Development of complement-based antiretroviral therapy in a mouse model

Although animal retroviruses are efficiently destroyed by human serum, human retroviruses, such as Human Immunodeficiency Virus (HIV) are resistant to the attack by the complement system. Responsible for this intrinsic resistance of HIV are different regulators of complement activation (RCA) which were acquired by the virus during the budding process. Neutralization of these RCA by antibodies or peptides induces lysis of human retroviruses demonstrating that the human complement system is a potential weapon in the immune response to retroviral infection. The aim of the proposal is the development of a murine model to establish complement-based approaches for antiretroviral therapy and to investigate the impact of Complement on a viral infection process. One of the best viral candidates for this purpose is mouse mammary tumor virus (MMTV). Although belonging to the B-type retrovirus family, MMTV shares many similarities to HIV. Our preliminary results indicate that MMTV acquires also different RCA, which mediate resistance to murine complement and has therefore adapted the same protection mechanism as HIV. To overcome the intrinsic resistance of retroviruses against complement in vivo two major aims will be pursued: 1. In vitro investigations will be performed to clarify in detail whether the principle mechanisms for the HIV- human complement interactions apply for MMTV and mouse complement. Thus, the following questions will be addressed: 1.1. In vitro investigations to clarify whether the principle mechanisms for the HIV-human complement interactions apply for MMTV and mouse complement. 2.2. Application of these principles in vivo and attempts to establish an anti MMTV therapy based on interference with the MMTV-complement relationship. 2.3. Role of C3 in the induction and maintenance of immune responses upon MMTV infection. Results obtained from the study will provide the basis for an alternative approach for antiretroviral therapy, which may be applied to patients infected with pathogenic retroviruses, such as HIV or HTLV. In addition, further insights on the interaction of Complement during chronical viral infections will be provided, which may help to understand the complex interaction between viruses and the adaptive and acquired immune response.

Although animal retroviruses are efficiently destroyed by human serum, human retroviruses, such as Human Immunodeficiency Virus (HIV) are resistant to the attack by the complement system. Responsible for this intrinsic resistance of HIV are different regulators of complement activation (RCA) which were acquired by the virus during the budding process. Neutralization of these RCA by antibodies or peptides induces lysis of human retroviruses demonstrating that the human complement system is a potential weapon in the immune response to retroviral infection. The aim of the proposal is the development of a murine model to establish complement-based approaches for antiretroviral therapy and to investigate the impact of Complement on a viral infection process. One of the best viral candidates for this purpose is mouse mammary tumor virus (MMTV). Although belonging to the B-type retrovirus family, MMTV shares many similarities to HIV. Our preliminary results indicate that MMTV acquires also different RCA, which mediate resistance to murine complement and has therefore adapted the same protection mechanism as HIV. To overcome the intrinsic resistance of retroviruses against complement in vivo two major aims will be pursued: 1. In vitro investigations will be performed to clarify in detail whether the principle mechanisms for the HIV- human complement interactions apply for MMTV and mouse complement. Thus, the following questions will be addressed: 1.1. In vitro investigations to clarify whether the principle mechanisms for the HIV-human complement interactions apply for MMTV and mouse complement. 2.2. Application of these principles in vivo and attempts to establish an anti MMTV therapy based on interference with the MMTV-complement relationship. 2.3. Role of C3 in the induction and maintenance of immune responses upon MMTV infection. Results obtained from the study will provide the basis for an alternative approach for antiretroviral therapy, which may be applied to patients infected with pathogenic retroviruses, such as HIV or HTLV. In addition, further insights on the interaction of Complement during chronical viral infections will be provided, which may help to understand the complex interaction between viruses and the adaptive and acquired immune response.