艾滋病疫苗突破需要颠覆性思维

HIV vaccine development needs unconventional and creative approach

艾滋病疫苗研发仍然是一个世界性难题,自艾滋病被发现以来,科学界和产业界已经为此不懈努力了30余年.艾滋病疫苗的研发经历了从以产生抗体为主要目标,到以细胞免疫的产生为主要方向,再到抗体和细胞免疫并重的艰辛历程.RV144疫苗部分保护效果的实现使人们看到了艾滋病疫苗成功研发的希望,但目前对于人类免疫缺陷病毒(HIV)感染的保护性免疫机制仍存在诸多不足,尤为重要的是,病毒直接摧毁机体免疫细胞——CD4^+T细胞,仍未找到HIV感染的"阿喀琉斯之踵",有效的艾滋病疫苗研发仍然面临着诸多不确定因素.近年来,HIV感染长期不进展人群(long-term nonprogressors,LTNPs),尤其是精英控制者中广谱中和抗体的发现及作用机制的研究极大推动了反向疫苗学的发展,在基础研究方面已经取得了许多令人鼓舞的成果,新的保护性T细胞亚群也不断被发现,这些进展拓展了我们对HIV感染保护性免疫的认识,为有效的HIV疫苗研发提供了新的方向.HIV疫苗研发困境既有病毒自身的原因,也有思维认识及现有技术手段局限等因素,要大胆尝试新方法新技术,运用颠覆性科研思维开展HIV疫苗研发.

Development of vaccines against human immunodeficiency virus （HIV） is yet a challenging problem worldwide. Since its discovery, scientists and business experts have struggled to develop both protective and therapeutic vaccines for over 30 years. Vaccines have played central roles in protection of multiple pathogens and smallpox has been completely elim- inated because of the application of vaccines. However, the development of HIV vaccine has long been a well-known problem worldwide. The focus of strategies in HIV vaccine development has experienced from mainly the production of humoral immune response, then mainly cellular immune response, and recently stressing on both humoral and cellular immune responses. HIV vaccine development is still one of the most challenging problems worldwide. Though partial protection from RV144 has shown a glimmer of hope for successful HIV vaccine development, our understanding of protective immune against HIV infection remains less understood and successful HIV vaccine devel- opment is yet full of uncertainties. Host immune system consists of both innate immunity and adaptive immunity. Cellu- lar immune, constituted by both CD4~ and CD8~ T cells, and humoral immune responses have formed host adaptive im- mune system. T cells were found to be critical for control of disease progression after HIV infection. However, CD4~ T cells are the main target of HIV infection, resulting the impairment of host immune responses against HIV thereafter. Recent findings revealed that the functionality of HIV specific T cell responses may contributed more to the control of disease progression than responsive quantity. Additionally, multiple protective T cell subpopulations have also been identified which provided new directions for future HIV vaccine development. In recent years, the identification and mechanism study of broadly neutralizing antibodies in long-term nonprogressors （LTNPs） have dramatically promoted the progression of structure-based reverse vaccinology. Preliminary studies have shown promising protective efficacy in animal studies with HIV vaccines designed to produce mainly broadly neutralizing antibodies. The production of broadly neutralizing antibodies in LTNPs is a result of long-term virus-host immune adaption. However, our knowledge about how do the broadly neutralizing antibodies developed in LTNPs is still limited, which has restricted the design of HIV vaccines to mainly produce broadly neutralizing antibodies. The difficulties of HIV vaccine development consist of multiple aspects from both HIV itself and virus-host interac- tion, which has also made it more difficult than the other pathogens. Direct infection of immune cells and subsequent impairment of HIV specific immune responses, high mutation rates and multiple immune escape strategies, and for- mation of latent virus reservoir have all contributed to the difficult situation of HIV vaccine development. Moreover, limitations of the current understanding of protective immunity after HIV infection and available technologies nowadays may also contributed a lot. New methods and technologies which have shown promising therapeutic efficacies in dealing with other diseases should be applied to HIV vaccine design, such as gene-editing, immune therapy, and so on. Innova- tive strategies and creative thinking should be stressed to overcome current limitations and may lead to successful devel- opment of HIV vaccines in the future.