Cellular immune activation reflects antiviral immunity and is a favorable prognostic marker in patients with cytomegalovirus infection.
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Antigens, CD↗
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DNA immunization can stimulate florid local inflammation, and the antiviral immunity induced varies depending on injection site.
DNA immunization is being considered to augment, or even to supplant, more traditional methods of antiviral immunization. Different routes of administration lead to markedly different levels of marker protein expression, but only limited data are available concerning the antiviral responses induced by DNA inoculated by different routes, and their protective efficacy. In this report we evaluate antiviral immunity induced by inoculation of DNA by the intramuscular (i.m.) and intradermal (i.d.) routes, and make three novel observations. First, i.d. immunization is dose-dependent and, although not uniformly successful, can induce very high levels of cytotoxic T lymphocyte (CTL) activity, varying dependent on the vehicle in which the DNA is administered. Second, while antiviral immunity induced by i.m. DNA injection has been demonstrated by many groups, we show herein a marked difference in immunity depending on the muscle injected. Immunity induced by DNA injection of the anterior tibial muscle significantly exceeds that induced following injection of the quadriceps muscle as judged by three criteria, namely CTL induction, decrease in virus titer following nonlethal challenge, and survival following a normally lethal challenge dose of virus. Thirdly, we evaluate the local immune response induced following immunization with DNA encoding a viral antigen. We show that, when recipients are already immune to the encoded protein, a severe but localized inflammatory response may result.
Animals↗
Modulation of antiviral immune responses by exogenous cytokines: effects of tumour necrosis factor-alpha, interleukin-1 alpha, interleukin-2 and interferon-gamma on the immunogenicity of an inactivated rabies vaccine.
In vivo administration of exogenous cytokines may influence elicited immune responses, and hence may change the efficacy of a vaccine. We investigated the effects of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) on the immune response elicited by inactivated rabies virus vaccine in a mouse model. Each of the cytokines increased virus-specific IgG responses after primary and after secondary immunization. A single dose of 1.3 ng TNF-alpha or IL-1 alpha, when injected shortly before vaccination, only marginally stimulated resistance to challenge infection (four- and seven-fold, respectively) without enhancing virus neutralizing antibody (VNAb) responses. In contrast, a single injection of 10(3) units of IFN-gamma or five daily injections of 1.6 micrograms IL-2 increased vaccine dilutions protecting 50% of mice (PD50 values) 77- to 50-fold, respectively, with a concomitant enhancement of VNAb. At a 1:10,000 dilution of a standard inactivated rabies vaccine preparation both IFN-gamma and IL-2 increased protective immunity without enhancing VNAb responses; in non-vaccinated animals this treatment had no effect on resistance to challenge. Combined administration of IFN-gamma and IL-2 synergistically enhanced VNAb responses. In contrast to the other cytokines tested, IFN-gamma preferentially stimulated virus-specific IgG2a production. It also augmented the vaccine-induced priming of rabies virus-specific splenocyte proliferation. These results document that certain cytokines alone or in combination are potent immunological adjuvants which may direct and modulate immunization-induced antiviral immune responses.
Animals↗
Individual differentiation of innate antiviral immunity in humans; the role of endogenous interferons and tumor necrosis factor in the immunity of leukocytes.
The natural antiviral immunity of human lymphocytes, leukocytes from peripheral blood and whole-blood cultures was studied using the method of infection with two viruses belonging to different taxonomic groups, vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV). The kinetics of virus replication in the kinds of cultures and the dependence of culture infection on pre-infection incubation time were studied. When the cultures were infected immediately after preparation, most of them were found to be resistant to the viruses. However, when they were infected after several (1-5) days of incubation, VSV and EMCV multiplied in the cultures to high titers. The time of losing resistance was individually differentiated. The results indicate the presence of a non-specific antiviral immunity characteristic for individuals. The antiviral immunity of healthy donors was compared with that of people suffering from recurrent infections of the upper respiratory tract. This latter group expressed statistically significant lower innate immunity than healthy donors. However, there were no differences in interferon (IFN) and tumor necrosis factor (TNF) production between these groups. In order to examine the contribution of the endogenous IFNs and TNF-alpha in maintaining innate immunity, specific antibodies against IFN-alpha, IFN-beta, IFN-gamma and TNF-alpha were added to VSV-infected leukocytes resistant to infection. The antibodies reduced the antiviral resistance in 9 of 16 experiments. The results suggest that both endogenous interferons and TNF-alpha may participate in the constitution of innate immunity, though they are not the only mediators of it.
