Ayouba Ahidjo, Cannou Claude, Nugeyre Marie-Thérèse, Barré-Sinoussi Françoise, Menu Elisabeth
Institut Pasteur, Département de Virologie, Unité Régulation des Infections Rétrovirales, 25 rue du Dr Roux, 75724 Paris cedex 15, France.
Retrovirology. 2008 Mar 31;5:31. doi: 10.1186/1742-4690-5-31.
HIV-1 cell-to-cell transmission is more efficient than infection of permissive cells with cell-free particles. The potency of HIV-1 entry inhibitors to inhibit such transmission is not well known. Herein, we evaluated the efficacy of this new class of antiretrovirals to block cell-to-cell transmission of HIV-1 in a model of reconstitution of the human placental trophoblast barrier in vitro.
Our data show that CCR5 antagonists and T20 inhibit the passage of the virus across the BeWo cell monolayer in contact with PBMCs infected with an R5 (Ba-L) and a dualtropic (A204) HIV-1 with IC50s in the range of 100 - 5,000 nM for TAK779; 90 to 15,000 nM for SCH-350581 and 3,000 to 20,000 nM for T20. The CXCR4 antagonist AMD3100 is also effective against X4 HIV-1 infected PBMCs in our model with IC50 comprised between 4 nM and 640 nM. HIV-1 entry inhibitors are less efficient to block cell-to-cell virus transmission than cell-free HIV-1 infection of PBMCs and CCR5 antagonists do not prevent PBMC infection by dual tropic HIV-1 in contrast to cell-to-cell infection in our model.Surprisingly, T20 (and C34) do not block cell-to-cell transmission of X4 HIV-1 but, rather, increase 80 to 140 fold, compared to control without drug, the passage of the virus across the trophoblast barrier. Additional experiments suggest that the effect of T20 on BeWo/PBMC-X4 HIV-1 is due to an increase of effector-target cells fusion.
Our results support further evaluation of HIV-1 coreceptor antagonists, alone or combined to other antiretrovirals, in a perspective of prevention but warn on the use of T20 in patients bearing X4 HIV-1 at risk of transmission.
HIV-1的细胞间传播比无细胞病毒颗粒感染易感细胞更有效。HIV-1进入抑制剂抑制这种传播的效力尚不清楚。在此，我们在体外重建人胎盘滋养层屏障的模型中评估了这类新型抗逆转录病毒药物阻断HIV-1细胞间传播的效果。
我们的数据表明，CCR5拮抗剂和T20抑制病毒穿过与感染R5（Ba-L）和双嗜性（A204）HIV-1的PBMC接触的BeWo细胞单层，TAK779的IC50在100 - 5000 nM范围内；SCH-350581为90至15000 nM，T20为3000至20000 nM。CXCR4拮抗剂AMD3100在我们的模型中对X4 HIV-1感染的PBMC也有效，IC50在4 nM至640 nM之间。与PBMC的无细胞HIV-1感染相比，HIV-1进入抑制剂在阻断细胞间病毒传播方面效率较低，并且与我们模型中的细胞间感染相反，CCR5拮抗剂不能预防双嗜性HIV-1对PBMC的感染。令人惊讶的是，T20（和C34）并不阻断X4 HIV-1的细胞间传播，而是与无药物对照相比，使病毒穿过滋养层屏障的通过率增加80至140倍。进一步的实验表明，T20对BeWo/PBMC-X4 HIV-1的作用是由于效应细胞与靶细胞融合增加。
我们的结果支持进一步评估HIV-1共受体拮抗剂单独或与其他抗逆转录病毒药物联合用于预防，但提醒在有X4 HIV-1传播风险的患者中使用T20时需谨慎。
