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We studied the interrelation among herpes-virus infections, T-lymphocyte subsets, opportunistic infections, and renal histopathology in 28 recipients of renal allografts. All primary or reactivated herpesvirus infections occurring in the first three months after transplantation in recipients of cadaveric grafts accompanied persistent inversions in the ratio of OKT4 (helper/inducer) to OKT8 (cytotoxic/suppressor) lymphocytes. In the less heavily immunosuppressed recipients of organs of living related donors, these inversions were seen only in association with clinically apparent cytomegalovirus infections. Five of seven opportunistic infections occurred in patients with OKT4/OKT8 ratios of less than 1.0. Biopsy specimens from patients with renal dysfunction occurring in association with a low OKT4/OKT8 ratio frequently revealed glomerular damage rather than acute cellular rejection. Monitoring of T-lymphocyte subsets provides early evidence of herpesvirus infections and identifies patients at increased risk for opportunistic infection after renal transplantation.

Peripheral blood T-lymphocyte populations were monitored sequentially in diabetic recipients of renal allografts. Unfractionated buffy coat preparations were reacted with the murine monoclonal antibodies, OKT3 (all circulating T-cells), OKT4 (helper/inducer/regulatory T-cells), and OKT8 (cytotoxic/suppressor cells). Levels of peripheral blood lymphocyte subpopulations of diabetic patients monitored prior to transplantation revealed no significant abnormalities. Following transplantation, but prior to any therapy for acute rejection, the mean percentage of OKT3, 4, and 8 reactive cells in diabetic recipients closely resembled those observed in nondiabetic recipients. After treatment for acute rejection, a marked decrease in the mean OKT4/OKT8 ratio from normal (1.90 +/- 0.7) was observed in both diabetic (1.04 +/- 0.5), and nondiabetic (1.35 +/- 0.5) allograft recipients. Eleven of thirteen diabetic recipients with long-term functioning allografts were found to have a depressed OKT4/OKT8 ratio (mean 1.03 +/- 0.6). T-cell subset monitoring of diabetics with end-stage renal failure failed to reveal any significant differences from nondiabetic, uremic patients. The high incidence (75%) of allograft rejection noted in these diabetic allograft recipients similarly suggests normal immunocompetence. Following successful completion of rejection therapy, however, reduction in the ratio of OKT4 to OKT8 reactive cells suggests that an alteration in immune responsiveness has occurred. Immunological monitoring of these long-term diabetic recipients with functioning allografts suggests that the observation of a consistently depressed OKT4/OKT8 ratio may (1) be useful in predicting continued allograft function and (2) prompt the more rapid reduction of steroid medication to maintenance dosage since this pattern may be indicative of subclinical viral infection.

A combination of antiviral therapies that target different sites in the human immunodeficiency virus type 1 (HIV-1) replicative cycle may be necessary for optimal treatment of HIV-1 infections. We evaluated the interactions of a soluble virus receptor (recombinant soluble CD4 or rsT4) and a reverse transcriptase inhibitor (azidothymidine, AZT) against HIV-1 replication in vitro. A variety of cell types was studied including peripheral blood mononuclear cells, a CD4-positive T-cell line, and a CD4-positive human monocyte cell line. The combination of rsT4 and AZT inhibited HIV-1 synergistically over a broad range of drug concentrations and multiplicities of infection in several different HIV-1 replication assays. Drug interactions were evaluated by the median-effect principle and the isobologram technique using a computer analysis. In all of the cell types tested, combinations of rsT4 and AZT were synergistic in vitro, without additive cytotoxicity.

We have applied a panel of monoclonal antibodies against antigens present on the surface of human mononuclear cells to the study of mononuclear cell surface antigens expressed by seven species of New World primates. Antibodies to the sheep erythrocyte receptor (OKT11a) to a thymocyte antigen (OKT10), to the I region of the major histocompatibility locus (OKIa), and to an antigen found on the surface of human monocytes (OKM1) cross-reacted with mononuclear cell surface antigens of most of the species studied. Antibodies to antigens which have been correlated with functional capabilities in the human system (OKT4, OKT5, OKT8, 3A1) were much less reactive with platyrrhine mononuclear cells. These reagents may be quite useful in studies of primate phylogeny and immunology.

We have developed a monoclonal antibody that detects the first human B-cell-specific differentiation antigen expressed on transformed B lymphoblasts. The antigen is termed B-LAST 1 and is found on B cells transformed in vitro with Epstein-Barr virus (EBV) and pokeweed mitogen; in vivo with EBV and antigen; and on neoplastic B cells from chronic lymphocytic leukemia and poorly differentiated lymphoma. The antigen has a molecular weight of 45,000 and was not found on cells of T, null or myeloid lineage, whether obtained from peripheral blood, lymph nodes, neoplasms or cell lines. The antigen is expressed at a much higher level on EBV-infected cells than on any other cell type studied, but does not appear to be virally encoded. The significance of this antigen in the process of viral and nonviral transformation and its possible role as a target for T-cell-mediated immunity against virus-infected cells is discussed.

