIV-1-infected patients. All patients showed histologic changes diagnostic of molluscum contagiosum. In addition, the sections from HIV-1-infected patients showed areas of acanthosis, hyperkeratosis, and nuclear atypia. Electron microscopy of these areas revealed rare viral organisms in these areas. Similar acanthotic, hyperkeratotic areas were not seen in the biopsy specimens from the non-HIV-1-infected patients and no viral particles were found in the epidermis around the lesions. Viral structures consistent with molluscum contagiosum are present within the clinically normal epidermis around lesions of molluscum contagiosum in some HIV-1-infected patients. This may explain the large number of lesions seen in these patients and the difficulty in controlling the spread and recurrence of molluscum contagiosum in HIV-1-infected patients.

A mathematical model of vaccination against HIV to prevent the development of AIDS

Vaccination and post-exposure immunization against the human immunodeficiency viruses (HIV-1 and HIV-2) faces the problem of the extensive genetic and antigenic variability of these viruses. This raises the question of what fraction of all possible antigen strains of the virus must be recognized by the immune response to a vaccine to prevent development of acquired immunodeficiency disease (AIDS). The success of a vaccine can depend on the variability of the target epitopes. The different HIV variants must be suppressed faster than new escape mutants can be produced. In this paper the antigenic variation of HIV during an individual infection is described by a stochastic process. The central assumption is that antigenic drift is important for the virus to survive immunological attack and to establish a persistent infection that leads to the development of AIDS after a long incubation period. The mathematical analysis reveals that the fraction of antigenic variants recognized by the immune response, that is induced by a successful immunogen, must exceed 1-1/R, where R is the diversification rate of the virus population. This means that if each HIV strain can produce, on average, five new escape mutants, then more than 80% of the possible variants must be covered by the immunogen. A generic result of the model is that, no matter how immunogenic a vaccine is, it will fail if it does not enhance immune attack against a sufficiently large fraction of strains. Furthermore, it is shown that the timing of the application of post-exposure immunization is important.