Antigenic modulation of Friend virus erythroleukemic cells in vitro by serum from mice with dormant erythroleukemia.

Friend leukemia virus (FLV) erythroleukemic cells cultured in medium containing FLV-immune serum from dormant FLV-infected mice undergo modulation of FLV cell surface antigens. Modulation was determined by an increased resistance to FLV antibody-mediated complement-dependent lysis and was associated temporally with the capping of FLV-immune complexes at the cell surface. Modulated cells regained their susceptibility to FLV antibody-mediated complement-dependent lysis when transferred to medium containing normal mouse serum. After 48 h of culture in FLV-immune serum, 26% of the FLV erythroleukemic cells were devoid of FLV cell surface antigens as demonstrated by immunofluoresence. Antigenic modulation occurred to a greater extent in cells maintained in logarithmic growth than in cells in GO or resting phase. FLV-antigenic modulation is discussed as a possible mechanism by which antibody induces and maintains FLV-transformed cells in a dormant state.

Immunotherapy of murine leukemia. V. Protection against Friend leukemia virus-induced immune complex glomerulonephritis by passive serum therapy.

The development of immune complex glomerulonephritis in DBA/2 mice infected with Friend murine leukemia virus (F-MuLV) was compared with that in mice protected against virus-induced disease by administration of chimpanzee anti-F-MuLV antiserum (CaF-MuLV). Morphologic analysis of glomeruli from viremic (infected) normal chimpanzee serum-treated animals revealed significant renal disease within 2 weeks following virus inoculation, with glomerular immune complex deposits and C-type viral particles seen by electron microscopy. Localization of F-MuLV envelope and core antigens (gp71 and p30, respectively) was also detected by immunofluorescence, as was murine IgG and C3. However, age-matched DBA/2 mice treated with CaF-MuLV antiserum alone or following F-MuLV inoculation showed no evidence of systemic disease and neither localization of F-MuLV antigens nor detectable virus particles. These data indicate that in addition to erythroleukemia, F-MuLV infection results in severe immune complex glomerulonephritis and that passive immunotherapy can protect susceptible mice from both aspects of viral pathogenesis.

Immunotherapy of murine leukemia. VIII. Efficacy of passive serum therapy of Friend leukemia virus-induced disease in immunocompromised mice.

Previous studies have demonstrated that the passive therapy of Friend murine leukemia virus (F-MuLV)-induced disease with chimpanzee anti-F-MuLV serum is accompanied by the development of host antiviral humoral and cellular immunity, the latter measurable in adoptive transfer protocols and by the ability of serum-protected mice to resist virus rechallenge. The present study was designed to further examine the contribution of various compartments of the host immune system to serum therapy itself, as well as to the acquired antiviral immunity that develops in serum-protected mice, through the use of naturally immunocompromised animals [e.g., nude athymic mice and natural killer (NK)-deficient beige mutant mice] or mice treated with immunoabrogating agents such as sublethal irradiation, cyclophosphamide [Cytoxan (Cy)], cortisone, and 89Sr. The studies in nude mice indicate that while mature T-cells are not needed for effective serum therapy, they do appear to be necessary for the long-term resistance of serum-protected mice to virus rechallenge and for the generation of the cell population(s) responsible for adoptive transfer of antiviral immunity. Furthermore, this acquired resistance is not due to virus neutralization by serum antibodies since antibody-negative, Cy-treated, serum-protected mice still reject the secondary virus infection. Lastly, while the immunocompromise systems examined did effect various host antiviral immune responses, none of them, including the NK-deficient beige mutation, significantly diminished the efficacy of the passive serum therapy of F-MuLV-induced disease.

Use of adoptive transfer and Winn assay procedures in the further analysis of antiviral acquired immunity in mice protected against Friend leukemia virus-induced disease by passive serum therapy.