The detection of human immunodeficiency virus (HIV)-associated antigens was simplified by the application of dot immunobinding on a nitrocellulose matrix. Antigens were detected by applying the polyethylene glycol-precipitated supernatants of experimentally infected cultures directly onto nitrocellulose strips and sequentially incubating the strips with an anti-HIV antiserum and an alkaline phosphatase-conjugated, species-specific antiserum. The immune reaction was developed by adding the precipitable substrate indoyl phosphate. The dot immunobinding assay was nearly as sensitive as the reverse transcriptase assay in detecting HIV antigens in experimentally infected peripheral blood mononuclear cells, as well as in a T-cell line. The technique was also useful in the in vitro evaluation of antiviral agents. The dot immunobinding assay is a simple and sensitive technique that is useful in the detection of HIV antigens in studies of viral pathogenesis.

We have previously demonstrated that six weeks of prophylaxis with interferon-alpha delays cytomegalovirus excretion and decreases viremia in recipients of kidney transplants. In a double-blind trial to evaluate the effects of a longer course of prophylaxis, we gave either 3 X 10(6) units of interferon or placebo intramuscularly to 42 patients before transplant surgery was performed. After surgery, doses were given three times a week for six weeks and then twice a week for eight weeks (total of 102 X 10(6) units). Clinical signs of cytomegalovirus infection were markedly reduced in interferon recipients. These signs developed in 7 of 22 placebo recipients and 1 of 20 interferon recipients (P = 0.03). Opportunistic superinfections (Aspergillus fumigatus and Pneumocystis carinii) occurred only in patients given placebo. Cytomegalovirus-associated glomerulopathy developed in one interferon recipient and three placebo recipients. Survival of patients and grafts was equivalent in both treatment groups, and minimal toxicity was observed with interferon. In seropositive renal-transplant recipients, interferon-alpha affords effective prophylaxis against serious cytomegalovirus infections.

Virus-specific cytotoxic T lymphocytes (CTL) which kill virus-infected cells are thought to be a major host defence against viral infections. Here we report the existence of human immunodeficiency virus (HIV)-specific CTL in persons infected with this virus, the aetiological agent of AIDS (acquired immunodeficiency syndrome). Recombinant HIV-vaccinia viruses were used to express HIV antigens in B-cell lines established from subjects seropositive for HIV and seronegative controls. Circulating lymphocytes capable of killing HIV env-expressing autologous B cells were detected in eight of eight seropositive subjects; in addition, at least three seropositive subjects demonstrated gag-specific cytotoxic responses. No HIV-specific cytotoxicity was observed in seronegative subjects. Selective inhibition of the env-specific cytotoxicity by a CD3-specific monoclonal antibody indicates that the effectors are T cells. This demonstration of a cytotoxic T-cell immune response to HIV in infected individuals should prove useful in investigating the immunopathogenesis of HIV infection further and in evaluating AIDS vaccine strategies.

We conducted virus-isolation studies on 56 specimens from the nervous system of 45 patients in order to determine whether human T-cell lymphotropic virus Type III (HTLV-III) is directly involved in the pathogenesis of the neurologic disorders frequently encountered in the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex. We recovered HTLV-III from at least one specimen from 24 of 33 patients with AIDS-related neurologic syndromes. In one patient, HTLV-III was isolated from the cerebrospinal fluid during acute aseptic meningitis associated with HTLV-III seroconversion. HTLV-III was also isolated from cerebrospinal fluid from six of seven patients with AIDS or its related complex and unexplained chronic meningitis. In addition, of 16 patients with AIDS-related dementia, 10 had positive cultures for HTLV-III in cerebrospinal fluid, brain tissue, or both. Furthermore, we cultured HTLV-III from the spinal cord of a patient with myelopathy and from the sural nerve of a patient with peripheral neuropathy. These findings suggest that HTLV-III is neurotropic, is capable of causing acute meningitis, is responsible for AIDS-related chronic meningitis and dementia, and may be the cause of the spinal-cord degeneration and peripheral neuropathy in AIDS and AIDS-related complex.

A gene encoding a 113-amino acid, NH2-terminal fragment of CD4, rsT4.113, was constructed and expressed in Escherichia coli under the control of the tryptophan operon promoter. Following induction, rsT4.113 is produced at 5-10% of total E. coli protein, and it is found in inclusion bodies. The protein is purified in two steps under denaturing and reducing conditions. Solubilized rsT4.113 is first purified on a column of Q-Sepharose to remove low molecular weight contaminants and then purified to greater than 95% homogeneity by gel filtration. Renaturation of rsT4.113 is achieved at approximately 20% yield by dilution and dialysis. High performance liquid chromatography analysis of renatured rsT4.113 reveals a less than 15% contaminant of reduced protein. Purified and renatured rsT4.113 contains epitopes for both OKT4a and Leu3a, anti-CD4 monoclonal antibodies which block CD4-gp 120 association, but lacks measurable affinity toward a nonblocking anti-CD4 monoclonal antibody, OKT4. By comparison to a longer form (375 amino acids) of recombinant soluble T4 produced in mammalian cells that contains the entire extracellular domain, rsT4.113 has a comparable affinity for binding to OKT4a and Leu3a in a radioimmunoassay. Analysis of antiviral activity of rsT4.113 demonstrates that the E. coli-derived protein inhibits human immunodeficiency virus-induced syncytium formation with an IC50 of 5-10 micrograms/ml. These data demonstrate that the human immunodeficiency virus-binding domain of CD4 is localized within the NH2-terminal 113 amino acids of CD4 and is contained within a structure homologous to the kappa variable-like domain of immunoglobulins.

