Scientists at Harvard University investigated the functions of approximately 10,000 different viral proteins and identified more than 700 previously unstudied proteins that affect cell division, antigen presentation, and interferon (IFN) responses.
To do this, the researchers created a large library of viral genes encoding proteins. The library encompasses the diversity of known human and animal viruses, which makes it possible to identify proteins that can control cellular processes and suppress immune defenses, including proteins from emerging viruses with zoonotic potential.
Proteins That Affect Cell Division
Viral proteins interfere with cellular functions and reprogram them to create conditions that support viral replication and spread, disrupting normal cell function. Many viral proteins alter metabolism, cell membrane function, and gene activity. These changes can cause DNA damage, oxidative stress, and activation of apoptosis – programmed cell death.
Among the viral proteins that suppressed cell division were previously known toxic proteins. These included the herpesvirus protein UL41, which suppresses cellular gene activity, and the rotavirus protein NSP3, which disrupts cellular protein synthesis.
Viral proteins that increased cell division included the HIV Nef protein, the adenovirus E4-ORF1 protein, and the human papillomavirus E7 protein.
Proteins That Suppress MHC Class I Antigen Presentation
MHC class I molecules display fragments of proteins present inside the cell, including viral proteins, on the cell surface. CD8+ T cells recognize these viral antigens and destroy infected cells. Some viral proteins reduce MHC class I levels on the cell surface, making it harder for CD8+ T cells to recognize the infection. As a result, infected cells may persist longer, allowing the virus to continue replicating and spreading.
These viral proteins include HIV Nef and the K3 protein of Kaposi’s sarcoma-associated herpesvirus.
Another protein that reduces MHC class I levels on the cell surface is MC162R from molluscum contagiosum virus, the causative agent of a common childhood skin infection characterized by benign lesions. MC162R does not directly destroy MHC class I molecules. Instead, it recruits cellular E3 ligases of the NEDD4 family, which promote ubiquitination of MHC class I and its subsequent trafficking to lysosomes for degradation.
Proteins That Suppress Interferon Responses
To replicate successfully, viruses suppress both innate and adaptive immune defenses. IFNs play an important role in the antiviral response. They signal infection to cells and activate interferon-stimulated genes (ISGs). The products of these genes establish an antiviral state within cells that limits viral replication and spread.
Previously known viral proteins that suppress IFN-β or IFN-γ signaling include the P protein of rabies virus, the W protein of Nipah virus, the C′ protein of Sendai virus, and the ICP22 protein of herpes simplex virus 1. HIV Tat primarily suppresses IFN-γ signaling, while the C4/C10 proteins of poxviruses suppress IFN-β signaling.
Yatapoxviruses are a poorly studied group of poxviruses. One member of this group, Yaba-like disease virus (YLDV), has been associated with outbreaks in Kenya and cases of disease in several countries in sub-Saharan Africa, Spain, and the United States. The 151R protein of YLDV, as well as the 151R and 1L proteins of the related Yaba monkey tumor virus (YMTV), suppress IFN-β signaling.
The YLDV 151R viral protein suppresses IFN-β signaling by binding to IRF9, preventing it from interacting with STAT1 and STAT2, and blocking formation of the ISGF3 complex required to activate ISGs.
Reference
A viral ORFeome library for systems-level genetic dissection of host-pathogen interactions