Previous studies have demonstrated that spleen cells from DBA/2 mice protected against challenge with a leukemogenic dose of Friend leukemia virus (FLV) by passive administration of xenogeneic antiviral or anti-FLV Mr 71,000 viral envelope glycoprotein antisera can adoptively transfer antiviral resistance to unimmunized irradiated syngeneic recipients. In addition, elimination of T-cells by treatment with anti-Thy 1.2 antibodies plus complement had no effect on the ability of spleen cells from serum-protected mice to adoptively transfer antiviral resistance. We now show that similar depletion of B-cells with rabbit anti-mouse immunoglobulin G plus complement or macrophages by adherence to Sephadex G-10 columns also leaves intact the protective capacity of spleen cells from serum-protected mice. That these results reflect the ability of more than one spleen cell population to transfer antiviral resistance rather than the activity of a non-T, non-B, nonmacrophage cell compartment is supported by the finding that purified splenic T- or B-cells alone from serum-protected DBA/2 mice can adoptively transfer antiviral resistance. Given the previously reported effects of sublethal irradiation on FLV leukemogenesis which could potentially complicate the interpretation of adoptive transfer experiments carried out in this system, analogous studies were performed using a Winn-type assay in which putative effector cells were preincubated with virus before inoculation of the mixture in unirradiated mice. These Winn assay experiments yielded identical results in that serum-protected spleen cells again prevented viral leukemogenesis, and the separate elimination of T-cells, B-cells, or macrophages had no effect on their protective activity. In addition, mixed transfer of serum-protected and normal spleen cells also protected irradiated mice against FLV challenge, providing further evidence that this adoptive protection truly reflects the presence of virus-specific effector cells in the spleens of serum-protected mice and not an inability of these spleen cells to replace radiation-sensitive viral target cells in recipient animals, since these should be supplied by the normal spleen cells in the transferred mixture.

Immunotherapy of murine leukemia VI. Development of immunologic memory in mice protected against Friend leukemia virus-induced disease by passive serum therapy.

The resistance of DBA/2 mice to infection with a leukemogenic dose of Friend leukemia virus (FLV) as a result of the passive administration of chimpanzee anti-FLV serum is maintained for at least six months after infection and is accompanied by the continued synthesis of mouse anti-viral antibodies analogous to that previously found to be associated with short-term protection (approx. 30 days). Furthermore, the induction of immunologic memory in serum-protected mice is demonstrated by their long-term resistance to rechallenge with FLV of FLV-infected leukemic spleen cells, although cells of an established transplantable syngeneic FLV-erythroleukemia (FLC-745) are not rejected. In the course of these studies, a serum prophylaxis effect was defined in DBA/2 mice treated with the chimpanzee anti-FLV serum before, rather than after FLV infection. The prophylaxis effect is highly dependent on the time period between the last serum inoculation and virus challenge. The results indicate that the long-term resistance of therapeutically protected mice to subsequent virus or leukemic cell challenge is not due to the short-term prophylactic effect of serum treatment alone.

Antiviral efficacy of lobucavir (BMS-180194), a cyclobutyl-guanosine nucleoside analogue, in the woodchuck (Marmota monax) model of chronic hepatitis B virus (HBV) infection.

Lobucavir (BMS-180194), a cyclobutyl-guanosine nucleoside analogue, effectively reduced WHV-viremia in chronically infected carrier woodchucks (Marmota monax) by daily per os treatment. WHV-viremia in the animals was measured by the serum content of hybridizable WHV-genomic DNA. Lobucavir, given at daily doses of 10 and 20 mg/kg body weight, reduced WHV-viremia by a 10- to 200-fold range during therapy. Lobucavir, given at 5 mg/kg, suppressed WHV-viremia by a 10- to 30-fold range, whereas a 0.5 mg/kg dose had no significant effect. WHV-viremia was also measured by hepadnaviral endogenous polymerase activity (EPA) in sera of animals treated for 6 weeks at 5 and 0.5 mg/kg. Changes in EPA in sera of lobucavir treated animals were comparable to changes in WHV DNA levels. Viremia in treated carriers recrudesced to pretreatment levels by 2 weeks of therapy cessation. These results indicated that the minimally effective antiviral daily per os dose of lobucavir in WHV-carrier woodchucks was approximately 5 mg/kg.

