Antiviral activity of nerve growth factor in vitro.

The antiviral activity of 'nerve growth factor' (NGF) on non-oncogenic DNA, on RNA viruses and on Moloney sarcoma retrovirus was evaluated in vitro. NGF was active against herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and Moloney sarcoma virus (MSV) at non toxic concentrations. The effects of different treatment regimens on HSV-1 infections indicate that the inhibitory action of NGF occurs at the early stages of viral replication. No activity was noted against coxsackie virus B1 (Cox B1), respiratory syncytial virus (RSV), Semliki forest virus (SFV), encephalomyocarditis (Columbia SK) and adenovirus of infectious canine hepatitis (ICH) at the highest concentrations tested.

Activity of FCE 20696, a new synthetic immunomodulator, in models of viral and bacterial pathology.

The dibenzopyran derivative FCE 20696 is an immunomodulator which protects mice infected with several viral agents and with Mycobacterium tuberculosis. The compound is able to decrease the severity of the lung lesions caused by influenza virus infection. Doses ranging from 12.5 to 100 mg/kg are effective even after a single administration. Activity is demonstrated by intraperitoneal, subcutaneous and oral administration of the drug. In systemic infection with herpes simplex virus type 1, the 100 mg/kg dosage, administered subcutaneously, is able to increase both the percentage and the mean survival time of mice. To have effect by oral administration it is necessary to give the compound twice in the day. Moreover, some activity has also been observed in mice infected by M. tuberculosis, when the compound is administered orally at doses of 1-2.5 mg/kg twice weekly for 5 weeks, during the course of the disease.

Adenosine deaminase inhibitors. Synthesis and biological activity of deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine.

Two new deaza analogues of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 1), 7-deaza-EHNA (6) and 1,3-dideaza-EHNA (11), were synthesized and evaluated for adenosine deaminase (ADA) inhibitory activity and compared with EHNA, 1-deaza-EHNA (2), and 3-deaza-EHNA (3). Substitution of a methine group for a nitrogen atom in the 7-position of the purine moiety of EHNA produces a dramatic drop in the inhibitory activity (Ki = 4 X 10(-4) M) whereas compounds 2 and 3 are still good inhibitors (Ki = 1.2 X 10(-7) M and 6.3 X 10(-9) M respectively). EHNA and its deaza analogues so far synthesized were also tested in vitro for their antiviral and antitumor activity in a range of cellular systems. EHNA and 1-deaza-EHNA are equiactive as inhibitors of human respiratory syncytial virus (HRSV) replication (MIC = 6.25 micrograms/mL) while the other compounds are inactive. On the other hand, all the examined compounds displayed an antitumor activity comparable to that of the reference compound 1-beta-D-arabinofuranosyladenine (ara-A), 7-deaza-EHNA being the most active of all. The results obtained showed that there is no correlation between adenosine deaminase inhibition and antiviral or antitumor activity in this series of compounds. 3-Deaza-EHNA, the most active inhibitor of ADA among the EHNA deaza analogues, greatly potentiates the antitumor activity of ara-A in vitro. In vivo activity was observed only when the two compounds were used in combination.

Synthesis, DNA binding and antiviral activity of distamycin analogues containing different heterocyclic moieties.

A series of novel distamycin analogues possessing an additional benzene or heterocyclic ring have been synthesised and tested for selective DNA binding properties and antiviral activity. Inhibition of herpes virus in cell culture appears to be related to AT base pair specificity. Some of the new compounds are also more potent than the parent distamycin against Moloney sarcoma virus.

Interaction between 6/94 virus, a parainfluenza type 1 strain, and mouse macrophages.

The 6/94 virus, a type 1 parainfluenza virus recovered from multiple sclerosis brain cells after lysolecithin-induced fusion of these cells with African green monkey kidney cells (CV-1), has been found to grow in splenic and peritoneal macrophages obtained from outbred and different strains of inbred mice. Macrophages from C57BL animals were least susceptible to infection, a resistance apparently partially age related. The virus also has been found to replicate in IC21 cells, a line of simian virus 40 virus-transformed mouse macrophages. Viral growth was detected by development of hemadsorption in infected cells, followed by the appearance of infectious virus. The growth of 6/94 virus had different kinetics in mouse macrophages, in the standard continuous cell lines L, 3T3, and CV-1, and in primary mouse kidney and mouse embryo cells. The virus produced in macrophages could be passed in series to other macrophage cultures. In addition, once infected, the cultures continued to produce virus, and permanently infected cell lines were thus obtained. Macrophages from immunized mice with high titers of humoral neutralizing antibodies were found variably able to support virus growth.