Animals↗
Lymphotoxin-beta-deficient mice show defective antiviral immunity.
Lymphotoxin beta (LTbeta), a member of the tumor necrosis factor family, plays an important role in lymphoid organogenesis. In order to determine whether LTbeta is involved in cellular immunity, we investigated the antiviral immune response of LTbeta-deficient (LTbeta -/-) mice to lymphocytic choriomeningitis virus (LCMV). Cytotoxic T lymphocyte (CTL) responses to LCMV were severely diminished, leading to viral persistence in brain and kidney. However, major functions of LTbeta-deficient T lymphocytes and dendritic cells were intact. Reconstitution of irradiated LTbeta +/+ mice with LTbeta -/- bone marrow induced a disorganized splenic structure, accompanied by impairment of the LCMV-specific CTL response. These data indicate that the absence of LTbeta does not affect the intrinsic function of T lymphocytes or of dendritic cells but that the structural integrity of the spleen is strongly associated with generation of antiviral immunity.
Adoptive Transfer↗
Antiviral immune cytolysis at an early stage of paramyxovirus infection.
Antiviral antibody and rabbit complement added as early as 5 min after infection, and with relatively low virus/cell multiplicity, lysed mouse ascites lymphoma cells infected with Sendai or Newcastle disease virus. Inactive Sendai virus at much higher input also sensitized ascites cells and mouse fibroblast monolayers to early antiviral immune cytolysis. At 4 C where adsorption but no penetration occurred, antibody removed virus from the cell membrane and little cytolysis was observed. The ascites cells were sensitive to antibody and complement at all times after the start of penetration and uncoating, indicating that viral envelope antigen is constantly present on the cell membrane. Significant cross-reactions by immune cytolysis between Newcastle disease virus- and Sendai virus-infected cells suggested possible participation of host antigens of the viral envelope. No comparable antiviral immune cytolysis was observed with influenza strains PR8 and WSN. Cell viability was estimated by dye exclusion and the ability to form acid from glucose as indicated by colorimetric pH of the medium. The relation of antiviral immune cytolysis to changes in the membrane resulting in cell fusion is considered.
Absorption↗
Immunization with a lymphocytic choriomeningitis virus peptide mixed with heat shock protein 70 results in protective antiviral immunity and specific cytotoxic T lymphocytes.
Heat shock proteins (hsp's) isolated from murine cancer cells can elicit protective immunity and specific cytotoxic T lymphocytes (CTLs) by channeling tumor-derived peptides bound to hsp's to the major histocompatibility class I antigen presentation pathway. Here we have investigated if hsp70 can be used in a novel peptide vaccine for the induction of protective antiviral immunity and memory CTLs. A CTL epitope from the well-defined lymphocytic choriomeningitis virus (LCMV) system was mixed with recombinant hsp70 in vitro under conditions that optimize peptide binding to hsp70. Mice were immunized with the hsp70-peptide mixture and challenged with LCMV. Virus titers were reduced 10-100-fold in these mice compared to control mice. Immunization with the hsp70-peptide mixture resulted in the development of CTL memory cells that could be reactivated during LCMV infection, and that in a 51Cr-release assay could lyse cells pulsed with the same peptide, but not cells pulsed with another LCMV peptide. These results show that hsp70 can be used with CTL epitopes to induce efficient protective antiviral immunity and the generation of peptide-specific CTLs. The results also demonstrate the usefulness of hsp70 as an alternative to adjuvants and DNA vectors for the delivery of CTL epitopes to antigen-presenting cells.
Adjuvants, Immunologic↗
CD8+ T lymphocyte-mediated antiviral immunity in mice as a result of injection of recombinant viral proteins.
