Despite over 30 years of enormous effort and progress in the field, no preventative and/or therapeutic vaccines against human immunodeficiency virus (HIV) are available. Here, we briefly summarize the vaccine strategies and vaccine candidates that in recent years advanced to efficacy trials with mostly unsatisfactory results. Next, we discuss a novel and somewhat contrarian approach based on biological and epidemiological evidence, which led us to choose the HIV protein Tat for the development of preventive and therapeutic HIV vaccines. Toward this goal, we review here the role of Tat in the virus life cycle as well as experimental and epidemiological evidence supporting its key role in the natural history of HIV infection and comorbidities. We then discuss the preclinical and clinical development of a Tat therapeutic vaccine, which, by improving the functionality and homeostasis of the immune system and by reducing the viral reservoir in virologically suppressed vaccinees, helps to establish key determinants for intensification of combination antiretroviral therapy (cART) and a functional cure. Future developments and potential applications of the Tat therapeutic vaccine are also discussed, as well as the rationale for its use in preventative strategies. We hope this contribution will lead to a reconsideration of the current paradigms for the development of HIV/AIDS vaccines, with a focus on targeting of viral proteins with key roles in HIV pathogenesis.

中文翻译：

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对发病机制的新见解表明 HIV-1 Tat 是关键的疫苗靶点。

尽管在该领域进行了 30 多年的巨大努力和进步，但仍没有针对人类免疫缺陷病毒 (HIV) 的预防性和/或治疗性疫苗可用。在这里，我们简要总结了近年来进入疗效试验但结果大多不令人满意的疫苗策略和候选疫苗。接下来，我们讨论了一种基于生物学和流行病学证据的新颖且有些逆势的方法，这促使我们选择 HIV 蛋白 Tat 来开发预防性和治疗性 HIV 疫苗。为了实现这一目标，我们在这里回顾了 Tat 在病毒生命周期中的作用以及支持其在 HIV 感染和合并症自然史中的关键作用的实验和流行病学证据。然后我们讨论了 Tat 治疗性疫苗的临床前和临床开发，其中，通过改善免疫系统的功能和体内平衡以及减少病毒学抑制疫苗接种者的病毒库，有助于确定加强联合抗逆转录病毒疗法 (cART) 和功能性治愈的关键决定因素。还讨论了 Tat 治疗性疫苗的未来发展和潜在应用，以及将其用于预防策略的基本原理。我们希望这一贡献将导致重新考虑当前开发 HIV/AIDS 疫苗的范例，重点是靶向在 HIV 发病机制中起关键作用的病毒蛋白。有助于确定加强联合抗逆转录病毒疗法 (cART) 和功能性治愈的关键决定因素。还讨论了 Tat 治疗性疫苗的未来发展和潜在应用，以及将其用于预防策略的基本原理。我们希望这一贡献将导致重新考虑当前开发 HIV/AIDS 疫苗的范例，重点是靶向在 HIV 发病机制中起关键作用的病毒蛋白。有助于确定加强联合抗逆转录病毒疗法 (cART) 和功能性治愈的关键决定因素。还讨论了 Tat 治疗性疫苗的未来发展和潜在应用，以及将其用于预防策略的基本原理。我们希望这一贡献将导致重新考虑当前开发 HIV/AIDS 疫苗的范例，重点是靶向在 HIV 发病机制中起关键作用的病毒蛋白。