HIV vaccine development needs unconventional and creative approach

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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 eliminated 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 development is yet full of uncertainties. Host immune system consists of both innate immunity and adaptive immunity. Cellular immune, constituted by both CD4+ and CD8+ T cells, and humoral immune responses have formed host adaptive immune 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 interaction, 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 formation 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. Innovative strategies and creative thinking should be stressed to overcome current limitations and may lead to successful development of HIV vaccines in the future.