Design Of HIV-1 Subunit Vaccine That Can Induce Mucosal Immunity And Broadly Neutralizing Antibody

AIDS caused by HIV(human immunodeficiency virus)is a high risk disease which is prevalent all over the world.Currently,HARRT(highly active antiretroviral therapy)is mainly used to treat AIDS.This method can only control the viral load of patients,but cannot completely remove the latent virus.Researchers have been working on a vaccine that could effectively prevent HIV more than 30 years.However,due to the high variability of HIV and the complexity of its surface envelope proteins,no effective HIV vaccine has been developed to date.Along with HIV related research and the summary of AIDS vaccine clinical research experience of failure,the researchers gradually realized that: an effective HIV vaccine need to be able to successfully induce immune response more comprehensive,including broadly neutralizing antibody(bNAb),functional antibody,killer T cell immunity and mucosal immune responses(such as secretory IgA).The research on HIV vaccine in this paper mainly includes two parts.In the first part of the study,we designed a mucosal vaccine that can induce the specific mucosal immune response of HIV-1 with the envelope(Env)protein of HIV-1 as the antigen and Bacterium-like particle(BLP)as the carrier.In the second part,we designed a subunit vaccine with gp120 trimer template of 718 B.consensus gene sequence as antigen,aiming to induce bNAbs against HIV-1.1.The Study of an HIV-1 Mucosal Vaccine Based on BLPPrevious studies have indicated that the transmission of HIV-1 is mainly through the mucosa,and the establishment of the early infection mostly occurs in the mucosal tissues.Therefore,mucosal protection is crucial for the prevention and control of HIV-1 infection.Inducing antigen-specific mucosal immune response needs a suitable adjuvant or delivery system in order to facilitate the uptake of the immunogens and break mucosal tolerance.To date,many adjuvants has been attempted to improve the immunogenicity of HIV-1 mucosal vaccines including GM-CSF DNA,Cholera toxin,and MPLA,etc.Bacterium-like particle(BLP)is a new type of vector used to induce mucosal immune responses,and it has already been used for some vaccines against viruses transmitted through the respiratory tract.In addition,the safety of BLP has been demonstrated in clinical trials of the influenza vaccine,an advantage that other adjuvants do not have.In this study,we first designed a mucosal vaccine against HIV-1 based on BLPs.We found that gp120 trimers bound to BLPs could successfully induce Env-specific sIgA at mucosal sites in mice by nasal dripping.And nasal washes from guinea pigs immunized by nasal dripping showed neutralizing activity against HIV-1 tier 1 pseudoviruses.Thus,gp120 trimers bound to BLPs could induce safe and effective mucosal immune response.2.The Study of Inducing HIV-1 Broadly Neutralizing Antibodies by Recombinant Gp120 TrimersA small fraction of HIV-infected humans maintained a low viral load and do not cause AIDS,which is called elite controller.The researchers found neutralizing antibodies called bNAbs that could neutralize various subtypes of HIV-1 in their serum.In a previous study passive transfer of these bNAbs into non-human primates(NHPs)provides complete protection against mucosal challenge with the virus.Thus,the induction of bNAbs against HIV-1 in humans may have a similar protective effect.Researchers have tried a variety of approaches to obtain the appropriate immunogen to induce bNAbs.One strategy is to integrate and compare the sequences of HIV-1 genes from different subtypes,preserving the most common bases present.The sequences obtained by this method were of high similarity to other HIV-1 gene sequences analyzed,which the researchers called consensus sequence.A previous study showed that the Env designed by consensus sequences as antigen could induce similar or higher levels of binding antibody responses to different subtypes of HIV-1 than the Env with a single subtype as antigen.This study used the same strategy to design immunogen.We designed a consensus sequence of the HIV-1 epidemic strain in China based on four major HIV-1 subtypes,CRF07_BC,CRF01_AE,CRF08_BC and subtype B,and named it as 718 B.consensus.Using this sequence as template,we constructed and expressed gp120 trimer as antigen.The binding ability of gp120 trimer to HIV-1 bNAb was determined to confirm the good neutralization epitope exposure of gp120 trimer.After immunizing guinea pigs and rabbits with gp120 trimer,neutralizing activities against 10 HIV-1 tier 2 pseudoviruses were detected in guinea pig serum.Most current HIV-1 vaccines,after immunization,can only induce neutralizing antibodies against homologous tier 2 pseudoviruses,but cannot neutralize heterogenous tier 2 pseudoviruses.Although the same results have not been obtained in rabbits,this is still a welcome discovery.These results suggest that our subunit vaccine may have the potential to induce bNAbs in humans...