A radioimmunoassay was established for the human eosinophil granule major basic protein (MBP). The mean level of MBP in sera from 105 normal control patients was 454 ng/ml, whereas in a sample of 188 patients with various forms of diseases, including the hypereosinophilic syndrome, levels as high as 14,000 ng/ml were measured. Serum levels of MBP did not correlate with eosinophil counts in normal subjects, but a positive correlation was seen in patients with eosinophilia; the patients with eosinophil counts greater than 350/mm3 generally showed increased levels of MBP. Many patients with skin disease and normal eosinophil counts had elevated levels of serum MBP. Monomer MBP has a molecular weight of 9,300, but in sera of patients with eosinophilia, the MBP activity was of high molecular weight, greater than 50,000. Analyses of serum by Sephadex G-200 and by electrofocusing suggest that MBP is not simply polymerized, but rather is bound to a larger carrier molecule. Monomeric MBP can be isolated from serum by reduction of serum with dithiothreitol, alkylation with iodoacetamide, and acidification to pH 2 followed by fractionation on Sephadex G-50 at pH 2. Under these conditions, up to 80% of the MBP emerges in monomeric form. The results indicate that eosinophil granule proteins circulate in blood covalently bound to serum proteins, and that elevated concentrations of serum MBP are present in some diseases associated with eosinophilia.

The T-lymphocyte subset interactions in the cell-mediated response to Epstein-Barr virus (EBV) were studied in an in vitro system in which the ability of T lymphocytes to inhibit outgrowth of autologous EBV-transformed B lymphocytes is assessed. Inhibition could be demonstrated within lymphocytes of both the T4 and T8 surface phenotypes. Outgrowth inhibition was observed more frequently when the effector T-cell population contained cells of both surface phenotypes. In blocking experiments the OKT3 antibody completely prevents development of outgrowth inhibitory activity; the OKT4 and OKT8 antibodies were less effective in interfering with outgrowth inhibitory function. Maximal blocking activity occurred when antibody addition occurred in the early phase of generation of suppressor function. Pharmacologically achievable concentrations of interferon-alpha restored outgrowth inhibitory activity after blocking with monoclonal antibody. EBV reactivation was easily demonstrable in a group of 10 renal allograft recipients who received OKT3 antibody for treatment of acute rejection. These studies suggest that the immunoregulatory control of proliferation of EBV-transformed B lymphocytes is complex, and involves a collaborative interaction of lymphocytes of both the T4 and T8 surface phenotypes.

Important cardiac manifestations in the idiopathic hypereosinophilic syndrome include mitral regurgitation and peripheral embolization. To determine the anatomic basis of these abnormalities, real-time, wide-angle, two-dimensional echocardiography (2-D echo) was performed in 21 patients with the hypereosinophilic syndrome. Nine patients (43%) had clinical evidence of mitral regurgitation, and each had localized thickening of the posterobasal left ventricular wall behind the posterior mitral leaflet and absent (seven patients) or diminished (two patients) motion of the posterior leaflet. Anatomic observations at operation or necropsy in four patients with mitral regurgitation demonstrated that the echocardiographic abnormalities resulted from posterior mitral leaflet thickening and adherence of the leaflet to the underlying mural endocardium of the posterobasal wall. On 2-D echo, each of the six patients with peripheral emboli had either apical left ventricular echo-dense targets consistent with thrombus or thickening of the posterobasal wall of the left ventricle, and these findings were validated at autopsy or operation in three patients. Hence, in patients with the hypereosinophilic syndrome, 2-D echo is useful in identifying the probable etiology of two important cardiac manifestations. Thickening of the posterobasal wall is usually associated with impairment of posterior mitral leaflet function, resulting in mitral regurgitation. Because the hypereosinophilic syndrome is associated with peripheral embolization, thrombus formation and subsequent endocardial scarring, the noninvasive identification of intracavitary ventricular thrombi may be important.

Two patients developed fever, interstitial pneumonitis, and pancytopenia associated with extremely high titers of antibody to replicative antigens of the Epstein-Barr virus. In contrast to most patients seropositive for Epstein-Barr virus, neither patient had an antibody response to the Epstein-Barr nuclear antigen K polypeptide. In addition, virus isolated from one patient had a deletion of the B95-8 type in the EcoRI C region of the genome. An etiologic relation between Epstein-Barr virus replication and the clinical manifestations of this syndrome is further shown by the response of each patient to acyclovir therapy. These patients have a new Epstein-Barr-virus-associated syndrome and provide additional evidence that acyclovir may play a role in therapy for selected patients with Epstein-Barr virus infection.

