Immunological control of a persistent viral infection

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ABSTRACT is particularly problematic in immunocompromised Failure to control latent herpesviruses is particularly problematic in immunocompromised recipients who lack effective CD4 T cell function. individuals such as AIDS patients or transplant recipients who lack effective CD4 T cell function. Murine gammaherpesvirus-68 (IVIHV-68) is naturally occurring rodent pathogen, which is closely Murine gammaherpesvirus-68 (MHV-68) naturally occurring rodent which is closely related to the human pathogens Epstein Barr virus and Kaposi's sarcoma-associated related to the human pathogens Epstein virus and Kaposi's sarcoma-associated herpesvirus. Infection of mice with MHV-68 provides a tractable small animal model for studying herpesvirus. Infection mice with MHV-68 provides tractable small animal model for studying immunological control of gammaherpesvirus infection and for testing the ability of potential infection and for testing the ability of potential reactivation individuals. therapeutic agents to control viral reactivation in immunocompromised individuals. CD4 T cells are not required for acute control of replicating MHV-68, but are required for effective long-term highlighted the importance of CD40-CD40L interactions in 004 T cell help control. Our early work highlighted the importance of CD4O-CD4OL interactions in CD4 T cell help in the long-term control of MHV-68 and showed that CD4O stimulation alone, using agonistic that CD40 in the alone, antibodies, viral reactivation antibodies, was sufficient to prevent viral reactivation in the lungs of CD4 T cell deficient mice. cell mice. CD40 stimulation upregulates CD8O and 86 on dendritic cells, which interact with CD4O stimulation upregulates CD80 and 86 on dendritic cells, which interact with positive and and negative costimulators CD28 and CTLA-4, respectively. Interestingly, we have shown that, Interestingly, we have shown that, known CD80 and 86 are essential for long-term control of MHV-68, 0028, the although CD8O and 86 are essential for long-term control of MHV-68, CD28, the only known positive costimulatory receptor for CD80/86 is not required, suggesting the possibility of a novel required, positive costimulatory receptor for 0D80/86 superfamily, which receptor. CD28, CD8O and 86 are part of the CD28-B7 superfamily, which comprises several receptor. 0028, CD80 members that mediate positive or negative costimulation of T cells. In this application, we will members that mediate positive or negative costimulation of T cells. In this application, we will investigate the mechanisms by which CD40 and CD28-B7 family members interact to regulate investigate the mechanisms by which 0040 and CD28-B7 family members interact to regulate cell response CD8 T cell responses during the response to gammaherpesvirus infection . In Aim I we will infection. In Aim 1 we will investigate why CD4 T cells are required for the long-term control of MHV-68 , but are not required long-term control MHV-68, but are not investigate why 004 T cells (acute) control essential for short-term (acute) control of the virus. Our data suggests that two virus. alternative pathways of 008 T cell activation function alternative pathways of CD8 T cell activation function during acute, but not during long-term during long-term control. In Aim 2 we will investigate the possibility that a novel receptor for CD80/86 (B7-1, 2) control. In Aim 2 we will investigate the possibility that a novel receptor for 0D80/86 (B7-l, functions in the long-term control of MHV-68. In Aim 3, we will investigate the role of PD-1, an in control MHV-68. In Aim 3, will role PD-I, an inhibitory B7 family member that we have shown is upregulated on 008 cells in the absence of inhibitory B7 family member that we have shown is upregulated on CD8 T cells in the absence of CD4 T cells, in acute and long-term control of MHV-68. These studies will provide important 0D4 T cells, in acute and long-term control of MHV-68. These studies will provide important insight into differences in the mechanisms by which CD8 T cells mediate acute and long-term which acute and control control of persistent viral infections and may be of significant value in designing viral and in designing immunotherapeutic agents or vaccines to combat recurrent gammaherpesvirus infections Sarawar, Sally 1 c>. �-0 3,p C'(0 fl? can 0)3 CL) CSC BCD :cum ono o,-.o vo(Q chi �0= E I-- 0-0 II) 60, (00 ,�- �c' p-0 `ate.