Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS.

Peripheral blood lymphocytes from patients with the acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that frequently precede AIDS (pre-AIDS) were grown in vitro with added T-cell growth factor and assayed for the expression and release of human T-lymphotropic retroviruses (HTLV). Retroviruses belonging to the HTLV family and collectively designated HTLV-III were isolated from a total of 48 subjects including 18 of 21 patients wih pre-AIDS, three of four clinically normal mothers of juveniles with AIDS, 26 of 72 adult and juvenile patients with AIDS, and from one of 22 normal male homosexual subjects. No HTLV-III was detected in or isolated from 115 normal heterosexual subjects. The number of HTLV-III isolates reported here underestimates the true prevalence of the virus since many specimens were received in unsatisfactory condition. Other data show that serum samples from a high proportion of AIDS patients contain antibodies to HTLV-III. That these new isolates are members of the HTLV family but differ from the previous isolates known as HTLV-I and HTLV-II is indicated by their morphological, biological, and immunological characteristics. These results and those reported elsewhere in this issue suggest that HTLV-III may be the primary cause of AIDS.

Release of some trace metals from disposable coils during hemodialysis.

In a previous study, we demonstrated that certain disposable coils are contaminated with zinc and release substantial quantities of zinc during hemodialysis, producing high postdialysis plasma zinc concentrations. The present investigation was undertaken to monitor plasma and dialysis fluid zinc and copper throughout dialysis and to estimate plasma zinc and copper uptake. Aluminum, cadmium, and lead release from coils was also determined. Venous plasma, arterial plasma, and coil chamber fluid were sampled periodically during dialysis; the trace metal concentrations were determined by flame atomic absorption spectrophotometry. Release of considerable quantities of zinc from the coils into the dialysis fluid, with uptake into the patient's plasma, was found. Approximately one-half of the plasma zinc uptake occurred within the first 45 min. Coils from different lots released significantly (p less than 0.001) different quantities of zinc. Plasma uptake of zinc ranged from 3.2 mg to 23.0 mg, with a mean (+/-SD) of 15.0 +/- 6.1 mg. Copper release and uptake was low. No detectable release of lead, cadmium, or aluminum was observed. The results suggest that zinc release from disposable dialysis coils should be assessed before recommending that hemodialysis patients receive zinc supplements.

Elevated plasma zinc concentrations in renal dialysis patients.

It has been suggested that hemodialysis patients might benefit from zinc supplements. However, little attention is given to the trace element content of renal dialysis fluids or to contamination of such fluids with trace metals. Pre- and postdialysis plasma copper and zinc concentrations of patients at two hospital dialysis units were measured by atomic absorption spectrophotometry. The plasma zinc concentration increased substantially in 34 of 37 patients as a result of dialysis. Measurement of dialysate zinc concentrations after primary source of zinc. Because of the possibility of zinc toxicity, zinc nutritional status should be carefully evaluated before recommending zinc supplementation for dialysis patients. Uremic patients dialyzed with certain disposable Cuprophan-membrane coils receive substantial quantities of zinc during dialysis; other Cuprophan-membrane coils tested released negligible quantities of zinc.

Zinc and immunocompetence in elderly people: effects of zinc supplementation for 3 months.

One hundred and three apparently healthy elderly subjects age 60-89 y were randomly assigned to one of three treatments: placebo, 15 mg zinc/d, or 100 mg Zn/d for 3 mo. Plasma Zn was significantly increased only in the 100 mg Zn group. Zn concentrations in erythrocytes, platelets, mononuclear cells, and polymorphonuclear leukocytes were not significantly increased by any treatment. None of the treatments significantly altered delayed dermal hypersensitivity (DDH) to a panel of seven recall antigens or in vitro lymphocyte proliferative responses (LPR) to mitogens and antigens. Fifteen subjects had initially poor lymphocyte proliferative responses that improved in 14 of these individuals during the study; this was not due to Zn supplementation but might have been caused by one or more components of a vitamin-mineral supplement administered to all study subjects.

