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To determine if use of antiherpes drugs protects against the development of AIDS-associated Kaposi's sarcoma (KS), data from 935 homosexual men with AIDS from the Multicenter AIDS Cohort Study were analyzed. In nested case-control analysis, neither acyclovir use for human immunodeficiency virus infection (odds ratio [OR], 0.84 ; 95% confidence interval [CI], 0.56-1.26 ; P =.39) nor acyclovir use for any indication (OR, 1.02 ; 95% CI, 0.76-1.38 ; P =.89) was associated with a reduced risk of KS as initial AIDS diagnosis. In longitudinal analysis, acyclovir was also not protective against developing KS as a late manifestation of AIDS (after initial non-KS AIDS diagnosis). Among men with cytomegalovirus disease, ganciclovir use (relative risk [RR], 0.56 ; 95% CI, 0.22-1.44 ; P =.23) and foscarnet use (RR, 0.40 ; 95% CI, 0.051-3.10 ; P =.38) were associated (although not significantly) with a reduced risk of KS. Thus, acyclovir use does not appear to reduce the risk of KS, but further study of other antiherpes drugs such as ganciclovir and foscarnet is warranted.

Twenty-five patients with AIDS in AIDS Clinical Trials Group Protocol 002 were treated with either low or high dosages of zidovudine. This resulted in moderate, transient increases by 10 and 20 weeks in lymphocyte blastogenesis and interferon-gamma (IFN-gamma) production in vitro in response to phytohemagglutinin with and without recombinant interleukin-2. Immune responses to cytomegalovirus and herpes simplex virus type 1 antigens were augmented less frequently during therapy. Natural killer (NK) cell lysis of uninfected and human immunodeficiency virus-infected cells was also transiently increased by 10 and 20 weeks. IFN-gamma production, the only immune parameter directly associated with increases in numbers of CD4+ T cells, peaked at 10 weeks of treatment. The limited efficacy of zidovudine treatment in AIDS patients is associated with moderate, temporary increases in nonspecific and herpesvirus-specific T lymphocyte responses and NK cell function.

Women attending family planning clinics in western Pennsylvania were enrolled into a prospective epidemiologic study of herpes simplex virus (HSV) infection. Detection of antibodies to HSV-1 and HSV-2 was based on an immunodot assay using type-specific glycoproteins gG-1 and gG-2. Serologic and historical data at enrollment were analyzed for 4527 subjects; the seroprevalence of HSV-2 was 21.6%. By multivariate analysis, HSV-2 infection as determined by seroprevalence was significantly and independently associated with age, years of sexual activity, race, one or more episodes of other genital infections, lower annual family income, and multiple sexual partners. The presence of antibody to HSV-1 was associated with a lower frequency of antibody to HSV-2, suggesting that developed immunity to HSV-1 protected against HSV-2 infection. Of 926 participants who had antibody to HSV-2, only 117 (12.6%) reported a history of genital herpes. Hence the vast majority of HSV-2 infections were inapparent. Although seroprevalence of HSV-2 was higher among black (35.4%) than white (18.5%) women, black women appeared to have significantly less symptomatic genital herpes than white women (7.7% vs. 14.7%, P less than .01).

Epstein-Barr virus (EBV) is a human herpesvirus associated with an array of conditions that range from inapparent infection and infectious mononucleosis to lethal lymphoproliferative syndromes, nasopharyngeal carcinoma, Burkitt’s lymphoma, and B cell lymphomas in immunocompromised patients [1]. The precise role of the virus in carcinogenesis is unclear, although in Burkitt’s lymphoma the importance of viral transformation of infected B lymphocytes and chromosomal translocations has been emphasized [2]. It is even less clear in lymphomas and lymphoproliferative lesions arising in immuno-compromised patients, where the immunopathology may not be uniform and where chromosomal studies are largely lacking. Recently, we reported on the reversibility of lymphomas and lymphoproliferative lesions in a series of 17 transplant patients after reduction of cyclosporine and steroid immunosuppression [3]. In that preliminary report we noted that seven of these patients had evidence of primary EBV infections and eight had evidence of reactivated infection. Six tumors had evidence of EBV nuclear antigen (EBNA) and seven had evidence of EBV DNA by nucleic acid hybridization. This paper examines in detail the relation between infection with EBV and the tumors in 14 of these 17 patients. The three patients who were excluded had their original transplants in Colorado (patients 1, 2, and 3 [3]). New data provided here include (1) frequency of EBV infection in the general transplant population; (2) additional serological studies in patients with tumors; (3) correlation of laboratory evidence of EBV infection and clinical illnesses accompanying the appearance of tumors; and (4) details of hybridization studies with highly specific and sensitive probes consisting of cloned fragments of the EBV genome. Calne et al. [4] and Thiru et al. [5] first observed three cases of lymphoma in 34 transplant patients receiving cyclosporine, of whom one had evidence of primary infection. Hanto et al. [6] reported the results of studies on 19 renal transplant patients who developed lymphoproliferative disorders and lymphomas after transplantation. All the patients except one were receiving azathioprine, prednisone, and antithymocyte globulin. Two of their patients developed primary EBV infection, in six the infection reactivated, and 12 had evidence of EBV DNA in their tumors by hybridization studies. Bieber et al. [7] reported that five of 39 heart transplant recipients receiving cyclosporine, prednisone, and antithymocyte globulin developed lymphomas. Four tumors were positive for EBV DNA by cRNA-DNA filter hybridization, and three patients had serological evidence of EBV infection. We report here evidence for active EBV infection in all of our patients with tumors and a significantly higher frequency of primary infection than found in control transplant recipients. Antibody responses to all EBV antigens and details of hybridization studies have not been reported in previous studies of patients with tumors.

