The extracts of a certain African plant species, Euphorbia tirucalli, were found to have markedly enhancing effects on the activation of latent Epstein-Barr virus (EBV) genomes in the EBV carrying lymphoblastoid cells and also on EBV-induced transformation of human lymphocytes. The Euphorbia tirucalli was especially noticeable in highly endemic areas of Burkitt's lymphoma (BL), an EBV-associated malignancy, in Kenya and Tanzania. The activation of the latent EBV genome and the EBV-induced transformation enhancement were also observed with the soil and drinking water taken around the plants, strongly indicating that the people living in BL endemic areas are frequently exposed to such an EBV-enhancing plant promoter substance.
The abilities of peripheral blood lymphocytes from 9 patients with adult T-cell leukemia (ATL) and 14 healthy control adults to cause regression of proliferating B-cell foci induced by Epstein-Barr virus (EBV) were examined. Marked regression of EBV-transformed B-cell foci was observed in lymphocytes from all 10 EBV-seropositive donors but with none of those of the 4 EBV-seronegative donors in the control group. The lymphocyte of all 9 patients with ATL, who were EBV-seropositive, caused little or no regression of B-cell foci like those of EBV-negative healthy donors. These results suggest that the absence of regression of EBV-induced B-cell proliferation observed in ATL patients is due to impairment of EBV-specific killer T-cell activities.
Infection with the human immunodeficiency virus (HIV) leads to selective depletion of the helper/inducer lymphocyte subset and a subsequent state of acquired cellular immunodeficiency. Simultaneously, evidence of B-cell hyper-activity may exist. A subset of patients infected with HIV demonstrates a syndrome of persistent generalized lymphadenopathy (PGL). Lymph node biopsies reveal benign reactive changes with a pattern of florid follicular hyperplasia. A polyclonal hypergammaglobulinemia reflects humoral immune dysfunction. Patients with PGL are similar to those with full-blown AIDS with regards to demographics, immune and virologic studies. Our prospective natural history study of PGL patients initiated in November 1981 reveals a 15% rate of evolution to AIDS in the 200 patient cohort. Factors associated with increased risk of transformation to AIDS include severity of constitutional symptoms, shrinking adenopathy, oral candidiasis or viral hairy leukoplakia, peripheral cytopenias, elevated erythrocyte sedimentation rate or an antecedent episode of herpes zoster. Therapeutic interventions to prevent evolution to AIDS in high risk subsets of lymphadenopathy patients have been investigated. In addition to benign B-cell proliferation associated with HIV infection, malignant lymphomas have also been diagnosed in 29 patients in AIDS risk groups in our clinic population. All patients were male; 26 homosexuals, 2 IV drug abusers and 1 multiply transfused sickle cell anemia patient. Seven patients had antecedent PGL. Non-Hodgkin's lymphoma was diagnosed in 19 patients. Histologies were predominantly diffuse undifferentiated or large cell. Eleven patients were Stage IV at diagnosis. Of 10 patients with mixed cellularity Hodgkin's disease, 7 were Stage IV-B at presentation. Extranodal disease was frequent in patients with lymphomas. Fourteen patients lacked peripheral lymphadenopathy. Response to chemotherapy was good, but complicated by prolonged marrow suppression and development of AIDS-related opportunistic infections. Median survival was 7 months. Laboratory studies investigating the possible role of lymphotropic retroviruses in the development of AIDS-related lymphomas revealed that serum from all patients with high grade non-Hodgkin's lymphoma contained antibodies to HIV and that the majority also expressed antibodies to HTLV-I. This degree of seroreactivity to HTLV-I and HIV was characteristic only of lymphoma patients as sera from only 10 - 15% of AIDS and ARC patients in San Francisco had similar findings.
Serum samples from 850 individuals from Venezuela were tested for the presence of antibodies to HTLV-III/LAV virus, the probable etiological agent of acquired immune deficiency syndrome (AIDS). At the time of the study, none of the individuals tested had symptoms indicative of AIDS or related disorders. Viral antibodies were assayed by indirect immunofluorescence (IF) assay, using a chronically infected, HTLV-III/LAV producer cell line CEM/LAV-NIT established in our laboratory. Twenty individuals (2.5%), 8 of them (40%) female, were seropositive by IF and by confirmatory Western blotting and radioimmunoprecipitation assays. The seropositivity rate ranged from 2.4% (11 of 465) in the general healthy population, 4% (2 of 50) among patients with Chagas' disease, and up to 29.2% (7 of 24) among patients with acute malaria infection. The titers of HTLV-III/LAV antibodies ranged from 1:40 to 1:640. In addition, 2 of 36 patients with hemophilia A (5.5%) also had antibodies to HTLV-III/LAV. Two of 7 patients with acute malaria had specific antibodies both to HTLV-III/LAV and HTLV-I, as determined by IF and Western blotting. None of over 169 randomly chosen, healthy blood donors from seven major Venezuelan cities, as well as none of 99 patients with leukemia/lymphoma, had antibodies to HTLV-III/LAV. The presence of specific antibodies among various Venezuelan populations indicates that HTLV-III/LAV, or a closely related cross-reactive virus, is indigenous in Latin American subjects as was previously indicated for tropical populations of central Africa. Isolation and characterization of this virus will help to understand the origin and etiology of AIDS.