Zinc and immunocompetence in the elderly: baseline data on zinc nutriture and immunity in unsupplemented subjects.

Zinc nutriture and immune function were studied in 100 subjects, age 60-89 yr. Mean (+/- SD) zinc concentrations found were 84.8 +/- 15.5 micrograms/dL (13.0 +/- 2.4 microM) for plasma, 1.04 +/- 0.24 micrograms (0.016 +/- 0.004 mumol)/10(9) cells for erythrocytes, 4.06 +/- 1.85 micrograms (0.062 +/- 0.028 mumol)/10(9) cells for mononuclear cells, 3.91 +/- 1.77 micrograms (0.060 +/- 0.027 mumol)/10(9) cells for polymorphonuclear leukocytes, 0.53 +/- 0.39 micrograms (0.0081 +/- 0.0060 mumol)/10(9) cells for platelets, and 222 +/- 101 micrograms (3.39 +/- 1.54 mumol)/g for hair. Zinc ingestion was below the RDA in more than 90% of study subjects. The incidence of anergy to a panel of seven skin test antigens was 41%; responses to these antigens were significantly associated with the plasma zinc concentration. Subjects with depressed lymphocyte responses to mitogens had significantly lower platelet and significantly higher mononuclear cell zinc concentrations than those with normal responses.

Status of selected nutrients and progression of human immunodeficiency virus type 1 infection.

BACKGROUND: Immune function is highly dependent on nutritional status because the large mass and high rate of cellular turnover of the immune system make it a major user of nutrients. Furthermore, nutrient requirements may be increased during acute and chronic infections, including HIV-1 infection. OBJECTIVE: The current study was designed to assess relations among HIV-1 progression and 11 nutritional and demographic variables. DESIGN: The participants were 106 HIV-infected outpatients and 29 uninfected control subjects (n = 89 men and 46 women; age range: 35-57 y). The HIV-infected subjects represented a broad range of disease progression. RESULTS: We found lower concentrations of plasma and erythrocyte magnesium and of erythrocyte reduced glutathione beginning early in the course of HIV-1 infection. Significantly decreased hematocrit and increased serum copper concentration developed only late in the course of the disease. Statistically significant univariate associations were found between the CD4(+) T lymphocyte count and hematocrit, plasma magnesium concentration, and plasma zinc concentration. The lowest erythrocyte magnesium concentrations occurred in HIV-infected subjects who consumed alcoholic beverages. Independent variables that were significant joint predictors of CD4(+) cell count in multiple regression analyses were hematocrit and plasma free choline and zinc concentrations. These 3 factors together explained 43% of the variability in CD4(+) cell counts. CONCLUSION: The results provide evidence that compromised nutritional and antioxidant status begin early in the course of HIV-1 infection and may contribute to disease progression.

Levodopa therapy improves motor function in HIV-infected children with extrapyramidal syndromes.

Five children with human immunodeficiency virus type-1 (HIV-1) infection, aged 4 to 13 years, manifested extrapyramidal dysfunction characterized by rigidity/stiffness, ambulation difficulties/shuffling gait, dysarthria/drooling/swallowing dysfunction, hypomimetic/inexpressive facies, and bradykinesia. Levodopa therapy caused an initial improvement in all symptoms, and the effect was sustained in most patients. Levodopa is a useful adjunctive therapy in HIV-1-infected children with extrapyramidal syndromes, by enhancing motor function and improving their quality of life.

Immunologic parameters in chronic fatigue syndrome, major depression, and multiple sclerosis.

