Resistance to erythroleukemia induced by infection with the Friend virus complex (FV) has been ma... more Resistance to erythroleukemia induced by infection with the Friend virus complex (FV) has been mapped to several genes residing both within and outside the murine major histocompatibility complex (MHC). MHC genes located in the A, D, and Qa/Tla regions of the murine H-2 complex have been shown to affect disease resistance through their capacity to regulate various aspects of the host immune response to viral antigens. This study establishes H-2E as the fourth MHC locus controlling immunological resistance to FV. Our investigation into the role of H-2E molecules revealed two distinct and opposite effects on recovery from Friend disease. H-2b/b mice normally lack a functional E gene product and are resistant to high doses of FV. The expression of H-2E molecules in H-2 recombinant or transgenic mice of this genotype resulted in a significant decrease in spontaneous recovery from FV-induced leukemia. In contrast, H-2E expression also appeared to influence recovery from Friend disease in...
Retroviruses can establish persistent infection despite induction of a multipartite antiviral imm... more Retroviruses can establish persistent infection despite induction of a multipartite antiviral immune response. Whether collective failure of all parts of the immune response or selective deficiency in one crucial part underlies the inability of the host to clear retroviral infections is currently uncertain. We examine here the contribution of virus-specific CD4(+) T cells in resistance against Friend virus (FV) infection in the murine host. We show that the magnitude and duration of the FV-specific CD4(+) T-cell response is directly proportional to resistance against acute FV infection and subsequent disease. Notably, significant protection against FV-induced disease is afforded by FV-specific CD4(+) T cells in the absence of a virus-specific CD8(+) T-cell or B-cell response. Enhanced spread of FV infection in hosts with increased genetic susceptibility or coinfection with Lactate dehydrogenase-elevating virus (LDV) causes a proportional increase in the number of FV-specific CD4(+) T cells required to control FV-induced disease. Furthermore, ultimate failure of FV/LDV coinfected hosts to control FV-induced disease is accompanied by accelerated contraction of the FV-specific CD4(+) T-cell response. Conversely, an increased frequency or continuous supply of FV-specific CD4(+) T cells is both necessary and sufficient to effectively contain acute infection and prevent disease, even in the presence of coinfection. Thus, these results suggest that FV-specific CD4(+) T cells provide significant direct protection against acute FV infection, the extent of which critically depends on the ratio of FV-infected cells to FV-specific CD4(+) T cells.
More than 15 years after the discovery of human immunodeficiency virus (HIV), researchers are sti... more More than 15 years after the discovery of human immunodeficiency virus (HIV), researchers are still struggling to design a protective AIDS vaccine. A remaining problem is a lack of basic knowledge about the immunological requirements for protection against retroviruses. Infection of macaque monkeys with simian immunodeficiency virus is still the best model for HIV vaccine research. However, in this model it remains difficult to determine protective immunological mechanisms because of limited numbers of experimental animals and their genetic heterogeneity. Thus, fundamental concepts in retroviral immunology have to be defined in other ways such as mouse models. This minireview summarizes new findings on cellular and molecular mechanisms in protection of mice against Friend murine retrovirus infection. It has been shown that complex immune responses, including B and T cell responses, are required for efficient protection in this model. Multiple viral antigens are necessary to elicit such broad immune reactivity. Efficacious vaccines must protect not only against acute disease, but also against the establishment of persistent infections or the host is at serious risk of virus reactivation. The minireview closes with a discussion on the relevance of findings from the mouse model on the design of a protective vaccine against HIV.
Resistance to erythroleukemia induced by infection with the Friend virus complex (FV) has been ma... more Resistance to erythroleukemia induced by infection with the Friend virus complex (FV) has been mapped to several genes residing both within and outside the murine major histocompatibility complex (MHC). MHC genes located in the A, D, and Qa/Tla regions of the murine H-2 complex have been shown to affect disease resistance through their capacity to regulate various aspects of the host immune response to viral antigens. This study establishes H-2E as the fourth MHC locus controlling immunological resistance to FV. Our investigation into the role of H-2E molecules revealed two distinct and opposite effects on recovery from Friend disease. H-2b/b mice normally lack a functional E gene product and are resistant to high doses of FV. The expression of H-2E molecules in H-2 recombinant or transgenic mice of this genotype resulted in a significant decrease in spontaneous recovery from FV-induced leukemia. In contrast, H-2E expression also appeared to influence recovery from Friend disease in...
Retroviruses can establish persistent infection despite induction of a multipartite antiviral imm... more Retroviruses can establish persistent infection despite induction of a multipartite antiviral immune response. Whether collective failure of all parts of the immune response or selective deficiency in one crucial part underlies the inability of the host to clear retroviral infections is currently uncertain. We examine here the contribution of virus-specific CD4(+) T cells in resistance against Friend virus (FV) infection in the murine host. We show that the magnitude and duration of the FV-specific CD4(+) T-cell response is directly proportional to resistance against acute FV infection and subsequent disease. Notably, significant protection against FV-induced disease is afforded by FV-specific CD4(+) T cells in the absence of a virus-specific CD8(+) T-cell or B-cell response. Enhanced spread of FV infection in hosts with increased genetic susceptibility or coinfection with Lactate dehydrogenase-elevating virus (LDV) causes a proportional increase in the number of FV-specific CD4(+) T cells required to control FV-induced disease. Furthermore, ultimate failure of FV/LDV coinfected hosts to control FV-induced disease is accompanied by accelerated contraction of the FV-specific CD4(+) T-cell response. Conversely, an increased frequency or continuous supply of FV-specific CD4(+) T cells is both necessary and sufficient to effectively contain acute infection and prevent disease, even in the presence of coinfection. Thus, these results suggest that FV-specific CD4(+) T cells provide significant direct protection against acute FV infection, the extent of which critically depends on the ratio of FV-infected cells to FV-specific CD4(+) T cells.
More than 15 years after the discovery of human immunodeficiency virus (HIV), researchers are sti... more More than 15 years after the discovery of human immunodeficiency virus (HIV), researchers are still struggling to design a protective AIDS vaccine. A remaining problem is a lack of basic knowledge about the immunological requirements for protection against retroviruses. Infection of macaque monkeys with simian immunodeficiency virus is still the best model for HIV vaccine research. However, in this model it remains difficult to determine protective immunological mechanisms because of limited numbers of experimental animals and their genetic heterogeneity. Thus, fundamental concepts in retroviral immunology have to be defined in other ways such as mouse models. This minireview summarizes new findings on cellular and molecular mechanisms in protection of mice against Friend murine retrovirus infection. It has been shown that complex immune responses, including B and T cell responses, are required for efficient protection in this model. Multiple viral antigens are necessary to elicit such broad immune reactivity. Efficacious vaccines must protect not only against acute disease, but also against the establishment of persistent infections or the host is at serious risk of virus reactivation. The minireview closes with a discussion on the relevance of findings from the mouse model on the design of a protective vaccine against HIV.
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Papers by K. Hasenkrug