A major portion of the nucleoprotein (amino acids 67 through 300) and the glycoprotein-2 of lymphocytic choriomeningitis (LCM) virus were synthesized by using recombinant technology and were injected together with SDS twice in portions of 5 micrograms into BALB/c mice. As evidenced by diminished replication of LCM challenge virus, both proteins induced antiviral immunity, which was comparable in extent with the immunity caused by infection with LCM vaccinia recombinant viruses. Primed LCM-viral CTLs could not be demonstrated in these mice by culturing splenocytes in the presence of LCM virus, and Abs appeared slowly and in low quantities; but, after injection of large infectious doses, CTLs appeared faster and in higher numbers than in mice not previously treated with viral proteins. Depletion of CD8+ cells, but not of CD4+ cells, by treatment of mice with mAb abolished the antiviral immunity, demonstrating that protection was mediated by CD8+ T lymphocytes. Absence of CD4+ T lymphocytes before and during the period of immunization did not measurably affect the animals' antiviral immune status, indicating that activation of the CD8+ T lymphocytes was not dependent on help by CD4+ cells.
Amino Acid Sequence↗
Mathematical model of antiviral immune response. II. Parameters identification for acute viral hepatitis B.
Considering the mathematical model of antiviral immune response, we describe a method of fitting the model to the data characterizing acute viral hepatitis B. The corresponding procedure employs an idea of sequential parameter estimation to make the problem of fitting manageable. The underlying mechanisms responsible for the quantitative manifestations of the four basic phases of acute hepatitis B are used to select the model parameters. The identified model of acute hepatitis B is then tested with regard to the following situations: the effect of HBsAg-specific antibodies on HBV challenge; the vaccination and the resistance to challenge using live hepatitis B virus; the dose of viruses--the incubation time relationships. The sensitivity of the model with respect to parameters variations is then analysed. The developed model allows us to quantitatively simulate the basic features of the antiviral immune response during acute hepatitis B and some closely related phenomena.
Acute Disease↗
Interferons (IFNs) are key cytokines in both innate and adaptive antiviral immune responses--and viruses counteract IFN action.
Interferons (IFNs) are transcriptionally regulated cytokines and key players in the innate antiviral immune response. Upon recognition of a virus, or its molecular patterns, by the Toll-like receptors of dendritic cells (DCs), high levels of IFNs are expressed by these cells. This in turn stimulates DC maturation and the subsequent expression of proinflammatory cytokines and costimulatory molecules, leading to the transition to an adaptive antiviral immunity. Conversely, viruses have developed diverse strategies to counterattack host defenses in order to generate their progenies.
Animals↗
[Humoral antiviral immunity in children with hematologic neoplasms].
Antiviral humoral immunity was studied in patients with Hodgkin's disease, idiopathic thrombocytopenic purpura (ITP), and aplastic anemia (AA). Insufficiency of antiviral humoral immunity as regards antigenically unrelated viruses and Mycoplasma pneumoniae was characteristic of all these conditions. A remission of Hodgkin's disease and ITP was associated with a reliable increase of the studied parameters in comparison with the acute period of the disease. After splenectomy humoral immunity parameters were virtually unchanged in patients with ITP, whereas in patients with Hodgkin's disease and AA the deficiency of antibody production is 40% increased after the operation.
Adolescent↗
Neonatal infection of mice with lactate dehydrogenase-elevating virus results in suppression of humoral antiviral immune response but does not alter the course of viraemia or the polyclonal activation of B cells and immune complex formation.
Neonatal infection of FVB mice with lactate dehydrogenase-elevating virus (LDV) prevented the normal formation of anti-LDV antibodies observed in mice infected at 5 days of age or older. Even 22 weeks post-infection, the concentration of circulating anti-LDV antibodies in neonatally infected mice was insignificant. However, the time course and level of persistent viraemia were the same in neonatally infected mice lacking anti-LDV antibodies as in mice infected at 5 or 15 days of age which developed normal antiviral immune responses. The results support the view that LDV replication in mice is unaffected by antiviral immune responses and instead is primarily dependent on the rate of regeneration of LDV-permissive macrophages. This view is further supported by the following findings. Treatment of mice with cyclophosphamide or dexamethasone, which are known to increase plasma LDV levels, increased the proportion of LDV-permissive macrophages in the peritoneum. Injection of mice with interleukin-3, which is known to stimulate macrophage development, increased plasma LDV levels in persistently infected mice 10- to 100-fold. During the first month of age when mice possess a higher proportion of LDV-permissive macrophages than older mice and peritoneal macrophages exhibit self-sustained growth, the persistent plasma LDV titres were also 10- to 100-fold higher than in older mice. The polyclonal activation of B cells induced by LDV that results in a permanent elevation of IgG2a or IgG2b in the circulation, and the formation of 180K to 300K immune complexes containing IgG2a or IgG2b were also the same in neonatally infected mice and mice infected 5 or 15 days after birth. Thus, the polyclonal activation of B cells occurs in the absence of an antiviral humoral immune response and the immune complexes do not contain anti-LDV antibodies. The immune complexes probably consist of autoantibodies formed in the course of the polyclonal activation of B cells and their cellular antigens.