We examined the long-term safety and efficacy of zidovudine therapy in 229 subjects with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex who previously participated in a placebo-controlled study of zidovudine. One hundred two placebo recipients (delayed treatment group) and 127 zidovudine recipients (original treatment group) were followed up while receiving zidovudine therapy for a mean of 21 months. Survival rates for the original treatment group were 84.5% and 57.6% at 12 and 21 months, respectively; for the delayed treatment group, 78.8% and 64.6% at 12 and 21 months, respectively, and 78.8% and 47.5% at 12 and 21 months, respectively, for 77 subjects with AIDS and 93.0% and 71.8%, respectively, for 50 subjects with AIDS-related complex in the original treatment group. Adverse reactions decreased over time and newly observed toxic reactions were unusual. The clinical course of these subjects suggests continued survival benefits with long-term zidovudine therapy.

Viral interactions may occur whenever a host is infected simultaneously with two viruses. Persons at high risk for acquired immunodeficiency syndrome (AIDS) may provide a substrate for such interactions. These could include complementary immunosuppression, potentiation of infection by altered receptors or genetic complementation, phenotypic mixing, or genetic recombination. The possibility of such interactions should be considered in the pathogenesis of AIDS.

Azidothymidine and ribavirin both inhibit replication of human immunodeficiency virus in vitro and show promise of clinical utility in patients infected with this virus. In this study, the possible interactions of these drugs were examined in vitro, and a reproducible antagonism between azidothymidine and ribavirin was found to occur under a variety of experimental conditions. The mechanism responsible for this antagonism appeared to be inhibition of azidothymidine phosphorylation by ribavirin. Because similar effects may occur in vivo, clinical trials of these two drugs in combination must be performed only under carefully controlled conditions.

An in vitro system for determining the efficacy of interferon alpha (IFN-alpha) in preventing B-cell outgrowth due to Epstein-Barr virus (EBV) was developed. Unfractionated cord blood mononuclear cells, T-cell-depleted cord blood mononuclear cells, or adult T-cell-depleted mononuclear cells were exposed to IFN-alpha for 18 to 20 h followed by incubation with the B95-8 strain of EBV for 2 h. B-cell outgrowth was monitored by microscopic examination, [3H]thymidine incorporation, and Epstein-Barr nuclear antigen detection. Cell density and viral inoculum both affected the sensitivity of outgrowth to IFN-alpha. IFN-alpha was most effective when added at each feeding after infection as well as before infection with EBV. The mean of the lowest IFN-alpha concentration tested at which transformation failed to occur after infection with the B95-8 strain of EBV at a 50% transforming dose of 10(2.0) to 10(3.0)/ml was similar for unfractionated cord blood mononuclear cells, T-cell-depleted cord blood mononuclear cells, and adult T-cell-depleted mononuclear cells. The B95-8 strain and clinical EBV isolates required similar IFN-alpha concentrations to prevent outgrowth. In this system, IFN-alpha at pharmacologically achievable concentrations prevented EBV-induced B-cell outgrowth. These data indicate that IFN-alpha deserves further study as a potential therapeutic agent for EBV-induced syndromes.

Characterization of the host immune response to human immunodeficiency virus type 1 (HIV-1) is critical to the rational design of an effective AIDS vaccine. In this study, cytotoxic T lymphocytes (CTL) specific for HIV-1 reverse transcriptase (RNA-dependent DNA polymerase) were found in blood samples from HIV-1-infected individuals. CTL targets were prepared by immortalizing B cells from ten seropositive and six seronegative individuals, and then infecting these cells with recombinant vaccinia viruses containing HIV-1 genes. CTL directed against autologous B lymphoblasts expressing HIV-1 reverse transcriptase were detected in fresh blood samples from eight HIV-1 seropositive subjects, but in no seronegative controls. The effector cells were identified as major histocompatibility complex-restricted CD3+CD8+ lymphocytes. Because the HIV-1 pol gene is highly conserved among different isolates and generates both humoral and cellular immune responses, it bears consideration for inclusion in a candidate AIDS vaccine.

The T-cell surface glycoprotein, CD4 (T4), acts as the cellular receptor for human immunodeficiency virus, type 1 (HIV-1), the first member of the family of viruses that cause acquired immunodeficiency syndrome. HIV recognition of CD4 is probably mediated through the virus envelope glycoprotein (gp120) as shown by co-immunoprecipitation of CD4 and gp120 (ref.5) and by experiments using recombinant gp120 as a binding probe. Here we demonstrate that recombinant soluble CD4(rsT4) purified from the conditioned medium of a stably transfected Chinese hamster ovary cell line is a potent inhibitor of both virus replication and virus-induced cell fusion (syncytium formation). These results suggest that rsT4 is sufficient to bind HIV, and that it represents a potential anti-viral therapy for HIV infection.