Cytopathogenic effect of African swine fever virus for pig monocytes: characterization and use in microassay.

A microculture assay is described for the titration of African swine fever virus (ASFV) using swine monocytes contained in mononuclear leucocyte (MNL) microcultures. Titration endpoints were determined by observing cytopathogenic effects (CPE) of ASFV infected monocytes with an inverted microscope at 40 X magnification. CPE was a late event following the detection of ASFV antigens in monocytes by radioimmune assay, immunofluorescence and hemadsorption. It began with the detachment, enlargement and rounding of monocytes which progressively formed into grape-like clusters of 3-20 or more cells which eventually lysed. The characteristic CPE was produced in monocyte microcultures by virulent, moderately virulent, Vero cell adapted, and nonhemadsorbing ASFV strains. The sensitivity and reproducibility of the CPE microassay was similar to that of the hemadsorption microassay.

Effect of macrophage-specific colony-stimulating factor (CSF-1) on swine monocyte/macrophage susceptibility to in vitro infection by African swine fever virus.

Swine cells of the monocyte/macrophage lineage (MM) proliferate and survive for several weeks in vitro in medium supplemented with the murine macrophage-specific hematopoietic growth factor, colony-stimulating factor 1 (CSF-1). The extent to which MM, cultured in CSF-1, supported African swine fever virus (ASFV) growth in vitro was investigated. MM, cultured in medium with CSF-1, were sensitive to infection and viral-induced cytopathogenic damage by both natural field isolates of ASFV and fibroblast-adapted ASFV strains, as were primary MM (P-MM). Without CSF-1, blood mononuclear leukocytes (MNL), containing lymphocytes and MM, and P-MM could be reliably used in microculture for ASFV titration when inoculated at times limited to no more than 3 to 5 days after culture inception; inclusion of CSF-1 in the media stimulated continued MM survival and growth, and allowed for the use of MNL and P-MM for ASFV titration when inoculated as long as 2 to 3 weeks after microculture inception. MM that were propagated beyond 1 week in secondary culture in medium with CSF-1 (MM-CSF) were useful in microcultures for infective-ASFV titration, only when the cells were kept in medium with CSF-1 and inoculated no later than 3 days of culture inception. In vitro studies of ASFV infection in P-MM and in MM-CSF showed comparable kinetics in ASFV-induced hemadsorption (HAd), cytopathogenic effect (CPE), cytoplasmic viral antigens and nucleic acid material. Compared to P-MM in culture without CSF-1, relatively minor delays in CPE onset induced by some ASFV strains were noticed in MM-CSF and in P-MM that were placed in media with CSF-1. The effects of ASFV on DNA synthesis in the virus-susceptible MM, cultured with or without CSF-1, were also examined at different times of infection by measurement of 3H-thymidine (3H-TdR) incorporation into total precipitable culture material. ASFV-infection of P-MM, placed in culture medium with CSF-1, caused a pronounced transient increase in total 3H-TdR incorporation at the early onset of CPE and HAd. When compared to uninfected P-MM that were stimulated by CSF-1 to synthesize DNA, infected P-MM failed to incorporate 3H-TdR after CPE was fully evident. For P-MM that were cultured without CSF-1 and for MM-CSF, that were kept in culture with CSF-1, transient increases in 3H-TdR incorporation at the onset of CPE and HAd by ASFV-infection were evident, but were much less pronounced.

In vivo and in vitro effects of moderately virulent African swine fever virus on mitogenesis of pig lymphocytes.