Animals↗
Evaluation of immunological paradigms in a virus model: are dendritic cells critical for antiviral immunity and viral clearance?
We have examined the role of dendritic cells (DCs) in the antiviral immune response and viral clearance using a transgenic mouse model (CD11c-diphtheria toxin (DT) receptor GFP) that allows for their conditional ablation in vivo. DT administration systemically ablated conventional and IFN-producing plasmacytoid DCs (pDCs) in transgenic, but not nontransgenic littermates, without elimination of splenic macrophages. Unexpectedly, early (12 and 48 h postinfection) viral clearance of vesicular stomatitis virus was normal in DC-depleted mice despite markedly reduced serum titers of type I IFN. DC-depleted mice remained virus-free with the exception of a subset (approximately 30%) that developed overwhelming and fatal brain infections 6 days postinfection. However, DT treatment profoundly inhibited clonal expansion of naive CD8+ vesicular stomatitis virus-specific T cells without altering the primary Th1 and Th2 cytokine response. Optimal clonal expansion required pDCs because selective elimination of these cells in vivo with a depleting Ab also suppressed expansion of tetramer+ cells, although Th1/Th2 cytokine production remained unaltered. Collectively, these data indicate that conventional DCs and to a lesser extent pDCs are critical for proliferation of naive antiviral T cells. However, other components of the primary adaptive immune response (Th1/Th2 cytokines) are essentially normal in the absence of DCs, which may account for the efficient viral clearance seen in DC-depleted mice. Thus, sufficient redundancy exists in the immune system to sustain efficient viral clearance despite loss of an APC considered essential for induction of a primary antiviral immune response.
Animals↗
Effect of cyclosporine A on the non-specific, innate antiviral immunity of mice.
Different infections are the most common complication of immunosuppressive therapy. In this context, the effect of cyclosporine A (CsA) on the innate antiviral immunity of mice was studied. The presence of immunity was shown by infection of resident peritoneal cells (RPC) of BALB/c mice with herpes simplex virus type 1 (HSV-1) and vesicular stomatitis virus (VSV). While the cells infected immediately after isolation were resistant to the viruses, the cells cultured for several days before infection lost the immunity. The lack of activity to neutralize HSV-1 and VSV in the sera of the mice excluded a participation of specific antibodies in the resistance. To study the effect of CsA on the innate immunity, BALB/c mice were intraperitoneally (i.p.) injected with cyclosporine (20 or 100 microg/mouse, twice a day) for 3 days. The other group of animals was injected in the same way with PBS only. Then the peritoneal cells were isolated and infected with VSV immediately after cell isolation. The kinetics of viral replication in the control and CsA-treated groups was compared. While in the cells from the control group VSV did not multiply, in the cells from the CsA-treated mice the virus reached considerable titers. The cyclosporine effect on VSV replication was dose dependent and statistically significant. We conclude that innate antiviral immunity was suppressed in the cyclosporine-treated mice and that this mechanism may be involved in the high susceptibility of patients to viral infections during immunosuppressive therapy.
Animals↗
Dendritic cells efficiently induce protective antiviral immunity.