The purpose of this study was to evaluate the immune dysfunction hypothesis of chronic fatigue syndrome (CFS) by comparing immunologic data from patients with CFS with data from patients with other fatiguing illnesses--major depression and multiple sclerosis (MS)--and with data from healthy sedentary controls. The subjects were 65 healthy sedentary controls, 71 CFS patients (41 with no axis-I diagnosis), 23 patients with mild MS, and 21 patients with major depression. Blood was sampled and assayed for the following: (1) immunologic serologic variables--circulating immune complexes (i.e., Raji cell and C1q binding), immunoglobulins A, E, G, and M, and IgG subclasses; (2) cell surface activation markers--the proportion of CD4+ cells expressing CD45RA+ and CD45RO+ and the proportion of CD8+ cells expressing CD38+, CD11b-, HLA-DR+ and CD28+; and (3) natural killer (NK) total cell count as well as the proportion of lymphocytes expressing NK cell surface markers (i.e., CD3-/CD16+ and CD56+. Of the 18 variables studied, differences between CFS patients and controls were found only for IgG1 and IgG3. When CFS patients were stratified by the presence or absence of concurrent axis-I disease, it was the group with axis-I disorder that had the lowest IgG1 values-contrary to expectation. When data from patients with MS and major depression were also evaluated, the subclass deficiency was no longer significant. The one group to show evidence for immune activation (i.e., an elevated proportion of CD4+ cells expressing the CD45RA+ activation marker) was the group with mild MS. These data support neither immune dysfunction nor immune activation in CFS or in major depression, for the variables studied. The reductions in IgG subclasses may be an epiphenomenon of patient or control subject composition. In contrast, MS, even in the mild and early stages, as in the patients studied here, is associated with immune activation.

Decreased suppressor-inducer T lymphocytes in multiple sclerosis and other neurological diseases.

Decreased numbers of CD4+CD45R+ suppressor-inducer T cells have been reported in patients with a variety of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis but not in patients with other neurological diseases. We now report our findings using murine monoclonal antibodies and two-color flow cytometric analysis on CD4+CD45R+ T cells in 22 patients with chronic progressive multiple sclerosis, 23 patients with other neurological diseases and 42 normal, healthy controls. Suppressor-inducer T cells were significantly reduced (p less than 0.001) in both patients with multiple sclerosis and other neurological diseases as compared to controls. Both patient populations had elevated helper T cell subset ratios. Thus, our data suggests that decreases in suppressor-inducer T cells may represent a common immunological defect among autoimmune and presumably non-autoimmune neurological disorders.

Induction of autologous mixed lymphocyte culture responses by myelin basic protein-reactive T cell clones.

Myelin basic protein is an autoantigen present in the central nervous system suspected to be the target of destruction in multiple sclerosis. In the present study, we have demonstrated that T cell clones specific for myelin basic protein have the ability to induce proliferative responses in resting T lymphocytes in the autologous mixed lymphocyte culture (AMLC). T cell recognition of the AMLC stimulatory determinants on the clones required the presence of autologous monocytes. T lymphocytes primed against an autologous myelin basic protein-specific T cell clone displayed specific memory responses against the original stimulating clone and failed to exhibit secondary reactivity to 'sister' myelin basic protein-reactive clones and to autologous T cell clones specific for another antigen. Monoclonal antibodies specific for class II HLA-DR antigens inhibited secondary AMLC responses. Modulation of the T cell receptor from the surface of the clones decreased their AMLC stimulatory ability. These results indicate that idiotype-like determinants on the T cell receptor of autoantigen-specific T cell clones are capable of triggering anti-idiotypic T cell responses.

Primary lymphoma of the central nervous system in children with acquired immunodeficiency syndrome.

Three children with acquired immunodeficiency syndrome and primary lymphoma of the CNS are described. All three children had clinical signs of focal mass lesions and progressive neurologic deficits. In one child the deterioration was extremely rapid. New lesions appeared on serial CT scans every few days, simulating an infectious process and leading to death within 3 weeks. Results of neuroradiologic studies in these patients demonstrated multicentric lesions that were often periventricular. On CT scans, the lesions were hyperdense before contrast and were enhanced with contrast medium. Double-dose delayed contrast CT scans and magnetic resonance imaging studies were more sensitive in indicating additional lesions. Histologically, all three tumors were B cell neoplasms; two lymphomas were large cell type, whereas one was small cell, noncleaved (Burkitt-like). Primary CNS lymphoma occurred with an incidence of 1/26 (4%) in our autopsy series and 3/100 (3%) of all pediatric cases of human immunodeficiency virus-type 1 infection, living and dead, that have been seen at the Children's Hospital of New Jersey. By comparison, opportunistic and reactivated latent CNS infections were less common in this same population and never appeared clinically as mass lesions. Therefore, in our experience, primary lymphoma is the most common cause of focal or multifocal mass lesions in the brains of children with acquired immunodeficiency syndrome. This tumor may be radiosensitive. In most cases, early biopsy is probably necessary to establish the diagnosis.