Six pigs were infected oro-nasally with a moderately virulent African swine fever (ASF) virus from the Dominican Republic (DR II). The effect of virus infection on the pig's immune system was tested by measuring peripheral leucocyte numbers and the ability of mononuclear leucocytes (MNL) to respond by lymphocyte proliferation (LP) to the mitogens phytohemagglutinin-P (PHA-P), concanavalin-A (Con-A), and pokeweed mitogen (PWM). All 6 pigs developed high viremias between 4 and 18 days post-inoculation (DPI) which became undetectable by 32 to 46 DPI. Virus was found in erythrocytes, plasma, and mononuclear leucocytes from peripheral blood. Overall, virus infection had only minor effects on the number of circulating leucocytes, lymphocytes, monocytes and granulocytes. At the early acute phase of infection slight neutrophilia and lymphocytopenia were observed with mildly elevated monocyte numbers and slightly depressed neutrophil numbers that continued from the time of evident reduction in viremia to beyond the period of viral clearance. The infected pigs readily produced high titers of ASF virus antibody shortly after the onset of viremia. No significant differences in LP responses of MNL from the 6 pigs to PHA-P, Con-A and PWM were observed after infection when compared to those obtained with MNL from normal pigs. The in vitro addition of infectious ASF virus to MNL from normal pigs did not affect LP responses to any of the three mitogens. These results do not support the hypothesis that immunosuppression is a consequence of ASFV infection of pigs.

In vitro induction of swine peripheral blood monocyte proliferation by the fibroblast-derived murine hematopoietic growth factor CSF-1.

The addition of conditioned medium from murine L929 fibroblasts (MGF) to cultures of swine peripheral blood mononuclear cells (MNL) resulted in growth of cells of macrophage/monocyte lineage (MO). Glass-adherent swine MNL, shown to be greater than 95% phagocytic MO, grew in the presence of MGF, whereas swine blood granulocytes and lymphocytes were not MGF-responsive. Primary and secondary MO growth were directly dependent on MGF presence and concentration. MGF-stimulated MO synthesized DNA, as measured by cellular incorporation of tritium-labeled thymidine (3H-TdR). This mitogenic response was maximal by 5 to 6 days in primary MO cultures and declined thereafter to a lower magnitude in secondary MO cultures. In the presence of MGF, viable MO numbers increased with an approximate population doubling time of 5 to 7 days in primary culture. This growth rate was prolonged, to about 10 to 12 days, for MGF-stimulated MO in secondary cultures. MGF removal from primary and secondary MO cultures resulted in rapid growth cessation and cell death. MGF-stimulated MO could not be sustained in secondary culture beyond 7 weeks. MGF-cultured MO were positive for latex phagocytosis, non-specific esterase, Fc-receptor expression, and could mediate antibody-dependent cell-mediated cytotoxicity. The MO-mitogenic principle of MGF was identified as the murine, macrophage-specific colony-stimulating factor, CSF-1 (M-CSF). The swine MO-proliferative response to MGF was inhibited by addition of monospecific goat antisera to M-CSF. Purified M-CSF stimulated the growth of swine MO from cultures of MNL and primary glass-adherent MO.

Loss of tumorigenicity following in vitro MuLV infection is associated with induction of peritoneal natural killer cell activity.

Infection by an attenuated replication-competent murine retrovirus (Friend leukemia virus-FLV4), but not other non-transforming retroviruses, stimulated rejection of transplantable thymomas (RL-cell line) and subsequent tumor immunity in syngeneic mouse recipients. FLV-infected RL-cells (RL-FLV) were unaltered in their in vitro growth, and grew progressively to kill sublethally irradiated animals and nude mice. Primary RL-FLV rejection was due to induction of increased natural killer (NK)-cell activity limited to peritoneal sites of tumor inoculation with a minor cytolytic macrophage population. Syngeneic mutant beige (NK-deficient) mice similarly rejected RL-FLV cells with increased peritoneal NK-cell activity and acquired immunity to the parental RL-tumor. While RL-FLV stimulated far greater peritoneal NK activity than did other tested retrovirus-infected RL-cells, the inherent susceptibility of these cells to lysis by normal NK cells was not altered by virus. RL-FLV induced NK effectors showed an indiscriminate lysis pattern that was independent of target cell type and retrovirus expression.

In vitro immune serum-mediated protection of pig monocytes against African swine fever virus.

