AN ANALYSIS OF THE INHIBITION OF HIV-1 INFECTION BY CHEMOKINE-FC CHIMERA

趋化因子受体CCR5和CXCR4分别是嗜巨噬细胞和嗜t细胞系HTV-1病毒分离株的主要共受体。因此，这些趋化因子受体是抗hiv药物的潜在靶点。然而，体内hiv - 1复制的不良反应和抑制作用尚不清楚。为了了解在体内阻断这些趋化因子受体的作用，我们生成了对其野生型趋化因子（即met-RANTES-Fc和P2G-SDF-l-Fc）以及野生型趋化因子fc嵌合体（即RANTES-Fc和SDF-l-Fc）具有拮抗活性的趋化因子fc嵌合体。尽管P2G-SDF-l-Fc在体外对SDF-1有明显的拮抗作用，但met-RANTES-Fc对RANTES没有拮抗作用。因此，我们将重点放在SDF-l-Fc嵌合体上，发现SDF-1-Fc和P2G-SDF-l-Fc在体外都具有抑制X4病毒复制的作用。BALB/c小鼠血液循环中SDF-1、SDF-l-Fc和P2G-SDF-l-Fc的表观半衰期分别为< h、4h和9h。小鼠腹腔注射P2G-SDF-l-Fc可显著降低B220+CD43；骨髓中的前B细胞和B220^IeM4未成熟B细胞，这与先前关于CXCR4缺陷小鼠的报道一致。然而，当这些嵌合体被注射到X4病毒感染后的人- pbl - scid小鼠体内时，与对照PBS处理相比，激动性SDF-l-Fc和拮抗性P2G-SDF-1-Fc都显著增强了病毒的复制，后者更强。这些嵌合体在体内促进HIV-1生长的机制目前尚不清楚，但这些数据表明，在体内阻断CXCR4应该谨慎考虑。

Chemokine receptors CCR5 and CXCR4 are the major co-receptors for macrophage tropic and T-cell line tropic HTV-1 viral isolates, respectively. Therefore, these chemokine receptors are potential targets for anti-HIV drugs. However, the adverse effect as well as the inhibitory effect of HIV-l replication in vivo remains unknown. To understand the effects of blocking these chemokine receptors in vivo, we generated chemokine-Fc chimeras with antagonistic activity against their wild-type chemokines (i.e. met-RANTES-Fc and P2G-SDF-l-Fc) as well as wild-type chemokine-Fc chimeras (i.e. RANTES-Fc and SDF-l-Fc). Although significant antagonistic activity was observed for P2G-SDF-l-Fc against SDF-1 in vitro, met-RANTES-Fc had no antagonistic effect against RANTES. Therefore, we focused on SDF-l-Fc chimeras, and found that both SDF-1-Fc and P2G-SDF-l-Fc had inhibitory effect of X4 virus replication in vitro. The apparent half-lives of SDF-1, SDF-l-Fc, and P2G-SDF-l-Fc in the blood circulation of BALB/c mice were about <lh, 4h and 9h, respectively. Intraperitoneal injection of P2G-SDF-l-Fc into mice caused significant reduction of B220+CD43; pre-B cells and B220^IeM4 Immature B cells in the bone marrow, which is in agreement with the previous reports of CXCR4 deficient mice. However, when these chimeras were injected into the human-PBL-SCID mice after infection of X4 virus, there was a dramatic enhancement of virus replication by both agonistic SDF-l-Fc and antagonistic P2G-SDF-1-Fc, more strongly in the latter, in contrast to the control PBS treatment. The mechanism of promotion of HIV-1 growth in vivo by these chimeras is not known at present, but these data implicated that blocking CXCR4 in vivo should be considered carefully.