According to WHO data, since the identification of the cause of acquired immunodeficiency syndrome (AIDS) in 1984, the human immunodeficiency virus (HIV) has infected more than 80 million people and caused 40 million deaths worldwide. At present, the WHO report says that more than 38 million people worldwide are infected with this retrovirus, and there is an increase of 1 million new cases of infection each year. While antiretroviral therapy can effectively control HIV, patients must adhere to medication to prevent the onset of AIDS.
Scientists have been striving to develop an effective HIV vaccine, but so far, they have not been successful. Recently, in a study entitled “A cell-free antigen processing system informs HIV-1 epitope selection and vaccine design” published in Journal of Experimental Medicine, scientists from Johns Hopkins University School of Medicine and other institutions used natural systems to identify special proteins that could help develop an effective HIV vaccine.
In this study, the researchers used a laboratory technique they developed in 2010 to replicate a cellular environment in which specialized immune cells, called antigen-presenting cells (APCs), break down proteins derived from HIV and make them visible to the front-line defense mechanism of the immune system, called CD4+ T lymphocytes or helper T cells. Scheherazade Sadegh-Nasseri, one of the researchers, stated, “Our simple method, reductionist cell-free antigen processing, can reproduce in a test tube complex events that occur in the human immune system, which are the immune system’s response to foreign invaders such as HIV. When an APC processes an antigen-derived protein and presents a fragment called an antigen epitope on its surface, the epitope becomes visible to helper T cells, triggering an immune response in the body.”
If researchers can identify which epitopes exhibit “immunedominance”, meaning they elicit the strongest immune system response to the virus, they may have the necessary components for formulating an effective long-term HIV vaccine. Immunodominant antigenic epitopes possess a unique structure that matches the cell surface proteins on APCs, namely major histocompatibility molecules (MHCs), acting as a lock and key mechanism. Srona Sengupta, MD, explained that if we think of HIV epitopes as a hot dog and MHC as a piece of bread, the feast is presented to CD4+ T cells. T cells that recognize the HIV epitope-MHC complex as foreign become activated and send signals to B cells, another type of immune cell that produces antibodies, in this case specific to HIV. Antibodies can bind to the virus, leading to the destruction of infected cells or preventing HIV from entering uninfected cells. This antibody response may hold the key to developing an effective vaccine.
“Previous efforts to map and identify the required immune dominant epitopes have proved unreliable,” the researchers said, Traditional methods use a somehow brutal system to test synthetic peptides that represent part of the real HIV protein, hoping that certain peptides can stimulate the body’s immune response and guide researchers to find the epitopes needed to develop vaccines. This strategy not only relies on its success or failure but also fails to account for chemical and molecular interactions in the real world, which can impact epitope production and function. This is one of the primary reasons why effective HIV vaccine strategies have remained elusive, as explained by the researchers. Dr. Sadegh-Nasseri stated, “Our acellular antigen processing system can replicate how epitopes are actually processed and presented in an APC cell environment, taking into consideration any factors that may be involved.” This breakthrough may inspire researchers to delve into the entire HIV proteome, encompassing all proteins produced by the virus, and identify specific epitopes selectively presented to CD4+ T cells by a chaperone protein called HLA-DM. This is significant because researchers know that HIV epitopes processed and edited by HLA-DM are immunodominant.
The researchers made an additional point that the recent study identified 35 epitopes that were previously unknown. Through the analysis of the acellular antigen processing system, the researchers unveiled three important findings:
* The identified epitopes are indeed produced in HIV infected group and contribute to the development of memory CD4+ T cells within the body.
* This novel processing system can be utilized to predict which part of the HIV protein is more effective in generating immune dominant epitopes that can be incorporated into the new vaccine.
* The use of full-length natural proteins in the system ensures the inclusion of any cellular environmental effects, such as viral epitope modifications caused by infected host cells after the virus’s production. These effects are taken into consideration, which is a capability lacking in current analytical techniques.
Interestingly, the researchers also identified multiple epitopes that can be modified by sugar molecular groups, which may be a significant finding for vaccine developers. However, this discovery might be overlooked by traditional analysis methods. Currently, researchers are diligently working to enhance this immune dominant epitope recognition system and utilize future data analysis to bolster the capabilities of vaccine developers. The aim is to facilitate the development of robust and effective protective strategies against HIV, SARS-CoV-2, and other pathogens.