Shapiro L, Pott G B, Ralston A H
Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
FASEB J. 2001 Jan;15(1):115-122. doi: 10.1096/fj.00-0311com.
Several observations suggest the existence of potent endogenous suppressors of human immunodeficiency virus type 1 (HIV-1) production, and inhibitors of serine proteases may participate in this effect. Alpha-1-antitrypsin (AAT) is the most abundant circulating serine protease inhibitor. Physiological AAT concentrations inhibited HIV-1 production in chronically infected U1 monocytic cells, reduced virus replication in freshly infected peripheral blood mononuclear cells, and blocked infection of permissive HeLa cells. In U1 cells, AAT suppressed activation of the HIV-1-inducing transcription factor NF-kappaB. Similar results were obtained using CE-2072, a synthetic inhibitor of host serine proteases. HIV-1 did not replicate in blood obtained from healthy volunteers, but marked replication was observed in blood from individuals with hereditary AAT deficiency. These results identify AAT as a candidate circulating HIV-1 inhibitor in vivo. Two different mechanisms of AAT-induced HIV-1 inhibition were identified, including reduced HIV-1 infectivity and blockade of HIV-1 production. A novel host-pathogen interaction is suggested, and an alternative strategy to treat HIV-1-related disease may be possible.
多项观察结果提示存在强效的内源性1型人类免疫缺陷病毒（HIV-1）产生抑制剂，丝氨酸蛋白酶抑制剂可能参与了这一效应。α-1-抗胰蛋白酶（AAT）是循环中最为丰富的丝氨酸蛋白酶抑制剂。生理浓度的AAT可抑制慢性感染的U1单核细胞中HIV-1的产生，减少新鲜感染的外周血单核细胞中的病毒复制，并阻断HIV-1对易感HeLa细胞的感染。在U1细胞中，AAT可抑制HIV-1诱导的转录因子NF-κB的激活。使用宿主丝氨酸蛋白酶的合成抑制剂CE-2072也获得了类似结果。HIV-1在健康志愿者的血液中不复制，但在遗传性AAT缺乏个体的血液中观察到明显的复制。这些结果确定AAT为体内循环HIV-1抑制剂的一个候选物。已确定AAT诱导HIV-1抑制的两种不同机制，包括降低HIV-1的感染性和阻断HIV-1的产生。提示了一种新的宿主-病原体相互作用，并且可能存在治疗HIV-1相关疾病的替代策略。
