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Type D retroviruses have recently been shown to induce a wasting syndrome with associated lymphadenopathy, thymic atrophy and transient decreased peripheral blood lymphocyte blastogenic responsiveness in juvenile macaque monkeys. The replication in vitro of D/New England virus was assessed in various lymphocyte subpopulations to determine the possible pathogenesis of the immune dysfunction induced by this virus. While D/New England did not replicate in cultured T lymphocytes or induce any demonstrable dysfunction of T cells in vitro, it did grow in the cells of the B lymphocyte lineage. D/New England growth occurred in vitro in African Burkitt's lymphoma and pre-B cell lines, but not in Epstein-Barr virus-transformed normal B lymphocytes. The infection of a restricted B lymphocyte population by this primate type D retrovirus may play a role in the aetiology of the immune abnormalities which it induces.

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The stability in vivo and circulatory clearance of immunotoxins were assessed in rhesus monkeys. The immunotoxins studied were T cell-specific monoclonal anti-T11 antibodies conjugated by disulfide linkage to ribosome-inactivating toxins. Intact immunotoxin was detectable in the circulation of the monkeys following a single intravenous infusion. This was demonstrated by quantitative flow-cytometric analysis, gel-filtration, and sodium dodecyl sulfate-gel electrophoresis. This intact conjugate was shown to be functional in the plasma of the infused animals in an in vitro cytotoxicity assay. However, a number of factors contributed to bring the level of circulating immunotoxin to a less than optimal level. When conjugated to a ribosome-inactivating toxin, the antibody was cleared more rapidly than was the native antibody. Furthermore, following infusion, some breakdown of the conjugate occurred, resulting in the generation of detectable levels of circulating free antibody. The present data indicate the feasibility of using immunotoxins as therapeutic tools in man.

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The type C retrovirus simian T-lymphotropic virus type III (STLV-III) has been isolated recently from immunodeficient macaque monkeys at the New England Regional Primate Research Center. The present studies were done to define the in vitro growth characteristics of this agent. STLV-III replicates efficiently in interleukin 2-dependent T-cell cultures of macaque peripheral blood lymphocytes (PBL), less efficiently in such cultures of human and gibbon PBL, and inefficiently in baboon PBL. No replication, as assessed by measuring reverse transcriptase activity in these culture supernatants, could be detected in similarly maintained cultures of chimpanzee, squirrel monkey, and cotton-top tamarin PBL. Like the human acquired immunodeficiency syndrome (AIDS) virus, human T-cell lymphotropic virus III/lymphadenopathy-associated virus (HTLV-III/LAV), STLV-III replicates in T4+ but not T8+ lymphocytes and its infection of macaque and human lymphocytes can be blocked with monoclonal anti-T4 antibodies. STLV-III differs from the human AIDS virus, however, in its apparent inability to grow in the Epstein-Barr virus-transformed B lymphocytes tested, the differing range of nonhuman primate T-cell populations that support its growth, and its less striking toxicity for T lymphocytes. These studies provide further characterization of an agent that will be extremely important in facilitating the development of vaccines and antiviral therapy for AIDS.

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The effects of in vivo administration of three monoclonal antibodies specific for T11, the E rosette receptor on T lymphocytes, were examined in the rhesus monkey (Macaca mulatta). These three monoclonal antibodies were of different isotypes and were shown in in vitro studies to have differing affinities for the monkey T11 structure. Furthermore, each antibody induced antigenic modulation of T11 from the cell membrane of the lymphocytes to varying degrees in vitro. In vivo infusion of each of these antibodies into normal rhesus monkeys caused remarkably different effects on the circulating T lymphocyte pool. Infusion of these antibodies at doses of 2 mg/kg caused the coating of circulating T lymphocytes with antibody, the modulation of T11 off the T cell surface and the transient clearance of T cells from the circulation. Yet, the variation in the extent to which these effects were seen with these different antibodies indicates that extrapolating from studies of the in vivo use of one antibody to the use of another may be quite difficult. These studies clearly indicate the strengths of this nonhuman primate system for exploring the uses of monoclonal antilymphocyte antibodies as therapeutic agents. They, however, also demonstrate that differences may exist in the affinity of a particular antibody for homologous lymphocyte surface structures in humans and in a nonhuman primate species. These differences may make it difficult to predict the precise effects that the infusion of an antibody will cause in humans on the basis of alterations it induces in nonhuman primates.