Phosphonoformate and recombinant alpha-A interferon synergistically inhibited the replication of human T-cell lymphotropic virus type III in cultured peripheral blood lymphocytes. T-cell proliferative capability was maintained by this combination, and toxicity was minimal.

Techniques presently available for detection of human T-cell lymphotropic virus type III (HTLV-III) antigens and antibodies are laborious or relatively nonsensitive. We adapted anticomplementary immunofluorescence (ACIF) for these purposes. In HTLV-III-infected cells, specific ACIF was demonstrated by a diffuse speckling pattern that often resulted in a peripheral cellular rim of fluorescence. A 97% concordance was demonstrated between the ACIF assay and other sensitive tests for HTLV-III antibody detection (Western blot and membrane immunofluorescence and fixed-cell immunofluorescence tests). The ACIF assay was both more sensitive and more specific when compared with the enzyme-linked immunosorbent assay. For detection of HTLV-III antigens, the ACIF assay appeared to be as sensitive as the reverse transcriptase assay and more sensitive, with less background reactivity, than the conventional immunofluorescence assay. The ACIF assay often detected low levels of HTLV-III antigens within 3 days of infection in vitro, compared with 5 to 7 days with the indirect immunofluorescence assay, and generally paralleled the reverse transcriptase assay. The ACIF assay is a simple, sensitive, and specific assay for detection of HTLV-III-related antigens and antibodies. It should prove useful in the diagnosis of HTLV-III infection, as well as in studies of pathogenesis.

By transfecting small fragments of Epstein-Barr virus (EBV) DNA into cells, we defined two nuclear antigens, termed M and K, and examined serum from 258 subjects for antibodies against these antigens. We hoped to learn whether such single-antigen systems would clarify the association of EBV with various diseases. Although reactivity to M antigen was found in only 14 per cent of healthy EBV-seropositive subjects, 90 per cent of Chinese and North African patients with nasopharyngeal carcinoma had antibody to M. Nearly all persons (96 per cent) who were EBV seropositive, as judged by their serologic reaction to a nuclear antigen encoded by the complete virus (EBNA), had a reaction to K antigen. However, serum samples from three patients with chronic active EBV infection did not react to K, even though the serum contained anti-M titers above 1:1000. Lymphoid cells from one such patient carried a normal gene for K and made K protein of correct size. Therefore, in this patient the absence of antibody to K had not resulted from a viral mutation that destroyed the K protein. These serologic studies show that some patients with chronic active EBV infection have an abnormal immune response to a specific viral gene product.

Both recombinant alpha A interferon and azidothymidine inhibit the replication of human immunodeficiency virus in peripheral blood mononuclear cells. Combinations of recombinant alpha A interferon and azidothymidine at concentrations that are easily achievable in patients synergistically inhibit human immunodeficiency virus in vitro with minimal toxicity. Combinations of antiretroviral compounds that act by different mechanisms may prove useful in the treatment of acquired immunodeficiency syndrome-related disorders.

In an attempt to examine further the association between active Epstein-Barr virus (EBV) infection and the chronic fatigue syndrome (chronic EBV syndrome, or chronic or atypical mononucleosis), antibodies acting against EBV-specific DNase and DNA polymerase, which are expressed only during virus replication, were assayed. Serum samples from 25 healthy EBV-seropositive individuals neutralized 3.5 +/- 5.1 U (mean +/- SD) of DNase activity and 14.7 +/- 8.5 U of DNA polymerase activity. From these values were selected upper limits of anti-EBV enzyme activity of 17.9 and 31.3 U neutralized in normal individuals, respectively (representing the 95% confidence limit). Serum samples from six groups of subjects representing a variety of EBV-related illnesses were then studied. Only patients with notably elevated anti-EBV antibody titers to viral capsid antigen (VCA) (greater than 10,000) had elevated levels of anti-EBV DNase (38 to 56 U neutralized) and anti-EBV DNA polymerase (72 to 106 U neutralized). Three additional patients and two geriatric controls with average anti-EBV early antigen/VCA titers had slightly elevated levels of antibody to EBV DNA polymerase. IgA anti-VCA, anti-early antigen antibodies, or both, were also detected in the same patients who had high EBV DNase and polymerase antibody levels. These antibody profiles are similar to those in patients with nasopharyngeal carcinoma. Since three of the six patients with elevated anti-EBV enzyme antibody levels developed fatal lymphomas, patients with chronic EBV and this antibody profile might be in another illness category at risk for malignant disease.

Recombinant human interferon alfa-A (rIFN alpha A) had a dose-related suppressive effect on human T lymphotropic virus type III (HTLV-III) replication in vitro in normal peripheral-blood mononuclear cells (PBMC). Both single-dose and multiple-dose regimens were inhibitory. Such inhibitory concentrations (4-1024 units/ml) were not toxic to PBMC in culture, and were within the ranges achievable in blood after injection. These studies suggest that clinical trials of rIFN alpha A in early HTLV-III infection are warranted.

