The effects of interferon and double-stranded RNA upon the virus-host interaction: studies with togavirus strains in mice.

Partially purified fibroblast interferon and double-stranded RNA (dsRNA) of fungal origin were administered as single graded doses to A2G and Balb/c mice shortly before intraperitoneal infection by specified virulent or avirulent strains of representative togaviruses (Semliki Forest virus, Venezuelan equine encephalomyelitis virus and yellow fever virus). Changes of efficiency of infection arising from interference at the level of clearance or replication and changes of the expression of virulence or protective immunity, were compared for different initial doses of interferon or dsRNA in relation to different levels of infection by defined virus strains. Interferon and dsRNA, although acting through quantitatively different mechanisms, both reduced effective dose of virus and influenced only the extent of primary replication and host stimulation. Neither agent changed in any way the outcome of infection in terms of expression of virulence (regulatory immunity) or protective immunity. These results are discussed in terms of the control of virus infections at stages before or after immune stimulation can be effective.

Differentiation of strains of yellow fever virus in gamma-irradiated mice.

The mouse sensitized by optimal, sub-lethal gamma-irradiation has been used for the differentiation of strains of yellow fever virus and for the resolution of their immunogenicity and pathogenicity as distinct characteristics. For different strains of yellow fever virus, the patterns f antibody-synthesis, regulatory immunity (pre-challenge) and protective immunity (post-challenge) are differentially sensitive to gamma-irradiation. These critical differentiations of strains of yellow fever virus in gamma-irradiated mice have been compared with those shown in normal athymic and immature mice in order to elucidate the range of quantifiable in vivo characteristics and the course of the virus-host interaction. This is discussed as a basis for the comparison of the responses of model and principal hosts to vaccines and pathogens.

The sensitivity to gamma-irradiation of the phases of the virus-host interaction: studies with strains of Semliki forest virus in mice.

A convenient and quantifiable model system, Semliki Forest virus (SFV) in the mouse, has been used to probe the wider problem of the radiation sensitivity of the distinct phases of the virus-host interaction. This has been investigated through the suppression and recovery of the several host defence mechanisms and cellular compartments involved. Direct observations have been made, following whole-body gamma-irradiation at up to 600 R, of the sequential modifications imposed upon the efficiency of primary infection, the stimulation of regulatory immunity (pre-challenge) and the stimulation or boosting of protective immunity (post-challenge). These phases of the virus-host interaction show distinct sensitivities to gamma-radiation which are discussed in terms of the impairment and recovery of the lymphocyte compartments probably involved.

The responses of normal an athymic mice to infections by togaviruses: strain differentiation in active and adoptive immunization.

Strains of yellow fever virus (YFV), Venezuelan equine encephalomyelitis virus (VEEV) and Semliki Forest virus (SFV) have been used to compare the stimulations of regulatory immunity (pre-challenge), antibody synthesis and protective immunity (post-challenge) in athymic-nude and normal mice. Similarly, direct assessments have been extended to athymic recipients of normal spleen cells and to adoptively immunized mice. The results indicate that the responses of mice to different togaviruses or strains of togaviruses may be differentially T-lymphocyte dependent at any one or more of the above three stages of host response. T-cell reconstitution or adoptive immunization may be effective only for the virus strains of highest immunogenicity. These results suggest a resolution of T-lymphocytes dependence at three levels of host response to virus infections. This approach may be of value in the similarly direct in vivo differentiation of other virus strains and as a practical framework for the consideration of the in vivo significance of the variety of in vitro lymphocytes markers.

The in vivo differentiation of strains of yellow fever virus in mice.

Strains of yellow fever virus isolated since 1927 in Africa and the Americas, and strains derived from them, have been differentiated by the responses of mice of different ages to intraperitoneal (i.p.) or intracerebral (i.c.) infection. Infection, antibody conversion, protection and death have been presented on age-dose response phase diagrams that serve as in vivo 'fingerprints' for the differentiation of virus strains and their modifications through passage and selection. Correlations between marker characteristics are discussed in terms of the efficiency of infection, regulatory (pre-challenge) and protective (post-challenge) immunity, and the expression of virulence. The requirement in virus strain specification for the resolution of events on pathogenic and immunogenic pathways is discussed.

Multi-factorial specification of virus-host interactions: studies with strains of Venezuelan equine encephalomyelitis virus in mice.