Neurologic manifestations of human immunodeficiency virus infection in children.

This report describes the neurologic manifestations of 36 children with human immunodeficiency virus (HIV) infection. In this cohort, in 16 of 21 children with acquired immunodeficiency syndrome (AIDS), three of 12 children with AIDS-related complex, and one of three asymptomatic seropositive children, a progressive encephalopathy developed. Neurologic signs were often detected early but tended to worsen coincident with progression of the immunodeficiency. The presence of progressive encephalopathy correlated with the absence of serum neutralizing antibodies to HIV and with a poor, usually fatal, outcome. The incubation period from initial HIV infection in the perinatal period to the onset of progressive encephalopathy varied from 2 months to 5 years. Intrablood-brain barrier synthesis of HIV-specific antibodies was demonstrated in eight of 14 children with AIDS and AIDS-related complex, indicating active brain infection with HIV. In three cases this was unassociated with progressive neurologic signs. Unique neuropathologic findings in children who died with HIV infection further suggest that the progressive encephalopathy is the result of primary and persistent infection of the brain with this retrovirus. These findings broaden the spectrum of HIV infection in children and have important implications for the development of antiviral therapy.

Live virus vaccines in human immunodeficiency virus-infected children: a retrospective survey.

Live virus vaccines can cause serious adverse reactions when administered to immunocompromised patients. Because children infected with human immunodeficiency virus (HIV) may be immunosuppressed, immunization of these children with live virus vaccines is a potential problem. A retrospective survey was conducted by the New York City Department of Health, with consultation from the Centers for Disease Control, to evaluate the frequency of serious adverse events following receipt of live vaccines among children with HIV infection receiving pediatric care in New York City and New Jersey. Outpatient records of 319 children being cared for by 16 participating physicians were reviewed. Of the 319 charts, 221 (69%) contained vaccination histories. Perinatal transmission of HIV infection was suspected for 208 (94%) of the 221 cases and infection via transfusion for the remaining 13 (6%). Of the 221 for whom immunization histories were available, 180 (81%) had received at least one dose of live oral polio vaccine and 70 (32%) had received measles, mumps, and rubella vaccine. There were 120 children for whom a temporal relationship between immunization and onset of symptoms of immunodeficiency could be seen; 46/120 had received at least one dose of oral polio vaccine and 23/45 had received measles, mumps, and rubella vaccine after onset of symptoms. Although follow-up of this population has been limited, there were no reports of serious adverse events such as typical or atypical measles, paralytic poliomyelitis, or aseptic meningitis in the month following vaccination.(ABSTRACT TRUNCATED AT 250 WORDS)

Older children and adolescents living with perinatally acquired human immunodeficiency virus infection.