Cytotoxic T lymphocytes (CTL) are essential for effective immunity to various viral infections. Because of the high speed of viral replication, control of viral infections imposes demanding functional and qualitative requirements on protective T-cell responses. Dendritic cells (DC) have been shown to efficiently acquire, transport, and present antigens to naive CTL in vitro and in vivo. In this study, we assessed the potential of DC, either pulsed with the lymphocytic choriomeningitis virus (LCMV)-specific peptide GP33-41 or constitutively expressing the respective epitope, to induce LCMV-specific antiviral immunity in vivo. Comparing different application routes, we found that only 100 to 1,000 DC had to reach the spleen to achieve protective levels of CTL activation. The DC-induced antiviral immune response developed rapidly and was long lasting. Already at day 2 after a single intravenous immunization with high doses of DC (1 x 10(5) to 5 x 10(5)), mice were fully protected against LCMV challenge infection, and direct ex vivo cytotoxicity was detectable at day 4 after DC immunization. At day 60, mice were still protected against LCMV challenge infection. Importantly, priming with DC also conferred protection against infections in which the homing of CTL into peripheral organs is essential: DC-immunized mice rapidly cleared an infection with recombinant vaccinia virus-LCMV from the ovaries and eliminated LCMV from the brain, thereby avoiding lethal choriomeningitis. A comparison of DC constitutively expressing the GP33-41 epitope with exogenously peptide-pulsed DC showed that in vivo CTL priming with peptide-loaded DC is not limited by turnover of peptide-major histocompatibility complex class I complexes. We conclude that the priming of antiviral CTL responses with DC is highly efficient, rapid, and long lasting. Therefore, the use of DC should be considered as an efficient means of immunization for antiviral vaccination strategies.
Animals↗
Overexpression of cytochrome C by a recombinant rabies virus attenuates pathogenicity and enhances antiviral immunity.
The pathogenicity of individual rabies virus strains appears to correlate inversely with the extent of apoptotic cell death they induce and with the expression of rabies virus glycoprotein, a major inducer of an antiviral immune response. To determine whether the induction of apoptosis by rabies virus contributes to a decreased pathogenicity by stimulating antiviral immunity, we have analyzed these parameters in tissue cultures and in mice infected with a recombinant rabies virus construct that expresses the proapoptotic protein cytochrome c. The extent of apoptosis was strongly increased in primary neuron cultures infected with the recombinant virus carrying the active cytochrome c gene [SPBN-Cyto c(+)], compared with cells infected with the recombinant virus containing the inactive cytochrome c gene [SPBN-Cyto c(-)]. Mortality in mice infected intranasally with SPBN-Cyto c(+) was substantially lower than in SPBN-Cyto c(-)-infected mice. Furthermore, virus-neutralizing antibody (VNA) titers were significantly higher in mice immunized with SPBN-Cyto c(+) at the same dose. The VNA titers induced by these recombinant viruses paralleled their protective activities against a lethal rabies virus challenge infection, with SPBN-Cyto c(+) revealing an effective dose 20 times lower than that of SPBN-Cyto c(-). The strong increase in immunogenicity, coupled with the marked reduction in pathogenicity, identifies the SPBN-Cyto c(+) construct as a candidate for a live rabies virus vaccine.
Animals↗
Social stress in male mice impairs long-term antiviral immunity selectively in wounded subjects.
An important property of the antiviral immune response is its time-dependent character. Beginning with a few antigen-specific cells upon infection, it evolves to a stage where there is an abundance of antigen-specific cells and antibodies that are needed to clear the pathogen, and ends with circulating antibodies and a population of virus-specific memory cells to protect the animal from reinfection. Short-term effects of stress on the immune system have been investigated extensively, showing that stress acutely changes many aspects of immunity. However, relatively little is known about the consequences of stress for the quality and quantity of long-term immunological memory. In the present study, we have investigated the effect of social stress, applied in mice at Days 1, 2 and 3 after inoculation with a herpes virus, on long-term antibody and memory cytokine responses to the virus. Male mice were subjected to three 5-min confrontations with an aggressive conspecific. Approximately half of the mice was wounded by bites of the aggressor during this stress procedure, and these mice were analyzed separately from nonwounded mice. It appeared that wounded mice showed suppressed protective antibody responses and impaired memory for virus-specific IL-4 and IL-10 production, whereas mice that were not wounded showed intact long-term immune responses and memory. It is concluded that the combination of wounds and the social stress of repeated confrontations is associated with impaired protective immunity as a consequence of suppressed antibody levels and impairment of some aspects of antiviral immunological memory.
Aggression↗
Cytotoxic T lymphocytes, chemokines and antiviral immunity.
Evidence that CD8+ CTLs produce chemokines following engagement of viral antigens, and that MIP-1alpha is required for an inflammatory response to virus challenge, suggests that these molecules are key elements in the generation of effective antiviral immunity. Here, David Price and colleagues argue that the antigen-dependent release of chemokines by CTLs provides an elegant mechanism linking localization, amplification and coordination of the antiviral immune response to specific recognition of infected host cells beyond the confines of the lymphoid system.
Animals↗