DEVELOPMENT OF T-INDEPENDENT VACCINES FOR HIV-1 INFECTION

HIV-1感染与辅助性T细胞功能下降有关， 旨在刺激免疫系统的疫苗或免疫疗法 艾滋病病毒携带者需要规避规定 辅助性T细胞 我们实现这一目标的策略是， 不依赖于T细胞并能诱导 在T细胞相对缺乏的情况下的抗体应答。 热灭活 流产布鲁氏菌（BA）表现为T非依赖性1型 人和鼠抗体应答中的载体。 因此，我们表明， 与BA结合的HIV 1蛋白能够引起中和， 小鼠体内的抗HIV抗体，即使在T细胞相对缺乏的情况下。 来自其他革兰氏阴性细菌的正弦脂多糖（LPS）可以 刺激B细胞，我们假设来自BA的LPS具有类似的 特性. 我们从BA中纯化LPS并首先测试其毒性。 与E.大肠杆菌（EC）LPS的BA是10，000倍 在兔子中引起发热的效力;在引起 在小鼠中的致死性;以及在诱导中的效力低300倍和1400倍 IL 1B和TNF α分别来自人单核细胞。 这些结果 表明来自BA的LPS比来自EC的LPS更不可能， 引起人体内毒素休克。 然后我们测试了来自BA的LPS， 小鼠免疫载体功能。 TNP-LPS-BA能诱导抗TNP-LPS BALB/c、无胸腺和CBA/N小鼠的抗体应答。 因此，LPS BA， 就像它所来源的细菌一样， 可用作疫苗的载体，所述疫苗可 绕过HIV-1衍生肽对辅助性T细胞的需求 与牛种布鲁氏菌偶联，用于诱导抗HIV-1 在小鼠和SCID-人模型中的中和抗体。

HIV-1 infection is associated with decreased T helper cell function, so that vaccines or immunotherapy designed to stimulate the immune system of persons harboring the AIDS virus need to circumvent the requirement for T helper cells. Our strategy to accomplish this has been to use immune carriers which are T-cell independent and are capable of inducing antibody responses in the relative absence of T cells. Heat inactivated Brucella abortus (BA), has been shown to behave as T-independent type 1 carrier in human and murine antibody responses. Thus, we showed that HIV 1 proteins conjugated to BA were capable of eliciting neutralizing anti-HIV antibodies in mice, even in the relative absence of T cells. Sine lipopolysaccharide (LPS) from other gram negative bacteria can stimulate B cells, we postulated that LPS from BA would have similar properties. We purified LPS from BA and first test it for toxicity. Compared to LPS from E. coli (EC) LPS from BA was 10,000 fold less potent in inducing fever in rabbits; 300 fold less potent in causing lethality in mice; and 300 fold and 1400 fold less potent in inducing 1L1B and TNFa, respectively, from human monocytes. These results suggested that LPS from BA was much less likely than LPS from EC, to induce endotoxic shock in humans. We then tested LPS from BA from immune carrier function in mice. TNP-LPS BA was able to induce anti-TNP antibody repsonses from BALB/c, athymic and CBA/N mice. Thus, LPS BA, like the bacterium from which it is derived, behaves as a T-indenpendent type 1 carrier and may be useful as a carrier for vaccines which could bypass the requirement for helper T cells in HIV-1 dervied peptides conugated to Brucella abortus for ability to induce anti-HIV-1 neutralizing antibodies in mice and in the SCID-human model.