Luis Lamberti Pinto Dasilva

Type I interferon (IFN-I) is critical for controlling viral infections through the activation of the JAK/STAT signaling pathway, which drives the transcription of interferon-stimulated genes (ISGs) with diverse antiviral functions. Despite its importance, the effectiveness of IFN-I treatment against HIV-1 is limited. The HIV-1 accessory protein Nef is highly expressed early during infection and is detectable in the serum of HIV-1-infected individuals. Furthermore, Nef is a key factor in viral pathogenesis and disease progression, that has been shown to antagonize specific ISG products via post-translational mechanisms. To investigate if Nef plays a broader effect in antiviral responses, we used a T cell line constitutively expressing Nef and analyzed the JAK/STAT pathway activation after IFN stimuli. Here, we demonstrate that Nef interferes with the JAK/STAT signaling pathway by selectively depleting STAT1 in T cells. This Nef-mediated depletion depends on Nef myristylation and proteasomal activity but not on lysosomal activity. In contrast, the levels of STAT2, an interaction partner of STAT1, as well as the phosphorylation of upstream kinases JAK1 and TYK2, remain unaffected by Nef. Importantly, the depletion of STAT1 in Nef-expressing T cells compromises the induction of antiviral ISGs by IFN-α. These findings reveal a novel role for Nef in T cells, suggesting a mechanism through which HIV-1 evades IFN-α-induced antiviral responses, potentially contributing to viral immune evasion.

In the Nicotiana tabacum flower development study, we identified SCI1 (Stigma/style Cell-cycle Inhibitor 1), a regulator of cell proliferation. SCI1 interacts with NtCDKG;2 (N. tabacum Cyclin-Dependent Kinase G;2), a homolog of human CDK11, which is responsible for RanGTP-dependent microtubule stabilization, regulating spindle assembly rate. In a Y2H screening of a cDNA library using NtCDKG;2 as bait, a RanBP1 (Ran-Binding Protein 1) was revealed as its interaction partner. RanBP1 is an essential regulatory protein of the RanGTPase system, contributing to the formation of the Ran gradient, which modulates different important cellular processes. RanBP1 is crucial in the nuclear import/export machinery during interphase and spindle checkpoint formation during cell division. These processes are well studied in animals, but very little is known about them in plants. We confirmed NtCDKG;2 and NtRanBP1 interaction by pairwise Y2H and characterized the localization of both proteins during plant cell division. We demonstrated the presence of NtRanBP1 in the cytoplasm during interphase and its nuclear arrest at mitosis onset. Meanwhile, we showed that NtCDKG;2 is localized in the mitotic spindle during cell division, indicating an analogous function to the human CDK11. We propose that the phosphorylation of the nuclear export signal at RanBP1 by NtCDKG;2 may be responsible for the reported nuclear arrest.

Oropouche fever, a debilitating illness common in South America, is caused by Oropouche virus (OROV), an arbovirus. OROV belongs to the Peribunyaviridae family, a large group of RNA viruses. Little is known about the biology of Peribunyaviridae in host cells, especially assembly and egress processes. Our research reveals that the small GTPase Rab27a mediates intracellular transport of OROV induced compartments and viral release from infected cells. We show that Rab27a interacts with OROV glycoproteins and colocalizes with OROV during late phases of the infection cycle. Moreover, Rab27a activity is required for OROV trafficking to the cell periphery and efficient release of infectious particles. Consistently, depleting Rab27a’s downstream effector, Myosin Va, or inhibiting actin polymerization also hinders OROV compartments targeting to the cell periphery and infectious viral particle egress. These data indicate that OROV hijacks Rab27a activity for intracellular transport and cell externalization. Understanding these crucial mechanisms of OROV’s replication cycle may offer potential targets for therapeutic interventions and aid in controlling the spread of Oropouche fever.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4⁺ T helper cells, but not CD8⁺ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.

Unlike many segmented negative-sense RNA viruses, most members of the Bunyavirales bud at Golgi membranes, as opposed to the plasma membrane. Central players in this assembly process are the envelope glycoproteins, Gn and Gc, which upon translation undergo proteolytic processing, glycosylation and trafficking to the Golgi, where they interact with ribonucleoprotein genome segments and bud into Golgi-derived compartments. The processes involved in genome packaging during virion assembly can lead to the generation of reassorted viruses, if a cell is co-infected with two different bunyaviruses, due to mismatching of viral genome segment packaging. This can lead to viruses with high pathogenic potential, as demonstrated by the emergence of Schmallenberg virus. This review focuses on the assembly pathways of tri-segmented bunyaviruses, highlighting some areas in need of further research to understand these important pathogens with zoonotic potential.

Oropouche virus causes Oropouche fever, a debilitating illness common in South America that is characterized by high fever, headache, myalgia, and vomiting. The tripartite genome of this zoonotic virus is capable of reassortment, and there have been multiple epidemics of Oropouche fever in South America over the last 50 years, making Oropouche virus infection a significant threat to public health.

The human immunodeficiency virus (HIV-1) modifies the host cell environment to ensure efficient and sustained viral replication. Key to these processes is the capacity of the virus to hijack ATPases, GTPases and the associated proteins that control intracellular protein trafficking. The functions of these energy-harnessing enzymes can be seized by HIV-1 to allow the intracellular transport of viral components within the host cell or to change the subcellular distribution of antiviral factors, leading to immune evasion. Here, we summarize how energy-related proteins deviate from their normal functions in host protein trafficking to aid the virus in different phases of its replicative cycle. Recent discoveries regarding the interplay among HIV-1 and host ATPases and GTPases may shed light on potential targets for pharmacological intervention.