The antiviral activities of various interferon preparations against human immunodeficiency virus (HIV) were evaluated in vitro. Recombinant interferon alpha-A, and beta interferons and leukocyte-derived alpha interferons show similar concentration-dependent antiviral activity. Recombinant and lymphocyte-derived gamma interferons show minimal antiviral activity against HIV replication in normal peripheral blood mononuclear cells, but definite activity against HIV in the H9 lymphocytic and U937 monocyte-macrophage cell lines.

Ocular involvement with acute Epstein-Barr virus infection is usually limited to a transient follicular conjunctivitis, although other lesions have been reported. Chronic Epstein-Barr virus infection has recently gained attention, but ocular manifestations have not been emphasized. We describe three patients with chronic infection with prominent ocular involvement. Bilateral uveitis was noted in all patients, ranging from an anterior uveitis that was responsive to steroids to a severe panuveitis with vitritis, cataract, optic disc swelling, and macular edema. In one patient, topical acyclovir ointment resulted in a substantial decrease in the inflammatory reaction when added to systemic acyclovir therapy. Another patient displayed a keratitis that resolved with topical steroid therapy. Cataract and vitreous surgery were also beneficial in the management of these patients.

A 15-kg weight gain developed in a patient during the third week of ibuprofen therapy. The edema disappeared with discontinuation of the drug regimen and did not reappear during a subsequent six-month observation period. It should be recognized that ibuprofen may be associated with salt and water retention in the same fashion as previously described with phenylbutazone and indomethacin.

The ability of cells infected with human T lymphotropic virus type III (HTLV-III) to suppress lymphocyte responses to concanavalin A (ConA) was evaluated. Thirty homosexual men, both HTLV-III seropositive and seronegative, and 11 seronegative laboratory personnel were studied. Peripheral blood lymphocytes from all groups had lower responses to ConA in the presence of HTLV-III-infected H9 cells than in the presence of uninfected H9 cells. Among HTLV-III-seropositive males, responses to ConA in the presence of infected or uninfected H9 cells correlated with the number of T4 cells present. The studies suggest that HTLV-III-infected cells can suppress normal lymphocyte responses. Possible mechanisms of this suppression are discussed.

Human immunodeficiency virus (HIV) elicits the production of virus-specific antibodies in infected individuals. We investigated the ability of serum from HIV-infected individuals to mediate antibody-dependent cellular cytotoxicity in an in vitro 51Cr release assay system. Fresh peripheral blood mononuclear cells from healthy donors seronegative for HIV were used as cellular effectors against HIV-infected and uninfected H9 target cells in the presence of serum from HIV-infected or uninfected donors. Serum from HIV-infected, but not uninfected, donors significantly augmented cytolysis of virus-infected targets (P less than .005). There was no augmented killing of uninfected H9 cells with sera from either group. Studies using serum from mice that had been immunized with synthetic peptides from the HIV envelope region suggested that this response is directed, at least in part, at several determinants of the transmembrane portion of the HIV envelope glycoprotein.

Cytomegalovirus infections can cause significant morbidity and mortality in immunosuppressed patients, and present antiviral agents have had little efficacy against these infections. We describe the use of an acyclic nucleoside 9-[2-hydroxy-1-(hydroxymethyl) ethoxy methyl]guanine (BW B759U), in the treatment of two patients with cytomegalovirus retinitis. The efficacy of this agent was evident, with healing of retinal lesions and resolution of viremia and viral shedding. BW B759U appears to be similar pharmacokinetically to intravenous acyclovir in terms of half-life, peak serum levels, and renal excretion.

A total of 208 patients underwent brain biopsy for presumptive herpes simplex encephalitis and were randomized to receive either vidarabine, vira-A, at 15 mg/kg/day, or acyclovir, at 30 mg/kg/day for ten days. 69 patients (33%) had biopsy-proven disease; 37 received vira-A and 32 acyclovir. With the exception of age, patient populations were balanced for demographic characteristics. Overall survival for acyclovir recipients was 72% compared with 46% for vira-A-treated patients 18 months after therapy (p = 0.008). After adjustment for differences of age between treatment populations by multivariant regression analyses, acyclovir treatment remained superior to vidarabine therapy (p = 0.041). Mortality varied according to the level of consciousness at the onset of therapy. For lethargic, semicomatose and comatose patients, mortality was 42%, 46%, and 67%, respectively, for the vira-A-treated patients and 0%, 25% and 25%, respectively, for acyclovir-treated patients. Six months post-therapy morbidity assessments revealed five (14%) vira-A versus 12 (38%) acyclovir recipients who had returned to normal function, while eight (22%) and three (9%), respectively, had moderate debility. Outcome differences were significant (p = 0.02; Wilcoxon, 2-sample test) using an adapted scoring system. Age and Glasgow coma scale greater than 10 predicted the best outcome following acyclovir treatment. Disoriented patients who flex and respond by eye to pain had no mortality and 50% returned to normal. These data indicate that acyclovir is the treatment of choice for biopsy-proven herpes simplex encephalitis.