Interaction between 6/94 virus, a parainfluenza type 1 strain, and unstimulated mouse lymphocytes.

6/94 virus was found to grow in unstimulated splenic mouse lymphocytes depleted of monocyte macrophages. Both egg-grown virus and virus produced in mouse macrophage cultures induced the development of hemadsorption and the appearance of new infectious virus in the lymphocyte cultures. An antigenic relative. Sendai virus, on the contrary, was quickly inactivated in these lymphocyte cultures, in agreement with previous reports in the literature. The T lymphocyte population seemed to be the fraction principally involved in the replication of 6/94 virus. The immunization of mice with 6/94 virus and the appearance of high levels of humoral neutralizing antibodies did not inhibit completely the susceptibility of their lymphocytes to the infectious agent.

Interaction between 6/94 virus, a parainfluenza type 1 strain, and human leukocytes.

6/94 virus, a parainfluenza type 1 virus recovered by lysolecithin fusion of multiple sclerosis brain cell cultures with CV-1 cells, replicated in monocyte macrophages and lymphocytes from normal human donors and from a patient with multiple sclerosis. In macrophage cultures, hemadsorption-positive cells and high levels of infectious virus became apparent within 24 to 48 h after infection, persisted for 6 days, and then began to decrease. Phytohemagglutinin-stimulated macrophages yielded similar titers of virus, but the levels were maintained for a longer period of time. Macrophage-produced virus appeared to be infectious for other macrophages in the same culture. Both unstimulated and phytohemagglutinin-stimulated lymphocytes also supported virus replication. Significantly higher titers were produced in the stimulated cultures, T cell-enriched populations producing more virus than unseparated populations whether stimulated or unstimulated. The presence or absence of antibodies to the virus in the donors did not appear to influence the levels of virus obtained in any of the leukocyte cultures. However, an increase in blastic forms after 6/94 virus infection was noted in lymphocytes from donors with antibodies as revealed morphologically and by increased incorporations of tritiated thymidine. Furthermore, 6/94 virus-infected lymphocytes, unlike Sendai virus-infected lymphocytes, were able to respond well to mitogenic stimulation by phytohemagglutinin.

The effect of distamycin A on some biochemical functions of tissue cultures infected with Herpes simplex virus.

The antibiotic distamycin A displays no inhibition of protein synthesis in HeLa cell cultures. In HSV infected HeLa cell monolayers the drug exerts a partial inhibition of virus induced thymidine kinase synthesis but is devoid of inhibitory effect on the increase of activity of DNA polymerase and on total DNA synthesis. The antiviral activity of distamycin A is based on a mechanism which appears to be different from that displayed by other drugs such as actinomycin and IUD.

Antiviral activity of a pyrazino-pyrazine derivative.

The 2,3-dihydroxy-6-bromo-pyrazino-[2,3-beta]-pyrazine is a substance selected during the antiviral screening of pyrazino-pyrazine derivatives. The compound shows antiviral activity in vitro against measles, NDV, some influenza viruses and against herpes simplex and zoster, infectious canine hepatitis and vaccinia viruses. It had no effect on ECHO 9 virus. Therapeutic trials showed activity also on herpetic keratoconjunctivitis experimentally induced in rabbits.

Analysis of a viral agent isolated from multiple sclerosis brain tissue: characterization as a parainfluenzavirus type 1.

A virus originally isolated from cell cultures obtained by lysolecithin-induced fusion of human multiple sclerosis brain cells with CV-1 cells has been analyzed for its antigenic, RNA, and polypeptide compositions, and for selective biological properties. Our findings establish that this isolate, designated 6/94 virus, contains a 50S RNA genome and is, as yet, indistinguishable from Sendai virus in its antigenic and total polypeptide compositions. Despite these similarities, the 6/94 and Sendai viruses differ in certain phenotypic properties. 6/94 virus is markedly less cytocidal for chick fibroblasts, especially at 37 C and, after beta-propiolactone inactivation, it possesses a greater capacity for cell fusion and a lower toxicity than does comparably treated Sendai virus. In addition, 6/94 virus shows greater hemolytic activity.