MSGID: 1:317/3 6476cd93   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Researchers use 'natural' system to identify proteins most useful for   
   developing an effective HIV vaccine    
      
     Date:   
         May 30, 2023   
     Source:   
         Johns Hopkins Medicine   
     Summary:   
         Scientists have spent years trying to develop an effective HIV   
         vaccine, but none have proven successful. Based on findings from   
         a recently published study, a research team may have put science   
         one step closer to that goal.   
      
      
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   FULL STORY   
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   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 been responsible for some 40   
   million deaths worldwide, according to the World Health Organization   
   (WHO). Currently, the WHO reports more than 38 million people globally   
   live with the retrovirus, and each year, another 1 million new cases   
   are diagnosed. While antiretroviral therapy helps keep HIV in check,   
   patients must stay on their medication to prevent the development of AIDS.   
      
   Scientists have spent years trying to develop an effective HIV vaccine,   
   but none have proven successful. Based on findings from a recently   
   published study, a Johns Hopkins Medicine-led research team may have   
   put science one step closer to that goal.   
      
   Their work first appeared online April 14, 2023, in the Journal of   
   Experimental Medicine, and will be formally published in the July 3,   
   2023, issue.   
      
   Using a laboratory technique created at Johns Hopkins Medicine in 2010,   
   the study researchers replicated the cellular environment in which   
   specialized immune cells called 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.   
      
   "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.   
      
   Epitopes that are immunodominant have structures that uniquely fit   
   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."  Sadegh-Nasseri says previous efforts to map   
   and identify the desired immunodominant epitopes have proven 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 a major   
   reason why an effective HIV vaccine remains 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 adds that 35 epitopes identified in the recent   
   studies were previously unknown.   
      
   The researchers say that their analysis using the cell-free antigen   
   processing system revealed three important findings: (1) the epitopes   
   identified are indeed generated in humans who are HIV positive 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 may   
   yield the immunodominant epitopes that can be included in new vaccines;   
   and (3) the system's use of full-length natural proteins ensures that the   
   impacts of any cellular environmental influences (such as those causing   
   modifications of viral epitopes after infected host cells have produced   
   them) are taken into account.   
      
   Current analysis technologies lack such abilities, say Sadegh-Nasseri   
   and Sengupta.   
      
   "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.   
      
   Sadegh-Nasseri and Sengupta say that their team will continue to refine   
   the immunodominant epitope identification system and use the data from   
   future analyses to enhance the ability of vaccine developers 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.   
      
   Along with Sadegh-Nasseri and Sengupta, the members of the study team from   
   Johns Hopkins Medicine and Johns Hopkins University are 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. The team also includes Steven Deeks   
   and Rebecca Hoh from the University of California San Francisco, and   
   Aeryon Kim from Amgen Inc.   
      
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   Story Source: Materials provided by Johns_Hopkins_Medicine. Note:   
   Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Srona Sengupta, Josephine Zhang, Madison C. Reed, Jeanna Yu,   
      Aeryon Kim,   
         Tatiana N. Boronina, Nathan L. Board, James O. Wrabl, Kevin   
         Shenderov, Robin A. Welsh, Weiming Yang, Andrew E. Timmons,   
         Rebecca Hoh, Robert N.   
      
         Cole, Steven G. Deeks, Janet D. Siliciano, Robert F. Siliciano,   
         Scheherazade Sadegh-Nasseri. A cell-free antigen processing system   
         informs HIV-1 epitope selection and vaccine design. Journal of   
         Experimental Medicine, 2023; 220 (7) DOI: 10.1084/jem.20221654   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/05/230530174312.htm   
      
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