Modulation of alpha interferon levels by AZT treatment in HIV-seropositive patients.

The effect of AZT on serum HIV p24 antigen and endogenous serum alpha interferon levels was studied in AIDS and ARC patients. Following administration of AZT there was a rapid decline in the serum levels of both HIV p24 antigen and alpha interferon. When AZT treatment was interrupted, the levels of both HIV p24 antigen and of interferon rapidly increased. These findings suggest that HIV or some other AZT sensitive microorganism is the inducer of interferon which is characteristically found in the serum of AIDS and symptomatic HIV infected patients. They also suggest that the rapid decline in interferon levels may underlie some of the symptomatic benefit that follows administration of AZT.

Inhibition of HIV replication in lymphocyte cultures of virus-positive subjects in the presence of sho-saiko-to, an oriental plant extract.

An oriental remedy, Sho-saiko-to (SST) consisting of a mixture of aqueous extracts from seven different plants and whose most active component is the chemically defined compound baicalein was tested for its ability to inhibit the production of the human immunodeficiency virus (HIV). The testing was done with cultures of human lymphocytes obtained from HIV-positive asymptomatic subjects and patients with ARC or AIDS. The replication of the virus was monitored by quantitative assay of the reverse transcriptase (RT) activity and of the synthesis of antigen p24. The lymphocyte cultures (LC) were maintained in the absence and in the presence of 25, 50 or 100 micrograms/ml of SST, and monitored for up to 5 weeks. The results showed that in LC from asymptomatic subjects RT activity and synthesis of p24 was completely inhibited by low concentrations of SST. High concentrations of SST inhibited virus replication in 80% of LC from ARC patients, but were completely ineffective in LC from AIDS patients. It was observed that the RT activity was more sensitive to inhibition by SST than the synthesis of p24, and that the antiviral effect was dependent on the virus load of the LC.

Rubella and mumps vaccines.

As a fetal infection occurring during early pregnancy, rubella's potential for teratogenicity is unparalleled. In the postnatal period it is a relatively benign disease. Mumps, on the other hand, causes moderate morbidity and occasional mortality. Both infections cause considerable morbidity and disruption in the lives of young people gathered for group activities. Widespread use of safe and effective live attenuated vaccines has dramatically reduced the incidence of rubella, congenital rubella, and mumps in the United States. Nevertheless, significant numbers of young children, especially in areas of urban and rural immigration and poverty, fail to be immunized in a timely fashion; and some adolescents and young adults remain susceptible either because they escaped immunization in childhood or are primary vaccine failures. These individuals remain the source of individual cases and small outbreaks of rubella and mumps. For total eradication of these infections, we need to intensify vaccine efforts and to maintain surveillance efforts for mumps, rubella, and congenital rubella syndrome.

Growth in congenital rubella syndrome and correlation with clinical manifestations.

Growth patterns, final stature, and clinical manifestations were studied in a review of the records of 105 patients with congenital rubella syndrome followed longitudinally. Of the patients (35 male, 51 female), 86 had achieved final heights. Three patterns of growth were observed: normal growth, growth consistently below the 5th percentile, and growth within the normal range or slightly below the 5th percentile followed by early cessation of growth and final height usually below the 5th percentile. Significant cognitive deficits were not observed in patients with normal growth patterns, except for one patient with profound mental retardation. The magnitude of the cognitive deficits was closely correlated with the degree of growth failure (p less than 0.001). We postulate that the rubella virus exerts its effect on somatic growth both in utero and postnatally, at a central and peripheral level, through multiple mechanisms.

Virus isolation and immune studies in a cohort of homosexual men.

Virus shedding was detected in 77% of homosexual subjects and in only 6% of heterosexual controls. The overall virus isolation rate in homosexual subjects was not significantly different among HIV-seropositive (79%) and HIV-seronegative (74%) individuals. In about 20% of homosexual subjects, virus shedding from multiple sites was observed. The most frequently isolated virus was cytomegalovirus (CMV) (41%), followed by enteroviruses (23%), herpes simplex virus (HSV) (7%), and adenoviruses (6%). In the control group, about 50% of subjects were seronegative for HSV-1 and 2, and about 70% were negative for CMV and Epstein-Barr virus (EBV). Only 2% of homosexuals were seronegative for CMV, about 5% for HSV-1 and 2, and about 20% for EBV. No differences were found in antibody levels against varicella-zoster virus (VZV) among the control and homosexual groups. The proportion of seronegatives for Coxsackie and hepatitis viruses was significantly higher in control than in homosexual subjects. However, no differences in the proportion of seronegatives for measles, mumps, and rubella were observed. No HIV-antibody-negative individual was detected with an OKT4/OKT8 ratio of less than 0.75. On the other hand, only HIV-positive subjects, with a ratio of less than 0.75, had high serum IFN alpha titers. The results suggest that the high rate of virus shedding among HIV-negative homosexual subjects might be a factor in the development of AIDS in this high-risk population.

