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Four virulent strains of Venezuelan encephalitis virus attained higher concentrations of infectious virus in bloods of adult hamsters than two benign strains when given subcutaneously. One benign virus, the attenuated TC83 vaccine strain, reached higher concentrations in bone marrow and Peyer's patches than virulent subtype I strains, and another benign virus, subtype IV, grew to lower levels. When inoculated intracranially, the two benign viruses attained high concentrations in brain, but did not significantly alter in lethality although morbidity was increased. Intracardiac inoculation failed to increase virus concentrations of two benign viruses in blood or hematopoietic tissues above those found after subcutaneous inoculation, nor did it increase lethalities to those of virulent virus. Three benign virus strains were cleared more rapidly from hamster plasmas than six virulent strains. Differences in clearance rates were apparently not due to destruction of benign viruses by blood or tissue components. Thus viral concentrations in blood correlated directly and clearance rates inversely with hamster virulence, whereas the rate and extent of growth of a VE virus in hematopoietic or brain tissues did not correlate with ability to kill hamsters.

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Two strains of Venezuelan encephalitis virus that are avirulent for normal BALB/c mice inoculated subcutaneously were also avirulent for infected congenitally athymic (nude) mice of the same strain. Viremias were of similar magnitudes and durations in normal and nude mice. Brain concentrations were higher in nude mice with the one avirulent strain tested, although the periods of detectable virus

Evidence was sought during 1970-1975 of persistence of equine-virulent Venezuelan encephalitis (VE) virus in regions of Central America that were heavily involved in the epidemic-equine epizootic of 1969. (a) Four sentinel horses were exposed in an arid, upland region of the Atlantic drainage of Guatemala during August-October 1970, but no horse became infected. (b) The epicenter region of the 1969 outbreak, in southwestern Guatemala and southwestern El Salvador, was studied during July 1970-February 1974; no antibody developed in sentinel horses, sentinel hamsters did not die, mosquitoes yielded no virus, wild rats had no detectable VE virus HI antibody. Unexplained decreases in populations of wild terrestrial mammals possibly limited maintenance of VE virus. However, mosquitoes were plentiful and present in the same species composition found at a focus of enzootic VE virus about 35 km northwest of the epicenter region. (c) In studies at two Guatemalan ranches near the epicenter, where horses died in 1969, VE viruse infected sentinel horses along one of three lakes on one ranch during the wet season of 1972 but not during the dry or wet seasons of 1973; the titers of neutralizing antibodies in these four horses were higher against an enzootic strain of VE virus than against an epizootic strain. During 1970 and 1971, VE virus was isolated from sentinel hamsters exposed at a marsh on the other ranch, but Vero plaque characteristics were those of enzootic VE virus. (d) The only epizootic activity of VE virus discovered in Central America in 1970-1975 occurred in Nicaragua between April and June 1972. Several hundred horses died, and N antibody, like that engendered by epizootic virus, was found in two young, unvaccinated horses. Whether this represented persistence of epizootic VE virus or reintroduction of virus is unknown.

Pathogenicities of 10 temperature-sensitive mutants of Venezuelan encephalitis virus were studied using the hamster model of human virulence. The parental strain and nine of the temperature-sensitive mutants produced lethal infections in hamsters. Strain ts 126 showed reduced hamster virulence. Deaths with the lethal mutants usually occurred 1 to 3 days later than with parental virus. Nine mutants produced lower levels of viremia than parental virus. Attenuation of ts 126 was related to restriction of viral growth in spleen and probably bone marrow and to absence of the usual pathological lesions in hemopoietic tissues and brain, but was functionally unrelated to temperature sensitivity since temperatures of both normal and infected hamsters remained within the permissive range of the mutant. Deaths did not correlate with titers of the 10 mutants in blood at permissive temperatures or with reversions of four temperature-sensitive mutants to non-temperature-sensitive virus in hamsters.

Seventy-four strains of Venezuelan encephalitis (VE) virus recovered from sentinel hamsters or mosquitoes at enzootic habitats in Guatemala in the two years following the 1969 epidemic-equine epizootic were examined for ability to produce small plaques in Vero African green monkey kidney cell cultures, like isolates obtained during the epizootic. (a) One strain recovered from a sentinel hamster in late October 1969 at an enzootic habitat near the epicenter of the hemagglutination-inhibition (HI) and equine-virulence properties like epizootic virus; this strain retained its small plaque characteristic after inoculation and recovery from bloods of three horses. (b) None of the other 73 strains produced uniformly small plaques, but 31 formed a few small plaques among large ones. Virions from small plaques of five strains were cloned twice in Vero cell cultures. Four clones produced uniformly small plaques after one more passage in Vero cells; three had hemagglutination-pH properties compatible with epizootic virus or intermediate between epizootic and enzootic virus, but HI tests with these three hemagglutinins or with antibody to the fourth cloned strain showed them to be like Central American enzootic virus. One of three cloned strains tested in horses produced encephalitis and death in one of four horses; another strain produced encephalitis with recovery in one of two horses. (c) Thus these small Vero plaque clones resembled Central American enzootic strains of VE virus in HI and equine-virulence tests, and the small Vero plaque characteristic was not a satisfactory marker for consistently isolating equine-virulent, epizootic VE virions. Nevertheless, this technic led to recognition of one epizootic strain isolated at an enzootic habitat in Guatemala at the end of 1969 outbreak. Whether this strain was there before the outbreak or subsequently penetrated the habitat is uncertain. During the next two years, this strain did not become dominant in that enzootic focus.