Mice of different ages were infected i.p. or i.c. by 23 different strains of VEE virus. The course of the virus host interaction was specified in terms of the efficiency of infection, the outcome of infection as lethality or protection and the survival time. These separately quantifiable features all showed several host-maturation events that combine to provide a multifactorial specification of virus-strains and host-responses. This base-line for correlations with the responses of principal hosts (equidae and man) may be expanded to test correlations with the antigenic or in vitro characteristics of virus-strains.

The responses of nude-athymic mice to nominally avirulent togavirus infections.

Following intraperitoneal infection by an avirulent strain of Semliki Forest virus, athymic nude mice showed almost normal clearance of viraemia and a transitory peak of antibody activity at 5 to 9 days which fell to less than about 0.1% of the normal antibody activity from the 14th day. When nude mice received a transfer of normal spleen cells from sex-matched litter mates at 1 day before infection, a pattern of high and continous antibody synthesis was established for at least the following 7 weeks. This clear T-cell dependence of the regulation of serum antibody synthesis was unrelated to the development of regulatory (pre-challenge) or protective (post-challenge) immunity since, particularly for female nude mice, up to 60% were benignly and protectively infected in the absence of detectable antibody activity. The brains of such nude mice showed persistence of infectivity for at least 7 weeks at 10 to 10(4) p.f.u./brain after avirulent infection and at about 10(3) to 10(4) p.f.u./brain after virulent challenge. The prior transfer of normal spleen cells to nude mice enabled them to clear brain infectivity as efficiently as normal mice. These results are discussed in terms of the evident interplay of both T-lymphocyte dependent and T-lymphocyte independent functions in the control of brain infectivity, in the expression of virulence and in the stimulation of regulatory and protective immunity.

Immunomodification and the expression of virulence in mice by defined strains of Semliki Forest virus: the effects of cyclophosphamide.

Mice were infected i.c. or i.p. by an avirulent clone of Semliki Forest virus at various times before or after the i.p. administration of a single dose of cyclophosphamide. Consequent changes in the patterns of viraemia and antibody production are interpreted in terms of the potentiation of the initial infection or the decreased resistance to subsequent lethal challenge. These change demonstrate two distinct modes of immunomodification determined by the time of cyclophosphamide administration in relation to virus infection, but not correlated with the death or protection of individual mice. These results are discussed in relation to the early regulatory functions of T and B cells which may influence the expression of virulence but escape conventional assay during the critical first 3 days following infection.

Immunomodification and the expression of virulence in mice by defined strains of Semliki Forest virus: the effects of myocrisin and 1-asparaginase.

Studies in mice of the modes of immunomodification imposed by cyclophosphamide, have been extended to comparative studies with Myocrisin, 1-asparaginase and interferon. It has been shown for mice infected i.p. or i.c. by an avirulent clone of SFV, that the potentiation of disease may be marked by many distinct changes in the type of rate of response. For low i.p. doses of virus, enhancement (Myocrisin, 1-asparaginase) or impairment (interferon) of the efficiency of infection may be associated with death (potentiation by Myocrisin) or protection (immunoenhancement by 1-asparaginase). For higher doses of virus the increased mortality after infection (primary potentiation) is determined within 2 or 3 days and appears to be due to inhibition of phagocytosis (Myocrisin and 1-asparaginase) and of T cell functions (1-asparaginase and cyclophosphamide). The increased incidence of death after challenge (secondary potentiation) appears to be due to inhibition of B cell functions (cyclophosphamide) associated with suppression of antibody synthesis and persistence of viraemia. These results are discussed in relation to the expression of virulence by a heterogeneous and replicating antigen. The critical cellular and humoral changes which occur within 2 or 3 days of infection are emphasized.

Venezuelan equine encephalomyelitis virus (VEEV):strain differentiation and specification of virulence markers.

Fourteen strains of VEEV of diverse origin and antigenicity were classified into five virulence categories according to their efficiency of infection and nature of response in mice. Mice of ages up to 30 days represented distinct levels of responsiveness and were suitable for the differentiation of VEEV strains of highest to lowest virulence. Stepwise changes with age of the susceptibility or responsiveness of mice appeared to determined the type of response as predominantly lethal (D), dual or intermediate (DP) or protective (P).