Reverse transcriptase activity (RTA) in lymphocyte cultures of AIDS patients treated with HPA-23.

HPA-23 was used in a parallel, multiple dose study in patients with Centers for Disease Control (CDC)-defined AIDS. Sixteen patients were divided into four dosage groups, receiving 0.25, 0.5, 1.0, or 2.0 mg/kg HPA-23 respectively, by rapid IV infusion five days/week for eight weeks. Blood was collected before, at weeks 1, 3, and 7 of treatment, and two weeks post-therapy. Patient peripheral blood lymphocytes (PBL) were cultivated in the presence of fresh PBL from a healthy donor for 30 days. Media were changed and reverse transcriptase activity (RTA) was tested every four to five days. The results showed a significant decrease in RTA in patients treated with a dose of 0.5 or 1 mg/kg, but only a slight decrease in patients who received the lowest dose. In the group treated with the 2 mg/kg dose, two patients had toxic reactions and were discontinued; the other two showed a slight decrease in RTA. In 40% of treated patients, RTA did not increase again two weeks after the end of treatment. No significant immunologic and clinical changes were noticed during the observation period. In vitro experiments of Con A stimulated PBL in presence and absence of HPA-23 showed an increase in proliferation in the presence of the drug.

Long-term follow-up of serum-interferon and its acid-stability in a group of homosexual men.

For a period of over two years 99 volunteer healthy homosexual men were examined periodically for the presence of interferon (IFN) in their serum. Thirty-nine subjects had either undetectable IFN levels in serum or IFN was detected only once in three to five samples tested. In another 45 subjects low IFN levels were detected throughout the study period. None of these subjects had or developed any disease symptoms. In the remaining 15 subjects high serum IFN levels were detected at their enrollment or during the study period. All these subjects started to manifest clinical symptoms compatible with AIDS. In six subjects the mean time elapsed between the first detection of serum IFN and disease symptoms was 6.5 months. In all subjects but one, the IFN was of type alpha. The acid-stability of serum IFN alpha decreased with time, and when its decrease was abrupt it was associated with a more rapid evolution of AIDS. Sera containing acid-labile IFN alpha can induce IFN alpha synthesis in normal lymphocyte cultures (LC), but do not influence IFN gamma synthesis in LC stimulated with phytohemagglutinin. LC stimulated with viral antigens in the presence of serum with acid-labile IFN alpha synthesized IFN with an increased sensitivity for acid treatment. The results confirm the prognostic value of serum IFN alpha in the development of AIDS, and suggest that the transition to acid-lability may be a gradual process.

The history and medical consequences of rubella.

In 1814, George Maton, first recognized that a mild illness characterized by rash, adenopathy, and little or no fever was a discrete entity. Henry Veale, in 1866, named the disease rubella. The illness attracted little attention until 1942, when Norman Gregg noticed that first-trimester maternal rubella caused serious birth defects. The full spectrum and impact of rubella embryopathy remained unclarified until rubella virus was isolated in tissue culture in 1962 by two independent groups: Parkman, Buescher, and Artenstein; and Neva and Weller. Using the new tools of the virus laboratory, many investigators concentrated on the consequences of a severe rubella epidemic in 1964, which affected approximately 1% of pregnancies. Newly recognized transient manifestations of congenital rubella infection (CRI) include neonatal thrombocytopenic purpura, hepatitis, bone lesions, and meningoencephalitis and late-emerging sequelae such as diabetes mellitus and progressive rubella panencephalitis added to the cataract, heart disease, mental retardation, and deafness previously defined as due to CRI. Sharp contrasts were documented between the patterns of virus excretion and immune response of postnatal vs. congenital rubella. Licensure and widespread distribution of attenuated rubella virus vaccines in 1969 have prevented epidemic rubella. Pockets of illness remain, even in the United States. Continued effort will be required to eliminate the rubella problem.

