Diegel M L, Moran P A, Gilliland L K, Damle N K, Hayden M S, Zarling J M, Ledbetter J A
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
AIDS Res Hum Retroviruses. 1993 May;9(5):465-73. doi: 10.1089/aid.1993.9.465.
Cell-cell interactions induced between T cells and monocytes by certain soluble anti-CD3 monoclonal antibodies (MAbs) were previously shown to be required for high-level production of HIV-1 by peripheral blood mononuclear cells (PBMCs) from infected donors. Staphylococcal enterotoxin or superantigen (SAg) is another mitogen inducing monocytes-T cell interactions that exhibit potent induction of HIV-1 production. Antibodies to several adhesion molecules were used to test the requirements for T cell- and monocyte-associated adhesion molecules in HIV-1 production following activation with anti-CD3 or SAg. Blocking of either CD2-LFA-3, or CD18-ICAM-1, inhibited anti-CD3- or SAg-induced HIV-1 production by more than 90% without inhibiting CD4+ T cell proliferation. Inhibition of HIV production was observed when either the T cell or monocyte coreceptor was bound by MAbs to these adhesion molecules. Blocking of CD28-B7 interactions by soluble CTLA-4 fusion protein, a CD28 homolog, inhibited both HIV-1 production and CD4+ T cell proliferation. Fc binding was not required for HIV-1 inhibition by MAbs to CD2 and CD18, because Fab or F(ab')2 fragments of these MAbs inhibited HIV-1 production by more than 80%. A chimeric single-chain MAb to CD2 was produced, containing heavy and light chain variable regions from MAb 35.1 to CD2 linked to the constant regions of human IgG1 (CD2 SFv-Ig). This humanized CD2 SFv-Ig inhibited HIV-1 production by 30% to > 98%. These results thus indicate that simultaneous engagement of multiple adhesion pathways between T cells and monocytes are required for HIV production by patients PBMCs and may have implications for therapy of HIV infections.
先前已表明，某些可溶性抗CD3单克隆抗体（MAb）诱导T细胞与单核细胞之间的细胞间相互作用，是受感染供体的外周血单核细胞（PBMC）高水平产生HIV-1所必需的。葡萄球菌肠毒素或超抗原（SAg）是另一种诱导单核细胞 - T细胞相互作用的丝裂原，其对HIV-1的产生具有强大的诱导作用。使用针对几种黏附分子的抗体，来测试在用抗CD3或SAg激活后HIV-1产生过程中T细胞和单核细胞相关黏附分子的需求。阻断CD2-LFA-3或CD18-ICAM-1，可抑制抗CD3或SAg诱导的HIV-1产生达90%以上，而不抑制CD4 + T细胞增殖。当T细胞或单核细胞共受体被针对这些黏附分子的MAb结合时，可观察到HIV产生受到抑制。可溶性CTLA-4融合蛋白（一种CD28同源物）阻断CD28-B7相互作用，可抑制HIV-1产生和CD4 + T细胞增殖。MAb对CD2和CD18抑制HIV-1不需要Fc结合，因为这些MAb的Fab或F(ab')2片段可抑制HIV-1产生达80%以上。制备了一种针对CD2的嵌合单链MAb，其包含来自抗CD2 MAb 35.1的重链和轻链可变区，并与人IgG1的恒定区相连（CD2 SFv-Ig）。这种人源化的CD2 SFv-Ig可抑制HIV-1产生30%至>98%。因此，这些结果表明，T细胞与单核细胞之间多种黏附途径的同时参与，是患者PBMC产生HIV所必需的，并且可能对HIV感染的治疗具有重要意义。