Serum samples from pigs that had recovered from infection with a Dominican Republic isolate of African swine fever virus (ASFV) were mixed with dilutions of the virus, then assayed in microcultures of normal pig mononuclear leukocytes to determine whether the samples contained antibodies that protected monocytes against the virus. Protection was determined by the difference in titer (log10) between virus mixed with healthy pig serum and virus mixed with immune pig serum, using 50% cytopathogenic effect end points; protection was expressed as an immune serum-protection index. After addition of virus-serum mixtures to mononuclear leukocyte microcultures, a time-dependent decrease in protective index and production of infectious virus (determined by use of yield reduction assays) were observed. Protective effects were associated with the immunoglobulin fraction of serum, were rapidly lost on dilution, and were independent of complement. Antibody was most protective for the homologous Dominican Republic isolate of ASFV, with decreased protection against Lisbon '60 ASFV, and no protection against foot-and-mouth disease virus or bluetongue virus. Low concentrations of protective antibody were found during the acute viremic phase in infected pigs; antibody increased to maximal concentrations as the viremia decreased.

Moderately virulent African swine fever virus infection: blood cell changes and infective virus distribution among blood components.

Blood samples of pigs infected with a moderately virulent African swine fever virus (ASFV) isolate, obtained from the Dominican Republic (DR-II), were monitored temporally for viremia, infective ASFV association with major blood components, differential changes in blood cell composition, and plasma antibodies to ASFV. After intranasal/oral virus inoculation, pigs underwent acute infection and illness that resolved. Acute illness began on postinoculation day (PID) 4 and continued to PID 11, and pigs were febrile, with maximal infective ASFV titers detected in blood. By PID 11, initial antibody titers to ASFV antigens were detected in plasma. The WBC numbers were maintained near preinoculation counts; however, lymphocyte counts decreased slightly with a compensatory increment in neutrophil and monocyte numbers. From PID 11 to PID 25, rectal temperatures gradually returned to preinoculation values, titers of viremia began to decrease, plasma antibody to ASFV antigens increased to peak titers, and WBC numbers increased slightly. Percentages of lymphocytes returned to preinoculation values, neutrophil percentages decreased to slightly below preinoculation values, monocyte percentages were mildly increased, and eosinophil percentages were unaffected. From PID 25 to PID 46, titers of viremia further decreased, and plasma titers of antibodies to ASFV antigens remained high. In pigs with DR-II viremia (PID 4 to PID 46), most viral infectivity (greater than 95%) was RBC associated. Plasma contained less than 1% infectivity, and less than 0.1% of virus was in the WBC fraction (monocytes, lymphocytes, and granulocytes). After PID 46, viremia was no longer detectable.

In vitro growth inhibition of murine leukemia cells by antibody specific for the major envelope glycoprotein (gp71) of Friend leukemia virus.

An in vitro complement (C')-independent growth cytostasis model is described in which the replication of Friend leukemia virus (FLV)-induced erythroleukemia cells (of the FLC-745 cell line) is inhibited by goat serum directed against the major FLV envelope glycoprotein, gp71. The cytostatic effect is reversible, with the degree of this reversibility dependent on both the concentration and duration of exposure to immune serum. The inhibitory factor in heat-activated goat anti-FLV gp71 (delta G alpha FLV gp71) serum has been identified as virus-specific IgG antibody, and F(ab')2 fragments of this antibody are highly effective in suppressing FLC-745 cell growth. Studies with various murine leukemia and lymphoma cell lines, as well as with a panel of antisera directed against various murine oncornaviruses or viral proteins, have demonstrated that antibodies reactive with the group or type determinants of FLV gp71 are capable of mediating cytostasis. Under conditions of antibody-mediated growth inhibition of FLC-745 cells, specific modulation of gp71 expression is followed by nonspecific modulation of H-2d antigen expression. In addition, considerable cell death occurs in cytostatic cultures which is accompanied by continued division (as measured by DNA synthesis) of a portion of the cell population. Cytofluorimetric analysis of nuclei from growth-inhibited FLC-745 cells demonstrates a diminution in the frequency of cells in the G2/M phase of the cell cycle. It is suggested that antibody-mediate FLC-745 cell growth inhibition operates via a blockade of the cell cycle which prevents most cells in the population from traversing G2/M. While these blocked cells appear to be subject to slow cytolysis by a C'-independent mechanism, a portion of the cells escape this blockade and continue to replicate, thus offsetting the death of the former cells to yield a relatively constant density of viable cells for at least 72-96 h of growth inhibition. The possible relevance of this in vitro phenomenon to in vivo passive therapy against FLV-induced disease with G alpha FLV gp71 and similar antisera is briefly considered.