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In 1974, an 11-year-old white boy with the X-linked lymphoproliferative syndrome developed hyper-IgM after becoming infected with Epstein-Barr virus. However, he failed to develop normal immune responses against the virus. In December 1981, when red cell aplasia occurred, he was given packed erythrocytes and gammaglobulin. Nine weeks later, acute infectious mononucleosis developed. Concurrently, his T4/T8 helper/suppressor ratio decreased from 2.7 to 0.2, and IgM antibodies to Epstein-Barr virus appeared. Subsequently, circulating B cells became undetectable in his blood, and agammaglobulinemia appeared. Red cell aplasia abated transiently. This patient's course was complicated by Haemophilus influenzae and Mycobacterium tuberculosis pneumonias, and red cell aplasia and agammaglobulinemia have persisted. Epstein-Barr virus acting as a slow virus probably induced the red cell aplasia and agammaglobulinemia because of the aberrant immune responses to Epstein-Barr virus. Immunodeficient responses to Epstein-Barr virus should be sought in other patients with the diseases documented in our patient.

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Male homosexuals at risk for developing AIDS frequently exhibit chronic lymphadenomegaly (LAD). They are at high risk for developing malignant B cell lymphomas. A study of Epstein-Barr virus (EBV) revealed marked abnormalities in these patients. One hundred percent of the patients were seropositive. The patients with most severe acquired immune deficiency disorders manifested a decreased number of circulating B cells with EBV receptors and decreased lymphocyte transformation. Patients often showed defective memory T cell cytotoxic responses to autologous EBV infection in vitro. Three of five lymph node specimens contain significant EBV genome copies to suggest a significant etiologic role. In addition, a Burkitt-like lymphoma carried EBV genome. Although all of the men were seropositive for EBV, reactivation patterns were not as common as anticipated. Given the presence of EBV genome in the lymph nodes of the patients who lack anti-early antigen (EA) antibodies indicative of reactivation, we suggest that reliance on serology to indicate EBV involvement is insufficient for assessing the patient. The detection of a t(8;14) transposition in the monoclonal mu kappa Burkitt-like lymphoma containing EBV genome supports the view that cytogenetic transposition is a mechanism in lymphomagenesis.

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Eleven males with XLP were evaluated for EBV-specific antibodies during periods of 2 to 7 yr. Variable responses to EBV-specific antigens were found. All 11 patients had subnormal anti-EBNA titers, which probably reflected a T cell deficiency. The patients showed four different patterns in their anti-VCA response: 1) two boys who had experienced malignant lymphoma mounted no antibodies at all; 2) two patients showed intermittent anti-VCA titers; 3) four males had persistently elevated anti-VCA titers; and 4) three patients showed normal anti-VCA titers. ADCC against EBV-infected cells was abnormally low in six patients and was elevated in two patients given gamma-globulin. ADCC titers did not correlate with anti-VCA titers. However, most patients with XLP failed to effect regression of autologous EBV-infected lymphoblastoid cell lines, indicating a deficiency in long-lived T cell-mediated immunity to EBV.