Although therapy is currently available for many of the infections and neoplastic complications of AIDS, there is no effective therapy for the underlying immunodeficiency state. The authors review various attempts at treatment to date, and conclude that a major decrease in HIV-associated morbidity will require a combined approach, making use of our knowledge of the epidemiology, as well as the molecular and cellular biology, of the virus.

Serum neutralizing antibodies against the human immunodeficiency virus were frequently detected in infected individuals, and low or absent serum neutralizing titers correlated with poor prognosis. Multiple diverse human immunodeficiency virus isolates were found to exhibit similar susceptibility to neutralization by a panel of human seropositive sera, suggesting that neutralizing antibodies are largely directed against conserved viral domains. Furthermore, utilizing antisera raised against a library of synthetic env peptides, four regions which are important in the neutralization process have been identified within both human immunodeficiency virus envelope glycoproteins (gp41 and gp120). Three of these are in conserved domains and should be considered for inclusion in a candidate vaccine.

Eight cloned T cell lines specific for Epstein Barr virus-transformed B lymphocytes were derived. In the presence of the autologous virus-infected B cells, the T cell lines show HLA-restricted cytotoxic activity and also secrete alpha-interferon in sufficient amounts to inhibit infection and transformation. Four of these clones showed restriction to a single HLA locus (two for A3, and two for B7) and three showed exquisite self-restriction lysing only autologous targets. These seven clones expressed the classical cell surface phenotype of cytotoxic T cells being T3, 8, 11, and la-positive and T4-negative. An eighth clone that lacked the T8 surface marker appeared to recognize both B7 and BW51. HLA restriction was confirmed: 1) by the ability of a monoclonal antibody against an HLA-A,B,C framework antigen (W6-32) to block the cytotoxicity; 2) the failure of the clones to lyse Daudi, an EBV-positive, HLA-A,B, C-negative cell line; and 3) successful competition of the cytotoxicity by autologous but not allogeneic cold targets. The cloned T cells do not kill EBV-negative targets such as autologous pokeweed mitogen blasts and cell lines including CEM and the natural killer cell target K562. The results suggest T cell clones may be generated against an EBV-associated membrane antigen on transformed B cells, perhaps equivalent to the lymphocyte-determined membrane antigen, and that the recognition is restricted by a single HLA determinant. We propose that single T cells can play multiple roles in controlling EBV infection in vitro and in vivo including the elimination of transformed cells by cytotoxicity and the prevention by secreted interferon of further re-infection and transformation.

Varicella-zoster virus (VZV)-infected human foreskin fibroblasts synthesize viral glycoproteins of 125,000 (gp125), 118,000 (gp118), 92,000 (gp92), 63,000 (gp63), 59,000 (gp59), and 47,000 (gp47) Da. In biochemical studies, all of these VZV glycoproteins were shown to contain asparagine-linked (N-linked) oligosaccharide chains and, except for gp125 and gp47, to be sialoglycoproteins. Experiments with endo-beta-N-acetylglucosaminidase H (endo H) demonstrated that gp92 contained only complex type (endo H-resistant) N-linked glycosyl chains, while the other mature glycoproteins contained both high-mannose (endo H-sensitive) and complex-type oligosaccharides. Monoclonal antibodies recognizing multiple glycoproteins, gp63/gp125 or gp92/gp59/gp47, neutralized virus infection, suggesting the glycoproteins were important components of the virus envelope. This was confirmed for gp92/gp59/gp47 by immunoelectron microscopy, which revealed dense staining localized exclusively to the virion envelope and to the plasma membrane of virus-producer cells. The mature forms of all of these glycoproteins were also present in viral material isolated from vesicles of varicella and zoster patients, indicating that in infected individuals the viral glycoproteins are synthesized and processed in a manner similar to that in tissue culture cells.

We randomly assigned 208 patients who underwent brain biopsy for presumptive herpes simplex encephalitis to receive either vidarabine (15 mg per kilogram of body weight per day) or acyclovir (30 mg per kilogram per day) for 10 days. Sixty-nine patients (33 percent) had biopsy-proved disease; 37 received vidarabine, and 32 acyclovir. The mortality in the vidarabine recipients was 54 percent, as compared with 28 percent in the acyclovir recipients (P = 0.008). Six-month mortality varied according to the Glasgow coma score at the onset of therapy. For scores of greater than 10, 7 to 10, and less than or equal to 6, mortality was 42, 46, and 67 percent in the patients treated with vidarabine, as compared with 0, 25, and 25 percent in those treated with acyclovir. A six-month morbidity assessment using an adapted scoring system revealed that 5 of 37 patients receiving vidarabine (14 percent) as compared with 12 of 32 receiving acyclovir (38 percent) were functioning normally (P = 0.021). Eight vidarabine-treated patients (22 percent) and three acyclovir-treated patients (9 percent) had moderate debility. Patients under 30 years of age and with a Glasgow coma score above 10 had the best outcome with acyclovir treatment. We conclude that acyclovir is currently the treatment of choice for biopsy-proved herpes simplex encephalitis.