Immunosuppression-induced susceptibility of inbred hamsters (Mesocricetus auratus) to lethal-disease by lymphocytic choriomeningitis virus infection.

The role of the immune response in the pathogenesis of lethal and non-lethal lymphocytic choriomeningitis virus (LCMV)-infections of young adult Syrian golden hamsters (Mesocricetus auratus) of different strains was examined using immunosuppressive treatment with cyclophosphamide or with whole-body gamma-irradiation. In all hamsters, the LCMV strains, WE and Armstrong (ARM), caused systemic infections and induced comparable serum LCMV-antibody titers. However, lethal wasting-disease occurred which was hamster-strain and virus-strain dependent. With WE-inocula, MHA and PD4 inbred hamsters were all susceptible to lethal-disease and failed to completely eliminate infection. All LSH and CB inbred hamsters resisted lethal-disease and totally cleared WE-infection. Random colony-bred LVG hamsters and inbred LHC hamsters were intermediate in WE-susceptibility; some died with wasting, while others survived with minimal to no illness. ARM was avirulent for all hamsters and infections were totally cleared. By immunosuppressive treatment, all hamsters were rendered completely susceptible to lethal-disease by WE, and had unresolved infections and diminished serum LCMV-antibody titers. Immunosuppression also rendered all hamster strains partially susceptible to lethal infection by ARM. The hamster immune response was thus shown to suppress LCMV-infection and protect against lethal illness.

Susceptibility of inbred Syrian golden hamsters (Mesocricetus auratus) to lethal disease by lymphocytic choriomeningitis virus.

An acutely lethal LCMV disease model has been established in the Syrian golden hamster (Mesocricetus auratus) in which lethality and disease are dependent upon both the inbred hamster strain and the LCMV strain. Young adult inbred, male and female, hamsters were tested for lethal-disease susceptibility by lymphocytic choriomeningitis virus (LCMV) strains, WE or Armstrong (ARM). With WE inocula, PD4 and MHA inbred hamsters were highly susceptible to a wasting disease. LVG and LHC inbred hamsters were intermediate in susceptibility; some of these animals died of wasting illness, and others exhibited minimal disease and survived. CB and LSH hamsters were highly resistant to any disease by WE. Mean survival times of susceptible hamsters given lethal WE inocula approximated 2.5 weeks and were not dependent on virus dose. By 1.5 weeks after WE inoculation wasting disease signs were notable and consisted of lethargy, progressive body weight loss, and diarrhea. The LCMV strain, ARM, was avirulent for all hamster strains, causing neither death nor disease. Hamsters surviving WE or ARM inoculation appeared healthy, produced LCMV antibody, and acquired resistance to further lethal WE challenge. Despite hamster-lethality differences. WE and ARM appeared comparably immunogenic for all hamster strains, based on host antibody titers. A number of other differences between the LCMV strains were, however, noted which could be relevant to virus virulence and lethality for hamster hosts. These included guinea pig lethality, temperature sensitivity, and plaque morphology.

Susceptibility of Friend virus antigen-modulated erythroleukemic cells to lysis by T lymphocytes from mice with dormant Friend virus infections.