Transcription of Epstein Barr virus (EBV) genome during immortalization of tonsil lymphocytes was studied. Cytoplasmic poly(A) RNA was Northern blot hybridized with 32P-labeled cloned EBV fragments. A 5.1 kb band was detected by hybridization with BamHI-H, -F, -K, -A and het fragments. The implication of this finding is discussed. DNA obtained from cells established from a colony of immortalized tonsil lymphocytes in 0.4% soft agar was found to transform NIH 3T3 cells. The transformed cells were able to induce tumor in nude mice, although the originally established lymphocytes from the colony did not. This may indicate that a certain population of EBV immortalized cells may contain a potentially oncogenic gene which can function as an oncogene in NIH 3T3 cells.
Ten isolates of Cryptococcus neoformans recovered from individual patients with the acquired immunodeficiency syndrome (AIDS) were studied in conjunction with three other isolates from non-AIDS patients. On primary culture nine out of ten of the AIDS isolates grew as nonmucoid, dry, pasty colonies resembling those produced by "diphtheroids." One isolate formed moist colonies. In contrast, the three non-AIDS Cryptococcus neoformans isolates produced highly mucoid colonies. India ink mounts of primary cultures of the ten AIDS isolates after 48 hours incubation in 5% CO2 showed markedly smaller capsules than the three non-AIDS isolates. India ink preparations of fresh cerebrospinal fluid of two specimens from AIDS patients in which capsule sizes were systematically determined showed a few moderately encapsulated cells dispersed among numerous others that were poorly encapsulated. This observation was confirmed in mucicarmine-stained smears of cerebrospinal fluid. Poorly encapsulated Cryptococcus neoformans seem to be associated with infections in AIDS patients.
NZ rabbits were treated with various combinations of enemas and intrarectal insemination (1 or 3 ml of semen a week) to investigate the effects of intestinal uptake and immunogenicity of seminal components and of an unrelated antigen, bovine serum albumin (BSA), given simultaneously. For 5 months the treatment was limited to enemas and/or semen, and total immunoglobulins and antisperm and antilymphocyte antibodies were determined. Then, without interruption of the treatments, the animals received two courses of three consecutive daily intrarectal administrations of BSA, and the humoral response was determined 7 days after each course of administration. Only 1 of 18 intrarectally inseminated animals responded with production of antisperm antibodies; none had antilymphocyte antibodies. Total immunoglobulins, however, were significantly increased in animals receiving enemas alone (p less than 0.02) or followed by insemination (p less than 0.05). The humoral response to BSA was significantly (p less than 0.01) enhanced by prior administration of enemas but was moderately reduced by simultaneous administration of semen, in a dose-related fashion.
Seroepidemiological, clinical, immunological, and pathological features were studied in 315 intravenous drug abusers (IVDA) seen in five centers for drug addicts' assistance in the Friuli Venezia-Giulia region of Italy, close to the borders of Austria and Yugoslavia. No case of AIDS has been observed. Sixty-five (21%) were affected by persistent generalized lymphadenopathy (PGL). HTLV-III seropositivity was noted in 86 (27%) of the overall 315 IVDA, in 50 (77%) of 65 patients with PGL, and in 1 (0.5%) of 205 blood donors tested as a control group. Patients with PGL had a significantly lower OKT4/OKT8 ratio than the rest of the IVDA population and controls. Systemic symptoms were present in 52% of the patients with PGL, the most frequent symptoms being fatigue and night sweats. In 20 patients with PGL, DR typing revealed a significant increase in DR-5 frequency and a significant decrease of DR-2 frequency. The predominant histological features in the lymph nodes taken from 25 patients consisted of an exuberant follicular hyperplasia, capillary vessel proliferation, and plasmacytosis. Nineteen (22%) females reporting occasional prostitution were compared to 10 non-IVDA female prostitutes and concomitantly evaluated. HTLV-III seropositivity was noted in 11 (58%) of 19 IVDA female prostitutes and in none of the 10 non-IVDA prostitutes. Thirty-five couples composed of both IVDA were compared to 24 couples composed of an IVDA and a non-IVDA. Among the 24 couples of whom one or both partners were seropositive, concordance in HTLV-III seropositivity was present in 5/11 (45%) couples composed of both IVDA, and in only 1/13 (8%) couples composed of an IVDA and a non-IVDA. This suggests that the sharing of contaminated needles, universally practiced by our IVDA population, plays a more important role in the transmission of HTLV-III than sexual contact.
