Human immunodeficiency virus-type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS), causes a slowly progressive and fetal disease in man. HIV-1 infects target cells by the binding of its envelope glycoprotein, gp120, to CD4 expressed on T-cells and monocytes. One approach to eliminating HIV-1 and HIV-1-infected cells from the body would be to direct the virus or virus-infected cell to cytotoxic receptors on the surface of phagocytic cells. Receptors for the Fc region of immunoglobulin G (FcgammaR), that are highly expressed on human mononuclear phagocytes, mediate the clearance of immune complexes and opsonized pathogens. We have used bispecific antibodies (BsAb) to independently target HIV-1 to FcgammaRI, FcgammaRII or FcgammaRIII on human monocytes, monocyte-derived macrophages, and neutrophils. HIV-1 infection, as measured by p24 production, was significantly lower in monocyte cultures infected with HIV-1 in the presence of BsAb that target the virus to either FcgammaRI or FcgammaRII, when compared to control cultures infected in the absence of BsAb or in the presence of BsAb that target the virus to non-FcgammaR surface antigens. These findings support our hypothesis that FcgammaR on monocytes can function to clear HIV-1 and HIV-1-infected cells after BsAb opsonization. The primary objective of this proposal is to determine the ability of BsAb composed of anti-HIV-1 x anti-FcgammaR as well as sCD4 x anti-FcgammaR to target HIV-1 and HIV- infected cells to FcgammaRI, FcgammaRII and FcgammaRIII on monocytes in order to reduce the infectivity of HIV-1 and to mediate target cell lysis. We would use BsAb to: (1) define the conditions for optimal FcgammaR- mediated clearance of HIV-1 y normal human monocytes; compare the antiviral properties of human neutralizing monoclonal antibodies to the BsAb containing these human antibodies; and determine efficacy of BsAb targeting in the presence of sera that contain HIV-specific antibodies: (2) evaluate the ability of cytokines and hematopoietic growth factor to augment this activity: (3) determine whether bispecific molecules composed of sCD4 x anti-FcgammaR are more effective than anti-gp120 x anti-FcgammaR bispecifics in mediating this activity: and (4) determine the ability of monocytes from HIV-infected patients, under conditions that mimic the in vivo environment, to reduce the infectivity of HIV-1 and the killing of HIV-1-infected cells. These studies would indicate which trigger molecules on monocytes are most efficient in mediating neutralization or cytotoxicity and the importance of activating of monocyte effector cell function. Specifically targeting HIV-1 and HIV-1-infected cells to be removed and killed by monocytes represents an important approach to AIDS therapy and the work proposed in this study will set the work proposed in this study will set the framework for the design of therapeutic trials involving BsAb.
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