Spleen cells from DBA/2 mice with dormant Friend leukemia virus (FLV) infections or from mice immunized with x-irradiated FLC-745 erythroleukemic cells are not cytolytic for FLC-745 cells when tested directly, but acquire cytolytic activity in vitro by cultivation with x-irradiated FLC-745 cells. Spleen cells cultured from normal mice do not acquire such cytolytic activity. Cytolytic activity resides in the T lymphocyte population. Alloantiserum, but not antisera against FLV-virion polypeptides, inhibited the lysis of FLC-745 cells by cytolytic T lymphocytes. To understand further the role of cellular and humoral immune anti-FLV responses in mice with dormant FLV-infections, in vitro experiments were conducted that mimicked the in vivo FLV-specific immune environment of these mice. We found that FLV-immune serum from mice with dormant FLV-infections modulated FLV-antigen expression on the surfaces of FLC-745 cells without affecting their susceptibility to lysis by cytolytic T lymphocytes. These results suggest that cytolytic T lymphocyte restrain the outgrowth of FLV-antigen-modulated erythroleukemic cells in mice with dormant FLV infections and that the targets for cell-mediated lysis may be H-2d-associated antigens.

Immunotherapy of murine leukemia. VII. Prevention of Friend leukemia virus-induced immunosuppression by passive serum therapy.

Previous studies have suggested that the passive therapy of Friend leukemia virus (FLV)-induced disease with chimpanzee anti-FLV serum operates by reducing the level of infectious virus in the treated animal below the immunosuppressive threshold, thereby allowing the host to mount anti-viral immune responses which are responsible for long-term protection. The present study was undertaken to examine directly the effect of passive serum therapy on the marked immunosuppression induced by FLV in progressively infected mice, as well as to determine whether virus-specific host cellular immune effector functions are augmented in serum-protected animals. Using a variety of assays of host immunocompetence, including natural killing (NK), antibody-dependent cellular cytotoxicity (ADCC) in vivo and in vitro induction of allogeneic killers, and mitogen blastogenesis, a marked compartmentalization of FLV immunodepression was observed in progressively infected DBA/2 mice, possibly reflecting the distribution of FLV target cells in various host lymphoid populations. Thus, spleen-cell functions were suppressed most rapidly and to the greatest degree, followed by peritoneal cells and peripheral blood lymphocytes, while lymph node cells and thymocytes maintained normal levels of activity. In contrast, serum-protected mice demonstrated no sign of FLV-induced immunosuppression regardless of the host effector-cell population or immune function examined. However, we were not able to identify host anti-viral cellular immune functions which are significantly enhanced in serum-protected animals; thus the specific role of the host immune system in the passive serum therapy of FLV-induced disease remains undefined at the present time.

Delayed type-hypersensitivity response of inbred strains of Syrian golden hamsters (Mesocricetus auratus) to lethal or non-lethal lymphocytic choriomeningitis virus (LCMV) infections.

In adult Syrian golden hamsters (Mesocricetus auratus), intraperitoneal or footpad inoculation of the lymphocytic choriomeningitis virus (LCMV) strains, WE or Armstrong (ARM), caused systemic infection and induced serum LCMV-antibody. Hamster and virus strain-dependent lethal disease also occurred. With WE, MHA and PD4 inbred hamsters failed to eliminate infection and died of wasting disease. LSH and CB inbred hamsters resisted lethal WE-disease and cleared infection. LVG hamsters and inbred LHC hamsters were intermediate in WE-susceptibility; some died of wasting, while others survived with little illness. Resistance to lethal WE-disease directly correlated with a delayed-type hypersensitivity (DTH) response to live-virus footpad inoculation. In WE-resistant LSH and CB hamsters, DTH-responses were induced by intraplantar WE-inoculation; footpad edema began by 5 days, reached maximum thickness by 7 to 9 days, and subsided thereafter. In the other hamster strains, DTH to WE could not be elicited. Unlike WE, ARM was hamster-avirulent; infections were self-limited and did not induce DTH. All survivors of primary LCMV (WE or ARM)-infection resisted secondary WE-challenge, and did not develop DTH to LCMV. Immunosuppressive treatments, abrogating DTH and antibody responses to LCMV, rendered all hamsters susceptible to lethal WE-infection. Hamster DTH most likely mediated resistance to virulent LCMV-infection.