Researchers Utilize ‘natural’ Technique to Find HIV Vaccine Proteins

According to the World Health Organization (WHO), since it was identified in 1984 as the cause of Acquired Immune Deficiency Syndrome (AIDS), the human immunodeficiency virus (HIV) has infected more than 80 million people and caused 40 million deaths globally. According to the WHO, more than 38 million people worldwide are infected with the retrovirus, and 1 million new cases are detected each year. While antiretroviral therapy can help keep HIV at bay, patients must continue to take their medication to avoid developing AIDS. Scientists have worked for years to develop a viable HIV vaccine, but none has been successful. According to the findings of a recently published study, a research team led by Johns Hopkins Medicine may have brought science one step closer to that aim.

Their work was first published online in the Journal of Experimental Medicine on April 14, 2023, and will be fully published in the July 3, 2023, issue.

The researchers replicated the cellular environment in which specialized immune cells known as antigen presenting cells (APCs) break down proteins derived from HIV and make them visible (“presented”) to the immune system’s frontline of defense, cells known as CD4+ T lymphocytes, or helper T cells, using a laboratory technique developed at Johns Hopkins Medicine in 2010.

“Our simple method, called reductionist cell-free antigen processing, reproduces in a test tube the complex events that occur in the human immune system as a response to antigens, foreign invaders to the body such as viruses like HIV,” says senior study author Scheherazade Sadegh-Nasseri, Ph.D., professor of pathology at the Johns Hopkins University School of Medicine. “When APCs chew up proteins from an antigen and present the fragments, known as antigenic epitopes, on their surface, the epitopes become visible to helper T cells and initiate an immune response.”

“If we can identify which epitopes are ‘immunodominant’—the ones that elicit the strongest immune system response to the virus—then we may have the essential ingredients for the long-sought recipe to make an effective HIV vaccine,” explains Sadegh-Nasseri.

Immunodominant epitopes have structures that fit together like a lock and key with cell-surface proteins on APCs known as major histocompatibility molecules, or MHCs.

“If you think of an HIV epitope as a hot dog and the MHC as a bun, the ‘meal’ is what gets presented to CD4⁺ T cells,” says lead study author Srona Sengupta, an M.D./Ph.D. candidate in immunology at the Johns Hopkins University School of Medicine. T cells that can recognize the HIV epitope-MHC complex as foreign become activated and signal B cells—a different type of immune cell that produces antibodies, in this case, specific to HIV. Antibodies bind to the virus, destroying already infected cells or preventing HIV from entering uninfected ones—the key functions of an effective vaccine.”

Previous efforts to map and identify the desired immunodominant epitopes, according to Sadegh-Nasseri, have been unreliable.

“Traditional methods use a ‘brute-force’ system where synthetic peptides representing portions of real HIV proteins are tested in the hopes that some will stimulate an immune response and direct researchers to the epitopes needed for vaccine development,” says Sadegh-Nasseri. “Not only is this strategy hit or miss, but the method doesn’t allow for the real-world chemical and molecular interactions that can impact how epitopes are produced and function.”

This, she explains, is one of the fundamental reasons why a successful HIV vaccine is still elusive.

“Our cell-free antigen processing system,” says Sadegh-Nasseri, “replicates how epitopes are actually processed in the APC’s cellular environment and become presented, including any influencing factors that may come into play.”

“This enabled us to study nearly the entire HIV proteome [all of the proteins produced by the virus] and distinctly identify epitopes that are selected for presentation to CD4⁺ T cells by a chaperone protein called HLA-DM,” says Sengupta. “That’s important because we know that HIV epitopes processed and edited by HLA-DM are immunodominant.”

Sengupta goes on to say that 35 of the epitopes discovered in recent investigations were previously unknown.

According to the researchers, their analysis using the cell-free antigen processing system revealed three important findings: (1) the identified epitopes are indeed generated in HIV-positive humans and lead to the development of memory CD4+ T cells (the immune cells that remember an antigen for future encounters); (2) the processing system can be very useful in predicting which parts of HIV protein antigens might yield the immunodominant epitopes that can be included in vaccines; and (3) the processing system can be very useful in predicting which

According to Sadegh-Nasseri and Sengupta, current analysis technologies lack such capabilities.

Interestingly, we identified several epitopes that were modified by sugar groups, a potentially important finding for vaccine developers to know, but one that traditional analysis would have missed,” says Sengupta.

According to Sadegh-Nasseri and Sengupta, their team will continue to refine the immunodominant epitope identification system and use data from future analyses to improve vaccine developers’ ability to design robust and effective protective measures against not only HIV, but also SARS-CoV-2 (the virus that causes COVID-19) and other viral pathogens.

The study team from Johns Hopkins Medicine and Johns Hopkins University includes Nathan Board, Tatiana Boronina, Robert Cole, Madison Reed, Kevin Shenderov, co-senior author Robert Siliciano, Janet Siliciano, Andrew Timmons, Robin Welsh, Weiming Yang, and Josephine Zhang, in addition to Sadegh-Nasseri and Sengupta. Steven Deeks and Rebecca Hoh from the University of California, San Francisco, and Aeryon Kim from Amgen Inc. round out the team.

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