Using ELISA, Western blots and immunofluorescence techniques, we identified seropositivity for lymphadenopathy-associated virus/human lymphotropic virus-III (LAV/HTLV-III) in 4 of 18 hemophiliacs and 1 AIDS patient. The four seropositive patients had received factor VIII prepared by Armour Company. The hemophiliacs are all asymptomatic. Given this documentation of introduction of LAV/HTLV-III into China, a national surveillance program is underway.
Prevention of EBV-associated lymphoproliferative diseases in immune deficient individuals is preferred; however, standard therapy for the B cell lymphomas has been successful. Chemotherapy must be given cautiously lest further immune compromise result in opportunistic infections. Recently, Acyclovir has decreased morbidity of patients with acute infectious mononucleosis in immune competent persons. In contrast, immunodeficient patients with X-linked lymphoproliferative (XLP) syndrome do not seem to respond favorably. Hence, a prospective study is underway using prophylactic immunoglobulin containing (EBV)-specific antibodies. The mortality rate is 85% following EBV infection in XLP due to fatal infectious mononucleosis associated with fulminant hepatitis and virus-associated hemophagocytic syndrome, acquired hypogammaglobulinemia or malignant B cell lymphoma. We can detect XLP by noting failure of switching from IgM to IgG antibody production on secondary challenge with bacteriophage phi X174. Also, linkage studies with the XLP locus using restriction fragment length polymorphisms are being done to detect affected males pre-EBV infection. Our rationale for prevention of phenotypes of XLP is based on observations that infants in tropical Africa and males with XLP do not develop EBV-induced diseases while neutralizing maternal antibodies are present. An EBV vaccine will be used, when available, in seronegative males with XLP. Prevention of acquired immune deficiency by screening blood for human immune deficiency virus, encouraging prudent life styles, development of specific immunosuppressive agents, development of new antiviral agents (i.e., DHPG), and identification of high risk seronegative patients offer possibilities for preventing life-threatening EBV-induced diseases.
Lymphomas occurred in 3 of 16 Japanese patients with ataxia telangiectasia (AT) and Wiskott-Aldrich syndrome (WAS). The patients had a persistently reactivated Epstein-Barr virus (EBV) infection with a remarkable decrease in virus-specific cellular immunity. In these patients, the B lymphocytes were more sensitive to EBV-induced events and to cellular proto-oncogene activation than seen in the healthy counterparts. This immunologic and genetic background was considered to explain the massive lymphoproliferation in these primary immunodeficiency disorders.
Plasma proteins of patients with AIDS, ARC, hemophilia A, and some viral infections were studied using various electrophoretic techniques, and compared to healthy control subjects. On isoelectric focusing (IEF) gels the most prominent and consistent finding was a marked increase in a basic protein band (AABP) at pI approximately equal to 9.0 in plasma samples derived from AIDS and hemophilia A patients. Using SDS gels, we noted an increased amount of protein in the 90 KD region in AIDS patients as compared to control subjects. On two dimensional gels (2D gels) basic protein(s) with pI congruent to 8.1-9.0 and molecular weight of approximately 90 KD were noted to be increased. In addition, a basic protein of 27 KD along with two acidic proteins in the low molecular weight region were also elevated in AIDS plasma. Although a limited number of samples were analyzed, it seems probable that a number of proteins are altered in AIDS plasma. AABP stained positive with periodic acid Schiff (PAS) reagent, indicating that it is a glycoprotein. This protein did not bind to an anti-IgG sepharose column, suggesting that it is not an immunoglobulin. The purified protein also did not react with antibody to fibrinogen and hemoglobin beta-chain. There are many changes in the plasma protein pattern of AIDS and hemophilia A patients as compared to normal controls.
