Smithgall M D, Wong J G, Linsley P S, Haffar O K
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
AIDS Res Hum Retroviruses. 1995 Aug;11(8):885-92. doi: 10.1089/aid.1995.11.885.
Stimulation of human immunodeficiency virus type 1 (HIV-1)-infected donor 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, optimal T cell activation requires secondary or costimulatory signals delivered via various T cell accessory proteins (Alton A, et al.: Adv Immunol 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 either a CD28-specific MAb or by coculture of PBMCs with Chinese hamster ovary (CHO) cell lines stably expressing either of the CD28 counterreceptors, B7-1 (CD80) or B7-2 (CD86), concomitant with stimulation via CD3, results in increased virus replication compared to stimulation via CD3 alone. CD28 ligation also augments de novo infection of CD3-stimulated seronegative donor PBMCs with cell-free virus. Increased virus replication following CD28 ligation is not solely attributed to increased levels of endogenous IL-2, because addition of an anti-IL-2-neutralizing antibody only partially inhibits the response. In contrast, interfering with the interaction between CD28 and its counterreceptors on antigen-presenting cells (APCs) using CTLA4Ig effectively inhibits virus replication. At high concentrations CTLA4Ig also reduces cell proliferation. 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.
通过TCR - CD3复合物刺激人类免疫缺陷病毒1型（HIV - 1）感染供体的外周血单个核细胞（PBMC）可在体外诱导HIV - 1产生（扎林JM等人：《自然》[伦敦]1990年；347:92；哈法尔OK等人：《病毒学杂志》1992年；66:4279；莫兰PM等人：《艾滋病研究与人类逆转录病毒》1993年；9:455）。然而，除了通过TCR - CD3复合物传递的主要刺激信号外，最佳的T细胞激活还需要通过各种T细胞辅助蛋白传递的次要或共刺激信号（奥尔顿A等人：《免疫学进展》1990年；48:227）。在本文中，我们探讨了通过CD28对T细胞进行共刺激在HIV - 1复制中的作用。用CD28特异性单克隆抗体或通过将PBMC与稳定表达任一CD28反受体B7 - 1（CD80）或B7 - 2（CD86）的中国仓鼠卵巢（CHO）细胞系共培养来连接CD28，同时通过CD3进行刺激，与单独通过CD3刺激相比，会导致病毒复制增加。CD28连接还增强了无细胞病毒对CD3刺激的血清阴性供体PBMC的初次感染。CD28连接后病毒复制增加并非完全归因于内源性IL - 2水平的升高，因为添加抗IL - 2中和抗体仅部分抑制该反应。相反，使用CTLA4Ig干扰CD28与其在抗原呈递细胞（APC）上的反受体之间的相互作用可有效抑制病毒复制。在高浓度下，CTLA4Ig也会降低细胞增殖。这些体外结果表明，CD28在HIV - 1复制中起核心作用，干扰CD28共刺激途径可能会改变HIV - 1感染的进程。