Subacute encephalitis, characterized by demyelination, gliosis of the gray and white matter, focal necrosis, microglial nodules, atypical oligodendrocyte nuclei, and multinucleation of cells, was present in 27 of 30 (90%) autopsied patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex. Subacute encephalitis was mainly distributed in the frontal (58%) and temporal (69%) lobes, basal ganglia (77%), amygdala (80%), and hippocampus (64%). Ten (37%) with moderate or severe subacute encephalitis were demented; 82% with mild subacute encephalitis had no recognized neurologic disorder. Human T-lymphotropic virus type III (HTLV-III) was isolated from neural tissue or CSF in 11 of 13 patients, 10 with subacute encephalitis, and 1 without CNS lesions. We conclude that subacute encephalitis is common in AIDS patients and is most likely caused by CNS infection with HTLV-III.

The histopathological and immunopathological features of peripheral neuropathy were investigated in 21 patients with the acquired immunopathological syndrome (AIDS) or AIDS-related complex (ARC). Clinical syndromes observed in the 11 (52%) symptomatic patients included distal symmetrical polyneuropathy (DSPN) and chronic inflammatory demyelinative polyneuropathy (CIDP). Specimens from 19 of 20 patients (95%), both symptomatic and asymptomatic, had histopathological evidence of moderate or severe demyelination (79%), axonal degeneration (36%), and mononuclear cell inflammation (37%). Nerves from patients with CIDP and DSPN showed similar degrees of demyelination and axonal degeneration, but inflammation was more intense in CIDP. Immunohistochemical staining identified the majority of inflammatory cells as T lymphocytes or macrophages, with a predominance of CD8+ cytotoxic/suppressor cells. Diffuse immunostaining for human leukocyte antigen (HLA)-DR was present on endothelial cells, mononuclear inflammatory cells, and Schwann cells, and variable patchy immunostaining for HLA-DR was present on nerve fibers. Control nerve specimens showed staining for HLA-DR limited to endothelial, and a few mononuclear cells. The patterns of immunostaining were similar for AIDS and ARC patients. Human immunodeficiency virus (HIV) was cultured from peripheral nerve in 3 patients, but HIV antigen was not detected by immunohistochemical staining of 8 specimens. The findings implicate HIV infection in nerve, with T cell- and macrophage-mediated tissue destruction as the pathogenetic mechanism of the AIDS/ARC neuropathy.

The human immunodeficiency virus (HIV) may interact with the Epstein Barr virus (EBV) indirectly by effects on the T4 lymphocyte or directly by effects on EBV transformed B lymphocytes. We have confirmed the susceptibility of EBV transformed B lymphocytes to productive HIV infection, and have evaluated the cytotoxic activity of HIV seronegative and seropositive donors after sensitization by their autologous EBV infected (monoinfected) or EBV and HIV infected (coinfected) transformed cell lines in a 51Cr release cytotoxicity assay. When sensitized by the coinfected cell line and assayed against monoinfected and coinfected cell lines, the cytotoxic activity of the seronegative donors was inhibited when compared to the cytotoxic effectors sensitized by the monoinfected B cell line. The inhibition appeared to be unrelated to direct HIV infection of the T4 effector cells and was reversible by addition of recombinant interleukin-2. Although deficient in their EBV cytotoxic activity in comparison to the seronegative donors, the HIV seropositive donors lysed the coinfected cell line better than the monoinfected cell line, whether or not HIV superinfected cells were used during the sensitization phase. In HIV seronegative donors, HIV may inhibit the immune response to EBV transformed B lymphocytes. This inhibition is not observed in HIV seropositive donors. These studies suggest the development of cytolytic effector mechanisms directed at HIV infected cells during HIV infection.

Changes in thymus-derived (T) lymphocyte subpopulation numbers were studied in patients with acute and convalescent Epstein-Barr virus (EBV)-induced infectious mononucleosis (LM). T cell subsets were characterized by the presence of Fc receptors for IgG (TG), for IgM (TM) or by the absence of either receptor (Tnon-M, non-G). We found that in acute IM, total numbers of T and B lymphocytes were elevated (p less than 0.01). Of the T lymphocyte subsets, the total number of Tnon-M, non-G lymphocytes was increased six fold compared to normal subjects (p less than 0.001) and included the majority of the atypical T lymphocytes. The number of total TG and TM lymphocytes was moderately increased (p less than 0.05). In convalescent IM patients, the number of total T cells remained slightly elevated (p less than 0.02) whereas proportions and absolute numbers of B lymphocytes and T cell subsets returned to near normal levels. Thus, acute Epstein-Barr virus-induced IM is associated with a T lymphocytosis which is composed predominantly of atypical T cells which lack detectable Fc receptors for IgG or IgM.