OBJECTIVE: To describe the clinical, immunologic, and psychosocial characteristics of children living with perinatally-acquired human immunodeficiency virus (HIV) infection beyond the age of 9 years. METHODS: This is a descriptive cohort study of 42 surviving perinatally infected children older than 9 years followed at the Children's Hospital Acquired Immunodeficiency Syndrome (AIDS) Program (part of a university-based inner city medical center) as of June 1993. The study is based on medical record data of clinical, immunologic, and psychosocial parameters. RESULTS: The cohort includes 20 boys and 22 girls with a mean age of 136 months. The mean age at diagnosis of HIV infection was 88 months, and 59.5% were asymptomatic at the time of diagnosis. Currently, after a mean follow-up period of 48 months from diagnosis, 23.8% remain asymptomatic, 19.1% have non-AIDS-defining HIV-related symptoms, and 57.1% have AIDS; 85.7% of the cohort did not develop HIV-related symptoms until after 48 months of age (late-onset prolonged survivors). There was an average annual decline of 71.4 CD4+ cells/microL in the cohort from the ages of 7 to 16 years, and 21.4% have a current CD4+ lymphocyte count of greater than 500 cells/microL, 28.6% between 200 and 500 cells/microL, and 50% less than 200 cells/microL; 76% are orphaned as a result of maternal death, with the majority of the cohort (60%) cared for by extended family members. Disclosure of diagnosis has occurred in 57.1%. The vast majority of the cohort (76%) are attending regular school, with the remainder in special education. CONCLUSIONS: Although close to one quarter of the children and adolescents ages 9 to 16 years living with perinatally acquired HIV infection described in this cohort remain asymptomatic and have a relatively intact immune system, the remainder are living with significant HIV-related symptoms, many of which are chronic in nature and have an impact on daily living. The children in this cohort had both significant immunologic deterioration and symptomatic disease progression during the mean follow-up period of 48 months from the time of diagnosis with HIV infection.

Persistent human immunodeficiency virus type 1 antigenemia in children correlates with disease progression.

In a longitudinal study, human immunodeficiency virus type 1 (HIV-1) antigen (HIV-Ag) was measured in serum specimens from 54 children with HIV-1 infection followed for a median duration of 17 months. The persistent detection of free HIV-Ag in a group of 25 children was associated with clinical deterioration in 22 (88%) and a mortality of 52%, whereas the persistent nondetection of free HIV-Ag in a group of 18 children was associated with clinical deterioration in five (28%) and a mortality of 11% during the period of observation. Nine children had transient HIV-1 antigenemia and two children converted from HIV-Ag negative to positive during the study. Free HIV-Ag levels varied inversely with antibody reactivity to viral core proteins p24 and p17 determined by Western immunoblot, suggesting either the formation of immune complexes or a balance between viral expression and the host immune response. Five mother-infant pairs were studied for HIV-Ag expression in the perinatal period. In three of these pairs, both mother and infant were HIV-Ag negative, in one pair the mother had high levels of HIV-Ag and the infant was HIV-Ag negative. In the remaining mother-infant pair, the neonate became HIV-Ag positive but the mother was HIV-Ag negative prepartum and postpartum. These data suggest that HIV-Ag probably does not cross the placenta and that the detection of free HIV-Ag in the offspring of a HIV-1 infected mother most likely indicates viral infection.(ABSTRACT TRUNCATED AT 250 WORDS)

ELISPOT: a new approach to studying the dynamics of virus-immune system interaction for diagnosis and monitoring of HIV infection.

A new approach to detect and enumerate HIV-specific antibody-secreting cells (ASC) in the peripheral blood was developed using the enzyme-linked immunospot (ELISPOT) methodology. ASC to an HIV envelope recombinant protein were demonstrated in 75% of 16 adults and 72% of 21 children with untreated AIDS or ARC and in 63% of 34 asymptomatically infected adults but in none of the 51 HIV antibody-negative individuals. Only 1 of the 13 adults receiving AZT therapy yielded a positive reaction, and 27% of the 30 infants born to seropositive mothers were found to have HIV-ASC. The number of HIV-ASC in positive individuals varied from 8 to 202 per 10(6) circulating mononuclear cells. The reactivity was specifically inhibited by soluble HIV antigen and was abrogated by cycloheximide, indicating that the observed reaction was the result of de novo synthesis of HIV-specific antibodies. Nonspecific polyclonal B cell activation was unlikely to be responsible for the results observed as no reactivity was found to a common antigen, tetanus toxoid. Since circulating antigen-specific ASC reflect persistent or recent antigenic stimulation, our findings indicate that this new approach could provide a dynamic perspective of the natural course of virus-immune system interactions in individuals infected with HIV, as well as in those undergoing prophylactic or therapeutic interventions.

Lead poisoning--one approach to a problem that won't go away.