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Surface phenotypic markers and the function of lymphocytes in patients affected with the X-linked lymphoproliferative syndrome (XLP) were studied. This syndrome is characterized by a defective response to infection with Epstein Barr virus (EBV). Normal numbers of B and T cells were detected with anti-Ig and monoclonal OKT3 antisera, respectively. T cell subset values, however, were persistently altered: cells reacting with OKT8 were significantly elevated in five of nine patients, accompanied by a slight decrease in the percentage of OKT4-positive cells, leading to abnormally low OKT4 to OKT8 ratios. One patient had a high OKT4 to OKT8 ratio due to low number of OKT8-positive cells. Lymphocytes from patients showed normal proliferation after stimulation with T and B cell mitogens. In contrast, Ig synthesis by lymphocytes after stimulation with B cell mitogens was markedly deficient: low or undetectable levels of one or all classes of Ig were detected, whereas cell lines established from EBV-infected B lymphocytes from patients produced normal quantities of Ig. These studies imply immune regulatory impairments in the patient with XLP.

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Acquired immune suppression accompanying normal pregnancy may be associated with reactivation of Epstein-Barr virus (EBV). Pregnant women with reactivated EBV having anti-EA antibodies show high titers of antiviral capsid antigen (VCA) geometric mean titers (GMT) of 522 versus 170 in those lacking anti-early antigen (EA). Among twenty-seven seropositive women at parturition, 17 (63%) had generated antibody to EA, and all 27 (100%) demonstrated significant increases in antibody to VCA (p less than 0.01). In contrast, antibody titers to cytomegalovirus, herpes hominis, varicella-zoster, and rubella viruses in the pregnant women were comparable to those found in nonpregnant controls. (Am J Reprod Immunol. 1982; 2:217-221.)

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Analyses of 100 subjects with the X-linked lymphoproliferative syndrome (XLP) in 25 kindreds revealed four major interrelated phenotypes: infectious mononucleosis, malignant B-cell lymphoma, aplastic anemia, and hypogammaglobulinemia. Eighty-one of the patients died. Two male subjects were asymptomatic but showed immunodeficiency to Epstein-Barr virus (EBV). Seventy-five subjects had the infectious mononucleosis phenotype and concurrently, 17 subjects of this group had aplastic anemia. All subjects with aplastic anemia died within a week. Aplastic anemia did not accompany hypogammaglobulinemia or malignant lymphoma phenotypes. Hypogammaglobulinemia had been detected before infectious mononucleosis in three subjects, after infectious mononucleosis in five subjects, and was not associated with infectious mononucleosis in 11 boys with hypogammaglobulinemia. In nine subjects infectious mononucleosis appeared to have evolved into malignant lymphoma; however, the majority of patients with malignant lymphoma showed no obvious antecedent infectious mononucleosis. One subject had infectious mononucleosis following recurrent malignant lymphoma. Twenty-six of 35 lymphomas were in the terminal ileum. Results of immunologic and virologic studies of 15 survivors revealed combined variable immunodeficiency and deficient antibody responses to EBV-specific antigens. Mothers of boys with XLP exhibited abnormally elevated titers of antibodies of EBV. Subjects of both sexes with phenotypes of XLP should be investigated for immunodeficiency to EBV. Persons with inherited or acquired immunodeficiency may be vulnerable to life-threatening EBV-induced diseases.

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The asymptomatic hemizygous female carriers of the X-linked lymphoproliferative syndrome (XLP) have abnormal antibody responses to EBV. This suggests partial expression of the defect that leads to EBV-provoked life-threatening diseases in their affected sons. EBV specific antibodies were measured in 65 serum samples of 12 obligate carrier females and seven of their daughters (females at risk) during periods ranging from 1 to 5 yr. Abnormal qualitative antiviral capsid antigen (VCA) IgG titers were nearly fourfold higher than normal controls, two carriers had persistent IgM anti-VCA antibody, two-thirds had persistent IgA anti-VCA antibody, and half of the women had titers to early antigen (EA). Five of seven females exhibited a similar persistent pattern. In contrast, none of the unaffected family members nor 23 normal controls expressed IgA or IgM titers to VCA even with high exposure to the virus, and anti-EA was detected in only one control. Therefore, these findings may prove useful for detecting carriers of the syndrome. Abnormal anti-EBV titers similar to the carrier pattern have been reported in patients and other immunosuppressed individuals, and are indicative of active viral infection.

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