Bruce Walker, MD, Director of the Ragon Institute, said, “In 1994, we first encountered a patient who was able to naturally control HIV with their own immune system. Now we finally understand how he and others like him can achieve this.
Recently, there was good news coming from the Ragon Institute at Massachusetts Institute of Technology and Harvard University. Researchers have used a new method to identify specific amino acids in the structure of HIV proteins that are crucial for virus function and replication ability.
The biggest highlight of this study is that researchers have found that the immune system of individuals naturally able to control HIV infection targets these amino acids by killing pathogenic CD8 T cells, which can even be seen in controllers who do not carry versions of HLA-B proteins previously associated with HIV control. The research, published in Science, can guide the development of relevant vaccines to prevent and suppress HIV infection.
Why is HIV Vaccine Difficult to Deliver?
Since the first case of AIDS was found in 1981, the struggle against AIDS has lasted for 38 years. There have been 30 years of research on HIV vaccines, but the results of HIV vaccines have been delayed.
Over the past 25 years, researchers have found that highly functional CD8 T cells may be a response mechanism in individuals infected with HIV who can naturally suppress the virus through their own immune system.
In 2010, a study by the Ragon Institute found that specific variants of HLA-B protein can carry viral peptides to the surface of infected cells and present them to the immune system, indicating that cells will be destroyed by CD8 T cells. This variant is common in people who are immune to HIV, but not in those with progressive HIV infection. But subsequent research denied it
Why is it So Difficult to Develop an AIDS Vaccine?
It has to be said that the HIV virus is really “cunning”. For one thing, it changes too fast. The popular AIDS virus is all kinds, and it is still changing after entering the human body.
Furthermore, the HIV virus can also integrate into human cells and coexist with humans. In addition, HIV only infects humans, and there is a lack of good animal models for vaccine research.
Therefore, the first step of AIDS vaccine research and development is to determine the structure of the virus, so that we can do the right thing.
Nowadays, the Ragon team uses a new method to examine the complex structural bonds of viral proteins, which is based on structural network analysis to identify residues (specific amino acids in peptides) that are crucial for viral function.
Dr. Elizabeth Rossin, co lead author, explained, “All proteins fold into their final three-dimensional structure through a series of bonds between amino acids, so we can mathematically represent proteins as a network of connections between amino acids
Researchers used network analysis to obtain information on the structure of 12 out of the 15 proteins that make up HIV from a protein database.
They calculated the network score of each amino acid to reflect the quantity and relative importance of binding with other amino acids in the protein. The higher the degree of amino acid networking, the less likely it is to mutate in the thousands of virus sequences obtained from patients, indicating that highly networked residues are important for virus function.
To further validate this finding, researchers analyzed mutations as amino acids with high and low network scores, and found that highly networked residues severely damaged the ability of HIV infected cells and replication. On the contrary, mutated amino acids with low network scores have little or no impact on viral infectivity.
Research has found that the Gag p24 protein is important for the formation of viral protein shells, with the highest frequency of network amino acids, which supports previous research – it is more sensitive to the effects of mutations and T cell responses than other HIV proteins. Targeting Gag p24 is associated with lower viral levels.
How to Use Your Immune System to Control HIV?
Bruce Walker, MD, Director of the Ragon Institute, said, “In 1994, we first encountered a patient who was able to naturally control HIV with their own immune system. Now we finally understand how he and others like him can achieve this.
The Omizzur peptide team conducted network scoring on protective and risk related HLA variants and found that protective forms (such as HLA b57) typically exhibit highly networked viral peptides, while versions with increased risk are more likely to exhibit poorer networked peptides.
This discovery suggests that HLA-B57 has a greater possibility of presenting highly networked viral peptides to the immune system, which can induce CD8 T cells to respond to more critical viral targeting sequences.
Epilogue
AIDS is the fourth leading killer in the world. If the HIV vaccine comes out, AIDS patients can return to normal life without discrimination.
References:
[1] Study identifiers virtual peptides critical to natural HIV control
[2] Structural topology definitions protective CD8+T cell apices in the HIV protein