A reduction in sources of environmental lead exposure has resulted in substantial declines in mean blood lead concentrations of all age groups in the United States. However, some segments of the population continue to have unacceptable levels of lead exposure and elevated blood lead concentrations. In addition, virtually all residents of industrialized countries have bone lead stores that are several orders of magnitude greater than those of our preindustrial ancestors. Recent studies suggest that these skeletal lead stores adversely affect health and can contribute to reduced birth weights, aggressive behavior in children, and anemia, hypertension, and kidney disease in adults. Evidence is described that demonstrates that an increase in dietary calcium consumption can reduce lead absorption and toxicity from exogenous and endogenous lead exposure. A relatively inexpensive and effective way to reduce the substantial morbidity that will result from widespread lead exposure is by fortification of a variety of foods with low levels of calcium. This approach can complement other efforts to prevent lead exposure and reduce lead toxicity.

Dilated cardiomyopathy in children with acquired immunodeficiency syndrome: a pathologic study of five cases.

Clinicopathologic features with special reference to the heart are presented in five fatal cases of acquired immunodeficiency syndrome (AIDS) in children. Three children showed clinical evidence of cardiovascular compromise or congestive heart failure. Autopsy was performed in all cases. The enlarged heart showed biventricular dilatation with grossly unremarkable valves and coronary arteries and absence of mural thrombi. Microscopic examination of the heart revealed primarily myopathic abnormalities with hypertrophy of the myocardium and only rare foci of sparse inflammatory infiltrate. The pathogenesis of dilated cardiomyopathy in these children with AIDS is not known. Infection, immunologic factors, anemia, deficiency of nutritional factor(s), and longer survival may be related to the pathogenesis. Pediatricians should be alert to the possibility of cardiac involvement in pediatric AIDS.

Pathologic pulmonary findings in children with the acquired immunodeficiency syndrome: a study of ten cases.

Lung tissue and tissue from the lymphoreticular system obtained at open biopsy and/or autopsy were studied in ten children with the acquired immunodeficiency syndrome (AIDS). One or both parents of nine of the children had AIDS or risk factors for AIDS. The remaining child had hemophilia. The following pulmonary lesions were seen: 1) diffuse alveolar damage (DAD), 2) Pneumocystis carinii and/or cytomegalovirus pneumonitis, 3) lymphoid interstitial pneumonitis (LIP), and 4) desquamative interstitial pneumonitis (DIP). Combinations of such factors as mechanical ventilation, oxygen therapy, and opportunistic infection played a role in the pathogenesis of DAD. Opportunistic infections were related to the defective cell-mediated immunity in these children. The clinical, epidemiologic, immunologic, and pathologic features of the thymuses of these patients indicate that the immune deficiency was unlikely to have been of congenital origin. The immunologic abnormalities may also have been related to the pathogenesis of LIP and DIP. Neither LIP nor DIP has been described in adults with AIDS. Open lung biopsy is of practical importance in the diagnosis and treatment of pulmonary disease in children with AIDS.

Conduction system in children with acquired immunodeficiency syndrome.

Six children died of acquired immunodeficiency syndrome (AIDS), four of them females, ages 7 months, 13 months, 2 years 8 months, and 4 years; and two of them males, aged 2 1/2 and 7 years. They were born to IV drug-addicted parents. The conduction system (CS) and the entire heart were studied by serial section. In all cases the heart was hypertrophied and enlarged; one had total thrombotic occlusion of the right coronary artery with extensive infarction of the ventricular septum. Vascular changes also were found in all hearts, involving small arteries, arterioles, and venules. In the arteries, they involved the intima, media, and adventitia, and perivascular areas in a degenerative and inflammatory process. The elastic tissue was especially affected. A nonspecific myocarditis was present in four cases and epicarditis in all. Changes in the summit of the ventricular septum were present in four cases, consisting of increased fibrosis and arteriolosclerosis. The CS changes varied in location, showing either vasculitis, myocarditis, or fragmentation of the bundle with lobulation and fibrosis. The changes in the conduction system were not as severe as the changes in the surrounding myocardium. In one case the ECG was abnormal, showing left hemiblock. This corresponded to the finding of fibrosis, vacuolization of cells, and space formation in the left bundle branch.