Effects of immunization with CCR5-based cycloimmunogen on simian/HIVSF162P3 challenge
Effects of immunization with CCR5-based cycloimmunogen on simian/HIVSF162P3 challenge
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DOI：
10.4049/jimmunol.176.1.463
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发表时间：
2006-01-01
影响因子：
4.4
通讯作者：
Shoji, S
中科院分区：
文献类型：
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作者：
Misumi, S;Nakayama, D;Shoji, S
评价了靶向HIV-1辅助受体CCR 5的合成环免疫原在食蟹猴中诱导具有抗HIV-1活性的CCR 5特异性抗体的能力。化学制备了模拟人CCR 5构象特异性结构域的环状闭链十二肽（cDDR 5），其中Gly-Glu二肽连接源自CCR 5细胞外环-2的十一肽基弓（Arg（168）至CYS 178）的十肽基线性链（Arg（168）至Thr（177））的氨基和羧基末端。用cDDR 5缀合的多Ag肽（cDDR 5-MAP）免疫食蟹猴诱导抗cDDR 5血清产生，持续类似于第三次免疫后的15周。针对cDDR 5-MAP产生的抗血清与人和猕猴CCR 5反应，并且在体外有效地抑制R5 HIV-1实验室分离株（HIVJRFL）、R5 HIV-1原代分离株（进化枝A：HIV 93 RW 004和进化枝C：HIVMJ 4）和致病性猿猴/HIV（SHIVSF 162 P3）批量分离株的感染。为了检查抗CCR 5血清Ab对急性HIV-1感染的预防功效，用SHIVSF 162 P3攻击食蟹猴。cDDR 5-MAP免疫减弱了SHIVSF 162 P3复制的急性期。攻毒后1周，免疫组猕猴血浆病毒载量的几何平均值比对照组猕猴低217.10倍。综上所述，这些结果表明，cDDR 5-MAP免疫是一种有效的预防性疫苗策略，其在最初的HIV-1传播期间抑制和延迟病毒繁殖，以遏制感染后的HIV-1复制。
A synthetic cycloimmunogen targeting the HIV-1 coreceptor CCR5 was evaluated for its capacity to induce CCR5-specific Abs with anti-HIV-1 activity in cynomolgus macaques. The cyclic closed-chain dodecapeptide (cDDR5) mimicking the conformation-specific domain of human CCR5 was chemically prepared, in which the Gly-Glu dipeptide links the amino and carboxy termini of the decapeptidyl linear chain (Arg(168) to Thr(177)) derived from the undecapepticlyl arch (Arg(168) to CYS178) of extracellular loop-2 in CCR5. The immunization of cynomolgus macaques with the cDDR5-conjugated multiple-Ag peptide (cDDR5-MAP) induced anti-cDDR5 serum production for similar to 15 wk after the third immunization. The antisera raised against cDDR5-MAP reacted with both human and macaque CCR5s, and potently suppressed infection by the R5 HIV-1 laboratory isolate (HIVJRFL), R5 HIV-1 primary isolates (clade A:HIV93RW004 and clade C:HIVMJ4 and a pathogenic simian/HIV (SHIVSF162P3) bulk isolate in vitro. To 14) examine the prophylactic efficacy of anti-CCR5 serum Ab for acute HIV-1 infection, cynomoigus macaques were challenged with SHIVSF162P3. The cDDR5-MAP immunization attenuated the acute phase of SHIVSF162P3 replication. The geometric mean plasma viral load in the vaccinated macaques was 217.10 times lower than that of the control macaques at 1 wk postchallenge. Taken together, these results suggest that cDDR5-MAP immunization is an effective prophylactic vaccine strategy that suppresses and delays viral propagation during the initial HIV-1 transmission for the containment of HIV-1 replication subsequent to infection.