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A Detailed History of HIV Vaccine Research (I)

Background

AIDS is an infectious disease with high fatality rate and wide spread. Many countries around the world have been successful in the development of viral vaccines, but AIDS vaccine research has been unsuccessful, which is mainly related to the special biological characteristics of HIV. There is currently no specific treatment for HIV. The integrase inhibitor vaccine once led by David Baltimore was considered to be the most promising research, but this time-consuming and cost-effective experiment ultimately failed. After the vaccine experiment of integrase inhibitors failed, the field of AIDS research was full of pessimism for a while, but more views believe that the current research on AIDS is only astray. At present, DNA vaccines have become a promising new research direction, but many experts still report with caution. With the in-depth study of HIV, the completion of the basic work of HIV epidemic characteristics, cloning, sequencing and reassortment of epidemic strains, as well as the elucidation of the biological characteristics of the HIV virus itself, we still have reason to believe optimistically that humans will continue to develop new and more effective vaccines will eventually prevent and treat AIDS infection.

Why hasn’t HIV vaccine been developed so far?

HIV can be divided into main type M (main genotype) and A~I subtypes. The difference between different subtypes can reach more than 30%, and recombinants will also be generated between different differentiated bodies. Although HIV-infected people can produce a variety of neutralizing antibodies, these antibodies are usually specific to the virus strain and cannot cross-neutralize the mutation of HIV. It is very „smart“. Their error rate is at least 1,000 to 10,000 times higher than that of humans in the process of replication. The cost of HIV replication’s high error rate is the death of some mutant offspring, but its advantage is also obvious, that is, when the drug has an inhibitory effect on the old virus, it will immediately have a new virus to avoid the drug. With the death of a part of the virus, to win the survival of another part, this is the survival strategy of HIV. More importantly, HIV is not only different in different regions and individuals. Moreover, there is diversity within the same individual. This makes it difficult for the immune system to produce an effective immune response to all HIV in the body. Vaccine trials must be conducted in many countries, and the difficulty can be imagined.

During the process of virus invasion, the conformation of HIV surface glycoprotein 9041 and gp120 will change, which makes it difficult for the antibody to access the epitope. The glycosylation of the surface protein also hides some important epitopes, which prevents the antibody from interacting with it. In the process of natural infection, there is a strong antibody response to the coat protein, but this reaction cannot effectively neutralize mature virions. Before the virus binds to CD4, the conserved sites in gp120 are always hidden, so that HIV can effectively avoid the attack of antibodies. Some studies have shown that antibodies alone cannot provide good preventive or therapeutic effects on HIV.

Two to four weeks after HIV infection is the acute phase, sudden viremia. Since then, due to the role of specific cellular immunity, the viremia and clinical symptoms have basically disappeared, and an average of 8 to 10 years of asymptomatic period. It has been clarified that the probability of specific HLA types affecting the development of AIDS can be determined by measuring the characteristics of CTL responses to different epitopes in HIV. The progress of HLA-B27 and HLA-B57 towards AIDS is slow, while HLA-B*35 and Cw*04 can increase the allergic to HIV. The mechanism of CD8+ T cell activity is not yet clear. Some people think that it may be that CD8+ T cells have attacked a fairly conserved area inside the viral protein. They specifically recognize the presence of the antigen through the HLA class I protein on the surface of the infected cell. Decided to cause cell lysis. In addition, HIV-specific CTIL secretes other cells and chemical factors that have limited viral activity.

During acute infection, although the number of HIV-specific CD8+ T cells will surge, HIV can still escape the fate of eradication. Kelleher et al. believe that HIV can make CTL unable to recognize them by mutating key amino acids in epitopes, which makes it very difficult to produce vaccines with broad significance. HIV can also downregulate HLA class I through Nef activities.

In addition, in chronic infection with H1V, CD8+ T cells do not function well, they have an immature phenotype, resulting in low levels of perforin. The reason for this immaturity is not yet clear. Kalarns and others believe that it may be caused by the lack of CIM+ help. In other chronic viral infections, CD4+ T cells recognize the antigens present by macrophages to maintain the memory and maturity of CD8+, while in HIV infection, CD4+ T cells cannot play a helpful role because they are attacked early.

HIV is „hidden“ in lymphoid organs, central nervous system, and infected resting CD4+ T cells. In these parts, it does not express viral proteins, so killer T cells cannot find it. HIV’s Nef, Tat and Vpu proteins can down-regulate the expression of MHC class I and CD4, thus effectively reducing the intracellular immune response. Recently, we have noticed the change of antigenicity in the evolution of HIV, and this process has developed rapidly, which has provided new opportunities for the recombination between different virus strains (differentiants), which has brought great challenge to the development of HIV vaccines.

The role of most classic vaccines is to prevent pathogen infection rather than pathogen entry, but HIV is different. Even a small amount of HIV will cause AIDS, so the vaccine is required to produce high-efficiency neutralizing antibodies and effectively remember to clear all virus. There may be many reasons for the slow progress of vaccine research, but at least part of it should be attributed to the fact that the natural HIV antibody in the human body is not large enough to effectively neutralize the virus.

To be continued in Part II…

 

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