Host protein: HIV target

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  • Published: Apr 15, 2016
  • Author: David Bradley
  • Channels: Chemometrics & Informatics
thumbnail image: Host protein: HIV target

Innate weakness

CREDIT Haitao Guo: A human host protein that weakens the immune response to HIV and other viruses has been identified by researchers in the USA. Details published in the journal Cell Host & Microbe, could point the way to improved HIV antiviral therapies, perhaps even facilitating the development of an effective vaccine, and may also help develop new approaches to treating cancer.

A human host protein that weakens the immune response to HIV and other viruses has been identified by researchers in the USA. Details published in the journal Cell Host & Microbe, could point the way to improved HIV antiviral therapies, perhaps even facilitating the development of an effective vaccine, and may also help develop new approaches to treating cancer.

"Understanding the negative regulators of antiviral immune responses will be critical for advancing immune-modulated antiviral strategies," researchers from the University of North Carolina (UNC) School of Medicine and Sanford Burnham Prebys Medical Discovery Institute (SBP) explain. "Our study provides critical insight on a paramount issue in HIV research: Why is the body unable to mount an efficient immune response to HIV to prevent transmission?" asks co-senior author Sumit Chanda. "This research shows that the host protein NLRX1 is responsible - it's required for HIV infection and works by repressing the innate immune response."

The innate immune response functions by triggering a cascade of signalling molecules, interferons and cytokines, that prompt white blood cells, the cytotoxic T cells to attack and kill pathogens. Decades of HIV/AIDS research suggest increasingly that the body must mount a powerful attack against infection by the virus early if this innate immune response is to halt the viral invasion in its tracks, understanding the underlying processes might allow researchers to improve the effectiveness of vaccines.

Deficiency

"Importantly, we were able to show that deficiencies in NLRX1 reduce HIV replication, suggesting that the development of small molecules to modulate the innate immune response may inhibit viral transmission and promote immunity to infection," adds Chanda. "We anticipate expanding our research to identify NLRX1 inhibitors."

Human immunodeficiency virus, HIV, first identified as a lentivirus (a type of retrovirus) as the cause of AIDS, acquired immunodeficiency syndrome, is a single-stranded RNA virus. It infects lymphocytes, crucial workers of the immune system itself by rapidly reverse transcribe its genetic material into DNA which then integrates into the host cell DNA. HIV-1 reverse transcribed DNA presents in the cytosol, the fluid portion of the cell and triggers a sensor called STING (stimulator of interferon genes) that turns on the innate immune response. But, HIV's biomachinery can work around this attempt by the host to sabotage its replication.

"Until now, the mechanism by which NLRX1 promoted HIV infection was unexplored. We have shown that NLRX1 interacts directly with STING, essentially blocking its ability to interact with an enzyme called TANK-binding kinase 1 (TBK1)," explains Haitao Guo, a senior post-doctoral research associate in the group of Jenny Ting at UNC, lead author of the study. "The STING-TBK1 interaction is a critical step for interferon production in response to elevated cytosolic DNA, and initiates the innate immune response." Guo adds that, "This research expands our understanding of the role of host proteins in viral replication and the innate immune response to HIV infection, and can be extended to DNA viruses such as HSV and vaccinia." There are also implications of this work for studying, understanding and treating cancer in that the discovery of how NLRX1 reduces the immune response to HIV resembles the way in which immune checkpoints, such as PD-L1 and CTLA-1, in our body respond to the growth of cancer.

Checkpoint chemistry

Essentially, these checkpoints are immunological blockades that prevent the over-activation of the immune system on healthy cells. Cancer cells exploit these checkpoints to escape detection by the immune system and there are already approved checkpoint inhibitors available for some cancers. Of course, new and more effective chemical cousins of those inhibitors with fewer side effects are now being sought.

"Checkpoint inhibitors have made a huge impact on cancer treatment, and significant investment by the biotech/pharmaceutical sector is being made to identify STING inhibitors as the next generation of immune-oncology therapeutics," explains Ting. "This study, showing that NLRX1 is a checkpoint of STING, sheds more light on the topic and will help advance those efforts."

"What we hope to achieve ultimately is to identify NLRX1 small compound inhibitors, which may help to remove HIV-1 virus in vivo," Guo told SpectroscopyNOW.

Related Links

Cell Host Microbe 2016, online: "NLRX1 Sequesters STING to Negatively Regulate the Interferon Response, Thereby Facilitating the Replication of HIV-1 and DNA Viruses"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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