Out of 100 male homosexual persons screened for AIDS, 54 were found to be HTLV-III antibody positive. Of these, 34 (63%) had a positive history of syphilis, as compared to 16 (35%) of the 46 HTLV-III antibody negative persons (P less than 0.01). In the HTLV-III antibody positive group 12 (22%) had had more than three syphilis infections as compared to none in the negative group (P = 0.02). The frequency of a previous primary, secondary, and latent syphilitic infection was different in the two groups. During the 1970s and early 1980s the incidence of syphilis in the U.S.A. and in Denmark was increasing, but from 1982 the incidence decreased markedly, possibly a consequence of the fear of AIDS, which appeared in 1981-82. It is speculated that the high frequency of syphilis among homosexual men might have been a co-factor for the acquisition of the HTLV-III infection.
We investigated the distribution of autologous rosette forming cells (ARFC) in the peripheral blood from subjects at risk for the acquired immunodeficiency syndrome (AIDS). The mean percentage of ARFC with autologous plasma from 35 male homosexual individuals was significantly lower than that of 31 normal controls. The mean percentage of ARFC of SARA had a direct linear correlation with the percentage of T4+ cells (p less than 0.01). Within the SARA group, those with antibodies against HTLV-III/LAV had percentages of ARFC significantly lower than SARA with negative antibodies. Plasma from SARA decreased the percentage of ARFC of normal cells when compared to normal homologous plasma (p less than 0.005), whereas normal homologous plasma did not modify the low percentage of ARFC from SARA. These results indicate that SARA possess a depletion of this subpopulation of T cells. This is more pronounced in subjects with anti-HTLV-III/LAV antibodies. The low ARFC is related to a decrease in the number of cells that correlates with the number of T4+ cells. The inhibition of normal ARFC by plasma from SARA suggests the existence of plasma factors that could mask the lymphocyte receptors for their own red blood cells and/or coat erythrocytes preventing lymphocyte-erythrocyte binding.
Azimexon, a 2-cyan-aziridinyl immune modulator, was given at a dose of 250 mg/m2/day for 10 days IV to 12 patients with AIDS and 16 with AIDS related complex (ARC). A decrease in total number of AIDS related symptoms from 43 to 24 and in mean number from 2.6 to 1.5 was observed among ARC patients (p less than .01). The most commonly improved symptoms were diarrhea, fatigue, and weight loss with the least frequently improved being lymphadenopathy. The following improvements in immune parameters were observed among ARC patients. DTH to recall antigens improved with an increase in number of positive tests from 35 to 47 and in mean number of positive skin tests from 2.2 on day 0 to 2.9 on day 14 (P less than .05). The geometric mean of the absolute lymphocyte count was 1.395 X 10(3)/microliter on day 0 with a significant increase of 18.0 percent on day 5 (P less than .01) and a 7.7 percent increase on day 21. The geometric mean of the OKT4+ cells on day 0 was 0.250 X 10(3)/microliter with a 33.3 percent increase on day 5 (P less than .07) and a 14.1 percent increase on day 21. T4/T8 ratio increased by 32.7 percent on day 5 (P less than .05) and by 19.4 percent on day 21 from an initial geometric mean of 0.339 X 10(3)/microliter on day 0. The geometric mean of GVH responses increased by 18.2 percent on day 5 (P less than .05) and by 24.0 percent on day 21 (P less than .07) from an initial value of 41.04 mm3. No symptomatic or immunologic improvements were observed among AIDS patients, but rather a significant decrease in mitogenic responses. PHA responses decreased by 70.3 percent on day 5 (P less than .05) and 42.2 percent on day 21 from an initial geometric mean of 4.02 X 10(3) cpm/10(3). Con-A responses decreased by 75.1 percent on day 5 (P less than .05) and increased by 20.3 percent on day 21 from an initial value of 1.14 X 10(3)/10(5) cells. Pretreatment number of absolute OKT4+ cells was the most significant prognostic survival variable. Thus, 8/9 patients with less than 0.10 X 10(3) OKT4+ blood cell/microliter subsequently died as compared to only 1/17 with greater than or equal to 0.10 X 10(3) OKT4+ cells (p less than .001). The only toxic effect of this treatment was mild hemolysis which disappeared upon cessation of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
A forty-two year-old male homosexual with the acquired immunodeficiency syndrome (AIDS) developed Listeria monocytogenes septicemia and meningitis. The gastrointestinal tract was the likely portal of entry. The patient was treated with intravenous ampicillin with complete and permanent resolution of his listerial infection. Although L. monocytogenes infection has been reported as an uncommon complications of AIDS, we are unaware of Listeria meningitis being previously reported in an AIDS patient. It is hoped that this case report will alert health care workers to the possibility of Listeria infection in AIDS patients, particularly since this infection responds well to readily-available antibiotic therapy. The microbiology, epidemiology, clinical, and neurologic aspects of listerial infection and general aspects of the acquired immunodeficiency syndrome are discussed.
