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Novel Mechanism of Immune Activation in HIV-exposed, Seronegative People who Inject Drugs

PHILADELPHIA — (Nov. 13, 2018) — According to new research from The Wistar Institute, the S100A14 protein is expressed at higher levels in people who inject drugs and remain uninfected despite many years of high-risk, needle sharing behavior in areas with high HIV prevalence. The protein mediates activation of a type of immune cell called natural killer cells (NK), which play a key role in the host immune defense during the earliest phases of viral infection. These results were published in the journal JAIDS.

A small percentage of individuals who are at high risk of HIV infection because of their continued exposure to the virus remain uninfected. Previous research from Wistar has shown that these individuals, referred to as HIV-1 exposed seronegative (HESN), have a higher level of innate immune activation, including enhanced activity of NK cells and dendritic cells. 

“Understanding the basis of natural resistance to HIV is important because it may instruct the design of novel approaches for prevention of HIV infection based on manipulating the host immune defense,” said corresponding author Luis J. Montaner, D.V.M., D.Phil., director of the HIV-1 Immunopathogenesis Unit at The Wistar Institute Vaccine & Immunotherapy Center and the Herbert Kean, M.D., Family Endowed Chair Professor. “We investigated the mechanism of immune activation in a specific group of HESN individuals who inject drugs (HESN-PWID) and are at high risk of HIV infection because of needle sharing.” 

Using proteomic analysis, the team found that HESN-PWID individuals have a significantly higher expression of interferon-related proteins and S100 family proteins in their blood and within isolated NK cells compared with control donors. Montaner and colleagues focused on the S100A14 protein and showed that it potently activates a population of immune cells in the blood called monocytes, which in turn activate NK cells. 

“Our findings suggest that S100A14 represents a novel element in the host defense against HIV infection,” said Costin Tomescu, Ph.D., senior staff scientist in the Montaner Lab and co-corresponding author on the study. “Further studies will explore the potential role of this protein in augmenting the ability of NK cells to inhibit HIV replication and eliminate infected cells and could help develop novel approaches for prevention of HIV infection.” 

Other authors from The Wistar Institute include first author Krystal Colón and David W. Speicher. Other co-authors include Peter Smith, Mack Taylor and David S. Metzger from University of Pennsylvania.

This work was supported by National Institutes of Health (NIH) grants R21 DA040554, T32 AI007632, UM1 AI126620, R01 AI094603. Additional funding was provided by The Philadelphia Foundation (Robert I. Jacobs Funds), the Kean Family Professorship, Henry S. Miller, Jr. and J. Kenneth Nimblett, and the Penn Center for AIDS research (grant P30AI045008).

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

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