Forty-four heart and five heart-lung transplant recipients with cytomegalovirus (CMV) infection were investigated for risk factors associated with symptomatic CMV infection (17 patients) and CMV pneumonia (eight patients). Symptomatic infection was associated with primary rather than reactivated infection (P less than .005), younger age (P less than .005), heart-lung transplantation (P less than .001), and significant rises in titer of antibody to the early antigen of Epstein-Barr virus (P less than .001). Among recipients of heart transplants, patients with cardiomyopathy more often had symptomatic disease due to CMV (P less than .05). CMV pneumonia was associated with heart-lung transplantation and, in patients with primary CMV infection, earlier positive cultures for CMV after transplantation (P less than .02). CMV viremia was found in all patients with symptomatic infection, including the eight patients with CMV pneumonia, and the frequency of positive buffy coat cultures for CMV was significantly higher in patients with symptoms than in patients without symptoms (P less than .001). Neither symptomatic CMV infection nor CMV pneumonia was significantly associated with the use of antithymocyte globulin, restricted to therapy for rejection, and the use of high doses of acyclovir in 11 patients had no demonstrable impact on CMV culture positivity.

A newly recognized, avirulent large-plaque (ALP) variant of Sindbis virus failed to kill suckling mice after intracerebral inoculation and replicated at the site of inoculation to a lower titer than virulent strains. When this variant was mixed with virulent large-plaque (VLP) or virulent small-plaque (VSP) variants of Sindbis virus or with chikungunya virus and inoculated into suckling mice, the ability of the virulent viruses to kill suckling mice was inhibited. ALP also transiently inhibited replication of VSP in brains of suckling mice. ALP was shown to be ethersensitive; its infectivity and its interfering effect were neutralized by sera immune to Sindbis. Under conditions of the interference test, ALP induced interferon more rapidly than virulent strains of Sindbis virus.

It is a fairly common experience in laboratories using the standard AR-339 strain of Sindbis virus to observe variations in the plaque size of this virus [1-4]. The sizes range from large to small, and include in some cases intermediate plaque variants [3] and an "unusually" large plaque (U) obtained after cloning of a parent small plaque variant at 40 C [4]. We have used Sindbis virus extensively as an interferon inducer in cell cultures [5-7] and in "systemic induction" [8]; that is, in the production of serum interferon shortly after a large dose of virus is inoculated intravenously in rabbits and before the virus replicates to any significant extent [9-11]. In the course of using Sindbis virus, we have noted occasional large plaques (^5 mm) among the usual smaller plaques (^2 mm) in chick embryo cell cultures under Bacto agar (Difco). Recently, to study how variants of 1 virus may differ in the systemic induction of interferon [12], we decided to study the systemic interferon-inducing capacity of small plaque (SP) and large plaque (LP) variants of Sindbis virus. Preliminary results revealed not only that the LP variant induced more serum interferon in animals, but also that it was cleared from the blood stream

When 1-kg rabbits received iv 500 j'g of Boivin Escherichia coli endotoxin and were sacrificed 15 min later, production of interferon, as monitored by incubation of tissue slices in vitro, occurred primarily in the spleen, lung, liver, and thymus. When the temperature of incubation was 23 C, more interferon was produced than at 37 C. If the animals received 1 mg of actinomycin/kg 1 hr before administration of endotoxin, interferon production was accentuated in the spleen and lung. However, if the dose was increased to 5 mg/kg, no detectable interferon was produced. Production of interferon in slices was reversibly inhibited by cycloheximide or puromycin and was marginally accentuated after removal of these substances. These findings suggest that induction of interferon production by endotoxin, like induction by polyriboinosinic:polyribocytidylic acid (poly I:C) or virus, requires synthesis of messenger RNA and protein. Accentuated production by a marginal dose of actinomycin is explained by inhibited synthesis of messenger RNA for a control protein that inhibits interferon synthesis, as has been postulated for induction of interferon by poly I:C and by viruses.

In the previous paper [1], we described 2 variants of Sindbis virus which differed markedly in their behavior in animals. The large plaque (LP) variant was more effective than the small plaque (SP) variant in inducing interferon in the serum of rabbits and mice, and it was cleared from the blood stream of these animals at a much slower rate. To elucidate further the bases for these differences, the following studies of these 2 variants were undertaken and are reported herein: the size, density, and morphology of the 2 variants, the effect of agar inhibitor, neutralization kinetics, interferon induction and sensitivity, and pathogenicity for mice and the chick embryo.

An avirulent large-plaque (ALP) variant of Sindbis virus interfered in murine embryonic cell cultures with a virulent small-plaque (VSP) variant without inducing large amounts of detectable interferon. However, the properties of this interference were consistent with the interferon mechanism. (1) The interference could be inhibited by actinomycin D. (2) It extended to a heterologous virus, such as vesicular stomatitis virus. (3) No interference was demonstrated with Vero cells, a line known to be genetically defective for production of interferon. (4) When large doses of challenge virus were given together with ALP, interference was not observed. Thus, while the mechanism of interference by ALP has not been elucidated, we suggest that it is mediated by an intracellular precursor of interferon (preinterferon), which has the antiviral properties of interferon but is not detectable extracellularly.