High titer HIV-1 V3-specific antibodies with broad reactivity but low neutralizing potency in acute infection and following vaccination
High titer HIV-1 V3-specific antibodies with broad reactivity but low neutralizing potency in acute infection and following vaccination
复制标题
DOI：
10.1016/j.virol.2009.02.022
复制
发表时间：
2009-05-10
期刊：
影响因子：
3.7
通讯作者：
Shaw, George M.
中科院分区：
文献类型：
--
作者：
Davis, Katie L.;Gray, Elin S.;Shaw, George M.
鉴定HIV-1感染或接种疫苗后最早产生的中和抗体特异性是当前HIV/AIDS疫苗研究的重要目标。我们先前已经表明，将HIV-1 V3表位移植到HIV-2包膜（Env）支架中提供了检测和定量人血清中HIV-1 V3表位特异性中和抗体（Nab）的灵敏且特异的手段。在这里，我们采用这种HIV-2/HIV-1 V3支架策略来研究来自进化枝C或进化枝B HIV-1急性感染个体的纵向血清中以及用进化枝B HIV-1免疫原免疫的人类受试者中V3特异性Nab的发展和宽度的动力学。将含有与病毒类型（HIV-2或HIV-1）、亚型（进化枝B或C）或毒株（自体或异源）匹配的V3序列的HIV-2/HIV-1嵌合体用作试验试剂。我们发现，到感染后3-8周，14个进化枝C受试者中的12个具有针对含有异源进化枝CV 3的嵌合病毒的1：700的中值IC 50 V3特异性Nab滴度。到感染后5个月，所有14名受试者均为V3特异性Nab阳性，针对异源进化枝C V3的中位滴度为1：8000，针对进化枝B V3的中位滴度为1：1300。两名急性感染的进化枝B患者在感染13周时产生了异源进化枝B V3特异性Nab，滴度为1：300和1：1800，在感染7个月时滴度为1：5000和1：11000。针对含有自体进化枝B V3序列的嵌合体的滴度没有不同。用进化枝B HIV-1 Env免疫原免疫的10名未感染的正常人志愿者中的每一个，但5名假免疫对照受试者中没有一个，产生高达1：3000（中值1：1300;范围1：700-1：3000）的V3特异性Nabs滴度。HIV-1感染者或接种疫苗的受试者均未产生中和HIV-1原代病毒株的抗体。这些结果表明，高滴度、广泛反应性的V3特异性抗体是在急性和早期HIV-1感染期间和接种疫苗后首先引发的抗体，但这些抗体缺乏针对原发性HIV-1病毒的中和效力，这有效地保护V3免于抗体与功能性Env三聚体结合。(C)2009 Elsevier Inc. All rights reserved.
Identifying the earliest neutralizing antibody specificities that are elicited following infection or vaccination by HIV-1 is an important objective of current HIV/AIDS vaccine research. We have shown previously that transplantation of HIV-1 V3 epitopes into an HIV-2 envelope (Env) scaffold provides a sensitive and specific means to detect and quantify HIV-1 V3 epitope specific neutralizing antibodies (Nabs) in human sera. Here, we employ this HIV-2/HIV-1 V3 scaffolding strategy to study the kinetics of development and breadth of V3-specific Nabs in longitudinal sera from individuals acutely infected with clade C or clade B HIV-1 and in human Subjects immunized with clade B HIV-1 immunogens. HIV-2/HIV-1 chimeras containing V3 sequences matched to virus type (HIV-2 or HIV-1), subtype (clade B or C), or strain (autologous or heterologous) were used as test reagents. We found that by 3-8 weeks post infection, 12 of 14 clade C subjects had a median IC50 V3-specific Nab titer of 1:700 against chimeric viruses containing a heterologous clade C V3. By 5 months post-infection, all 14 subjects were positive for V3-specific Nabs with median titers of 1:8000 against heterologous clade C V3 and 1:1300 against clade B V3. Two acutely infected clade B patients developed heterologous clade B V3-specific Nabs at titers of 1:300 and 1:1800 by 13 weeks of infection and 1:5000 and 1:11000 by 7 months of infection. Titers were not different against chimeras containing autologous clade B V3 sequences. Each of 10 uninfected normal human volunteers who were immunized with clade B HIV-1 Env immunogens, but none of five sham immunized control subjects, developed V3-specific Nabs titers as high as 1:3000 (median 1: 1300; range 1:700-1:3000). None of the HIV-1 infected or vaccinated subjects had antibodies that neutralized primary HIV-1 virus strains. These results indicate that high-titer, broadly reactive V3-specific antibodies are among the first to be elicited during acute and early HIV-1 infection and following vaccination but these antibodies lack neutralizing potency against primary HIV-1 viruses, which effectively shield V3 from antibody binding to the functional Env trimer. (C) 2009 Elsevier Inc. All rights reserved.