Diabetes mellitus and autoimmunity in patients with the congenital rubella syndrome.

An increased incidence of insulin-dependent diabetes mellitus (IDDM) has been reported in patients with congenital rubella syndrome (CRS). Thus, studies of children with CRS would be of great importance in following the development of IDDM in a susceptible population. A total of 242 children with CRS, 30 of whom already have diabetes (mean age, 17.4 +/- 0.3 years) have been evaluated. In this latter group, the frequency of HLA DR3 is significantly increased and that of HLA DR2 significantly decreased. While pancreatic islet cell cytotoxic or surface antibodies (ICSA) are found in 20.2% of the total population of patients with CRS, they are present in 50%-80% of patients with glucose abnormalities. In all but five of the ICSA-positive patients, glucose abnormalities are currently present. In addition, glucose intolerance is found in greater than 50% of the DR3-positive nondiabetic patients with CRS evaluated to date. The data demonstrate that patients with CRS at risk for IDDM have the same genetic and immunologic features seen in classic IDDM, namely the presence of HLA DR3 and the absence of HLA DR2 and the high prevalence of ICSA before decompensation.

Cell-mediated immune response in rubella infections.

Cultures of lymphocytes from rubella-susceptible persons did not respond to stimulation with purified rubella antigen whereas those from persons who had experienced natural infection responded strongly to specific antigenic stimulation. The response of cultures of lymphocytes from vaccinees is weaker than that of naturally infected persons, and it appears that the response of lymphocytes from congenitally infected children depends on their gestational age at the time of interuterine infection. Vaccination or revaccination of immune subjects elicits a fast booster-type cell-mediated immune response. This property is useful for detecting the immune status of women exposed to rubella during pregnancy whose rubella history is unknown and whose humoral immune response is negative.

Cytomegalovirus isolation from healthy homosexual men.

The acquired immune deficiency syndrome (AIDS) has focused renewed interest on cytomegalovirus (CMV) both as an infectious complication of the syndrome and as a potential etiologic agent in the pathogenesis of the immunosuppression. We studied 30 healthy homosexual men in New York City to determine the prevalence of virus excretion and its relationship to CMV-IgM antibodies and to T-lymphocyte subsets. Cytomegalovirus was detected in the urine and/or semen of 11 subjects. Eight of 11 CMV shedders were CMV-IgM positive, but CMV IgM was found in only one of 19 not shedding the virus. While homosexuals as a group had lower OKT4/OKT8 ratios (0.8 +/- 0.4, mean +/- SD) than heterosexual controls (1.8 +/- 0.4, mean +/- SD), there was no significant difference in ratios between homosexuals excreting virus and those not excreting virus. Cytomegalovirus excretion by homosexual men seems to be more prevalent than previously appreciated and may pose a significant risk for sexual transmission.

Congenital rubella syndrome as a model for type 1 (insulin-dependent) diabetes mellitus: increased prevalence of islet cell surface antibodies.

An increased prevalence of Type 1 (insulin-dependent) diabetes has been reported in patients with congenital rubella. Rubella virus multiplies in the pancreas, and we have hypothesized that studies of children with congenital rubella would be of great importance in following the development of Type 1 diabetes in a defined, susceptible population. Two hundred and forty-one children with congenital rubella (mean age 17.4 +/- 0.3 years; 65% black and hispanic) have been evaluated, 30 of whom already have diabetes and 17 of whom have borderline glucose tolerance. In these latter two groups, HLA-DR3 is significantly increased and HLA-DR2 significantly decreased. Pancreatic islet cell cytotoxic surface antibodies are found in 20% of the total congenital rubella population, including in more than 50% in the time period before they develop diabetes and are not related to any specific HLA type. In addition, anti-microsomal and anti-thyroglobulin antibodies are found in 34% of this population. The data demonstrate that Type 1 diabetes developing in congenital rubella patients has the genetic and immunological features of classical Type 1 diabetes, namely the presence of HLA-DR3, the absence of HLA-DR2, islet cell surface antibodies before decompensation and an increased prevalence of anti-thyroid antibodies. Patients with non-diabetic congenital rubella represent an easily identifiable group in whom other immunological factors associated with Type 1 diabetes can be elucidated and possibly modified.