COSTIMULATION OF CD4(-CELLS VIA CD28 MODULATES HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INFECTION AND REPLICATION IN-VITRO() T)

Stimulation of human immunodeficiency virus type 1 (HIV-1)-infected do nor peripheral blood mononuclear cells (PBMCs) via the TCR-CD3 complex induces HIV-1 production in vitro (Zarling JM, et al: Nature [London] 1990;347:92; Haffar OK, et al.: J Virol 1992;66:4279; Moran PM, et al .: AIDS Res Hum Retroviruses 1993;9:455), However, in addition to the primary stimulatory signal delivered through the TCR-CD3 complex, opti mal T cell activation requires secondary or costimulatory signals deli vered via various T cell accessory proteins (Alton A, et al.: Adv Immu nol 1990;48:227), In this article we explore the role of costimulation of T cells via CD28 in HIV-1 replication, Ligation of CD28 with eithe r a CD28-specific MAb or by coculture of PBMCs with Chinese hamster ov ary (CHO) cell lines stably expressing either of the CD28 counterrecep tors, B7-1 (CD80) or B7-2 (CD86), concomitant with stimulation via CD3 , results in increased virus replication compared to stimulation via C D3 alone, CD28 ligation also augments de novo infection of CD3-stimula ted seronegative donor PBMCs with cell-free virus, Increased virus rep lication following CD28 ligation is not solely attributed to increased levels of endogenous IL-2, because addition of an anti-IL-2-neutraliz ing antibody only partially inhibits the response, In contrast, interf ering with the interaction between CD28 and its counterreceptors on an tigen-presenting cells (APCs) using CTLA4Ig effectively inhibits virus replication, At high concentrations CTLA4Ig also reduces cell prolife ration, These in vitro results suggest that CD28 plays a central role in HIV-1 replication and that interfering with the CD28 costimulatory pathway may modify the course of HIV-1 infection.