Different host proteins target different HIV proteins and antagonize their functions, depending on the stage of the HIV life cycle and the stage of infection. Concurrently, HIV proteins also target and antagonize various different host proteins to facilitate HIV replication within host cells. The preceding quite specific area of knowledge in HIV pathogenesis, however, remains insufficiently understood. We therefore propose, in this review article, to examine and discuss the HIV proteins that counteract those host restriction proteins which results directly in increased infectivity of HIV. We elaborate on HIV proteins that antagonize host cellular proteins to promote HIV replication, and thus HIV infection. We examine the functions and mechanisms via which Nef, Vif, Vpu, Env, Vpr, and Vpx counteract host proteins such as Ser5, PSGL-1, IFITMS, A3G, tetherin, GBP5, SAMHD1, STING, HUSH, REAF, and TET2 to increase HIV infectivity. Nef antagonizes three host proteins, viz., Ser5, PSGL1, and IFITIMs, while Vpx also antagonizes three host restriction factors, viz., SAMHD1, STING, and HUSH complex; therefore, these proteins may be potential candidates for therapeutic intervention in HIV infection. Tetherin is targeted by Vpu and Env, PSGL1 is targeted by Nef and Vpu, while Ser5 is targeted by Nef and Env proteins. Finally, conclusive remarks and future perspectives are also presented.

The brain is highly sensitive to damage caused by infection and inflammation1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis3. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus-cell binding and virus-cell fusion, respectively4-6. Notably, Tmeff1-/- mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.

The TRIM family is associated with the membrane, and its involvement in the progression, growth, and development of various cancer types has been researched extensively. However, the role played by the TRIM5 gene within this family has yet to be explored to a great extent in terms of hepatocellular carcinoma (HCC). The data of patients relating to mRNA expression and the survival rate of individuals diagnosed with HCC were extracted from The Cancer Genome Atlas (TCGA) database. UALCAN was employed to examine the potential link between TRIM5 expression and clinicopathological characteristics. In addition, enrichment analysis of differentially expressed genes (DEGs) was conducted as a means of deciphering the function and mechanism of TRIM5 in HCC. The data in the TCGA and TIMER2.0 databases was utilized to explore the correlation between TRIM5 and immune infiltration in HCC. WGCNA was performed as a means of assessing TRIM5-related co-expressed genes. The \"OncoPredict\" R package was also used for investigating the association between TRIM5 and drug sensitivity. Finally, qRT-PCR, Western blotting (WB) and immunohistochemistry (IHC) were employed for exploring the differential expression of TRIM5 and its clinical relevance in HCC. According to the results that were obtained from the vitro experiments, mRNA and protein levels of TRIM5 demonstrated a significant upregulation in HCC tissues. It is notable that TRIM5 expression levels were found to have a strong association with the infiltration of diverse immune cells and displayed a positive correlation with several immune checkpoint inhibitors. The TRIM5 expression also displayed promising clinical prognostic value for HCC patients.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne hemorrhagic fever disease with high fatality rate of 10%-20%. Vaccines or specific therapeutic measures remain lacking. Human interferon inducible transmembrane protein 3 (hIFITM3) is a broad-spectrum antiviral factor targeting viral entry. However, the antiviral activity of hIFITM3 against SFTS virus (SFTSV) and the functional mechanism of IFITM3 remains unclear. Here we demonstrate that endogenous IFITM3 provides protection against SFTSV infection and participates in the anti-SFTSV effect of type Ⅰ and Ⅲ interferons (IFNs). IFITM3 overexpression exhibits anti-SFTSV function by blocking Gn/Gc-mediated viral entry and fusion. Further studies showed that IFITM3 binds SFTSV Gc directly and its intramembrane domain (IMD) is responsible for this interaction and restriction of SFTSV entry. Mutation of two neighboring cysteines on IMD weakens IFITM3-Gc interaction and attenuates the antiviral activity of IFITM3, suggesting that IFITM3-Gc interaction may partly mediate the inhibition of SFTSV entry. Overall, our data demonstrate for the first time that hIFITM3 plays a critical role in the IFNs-mediated anti-SFTSV response, and uncover a novel mechanism of IFITM3 restriction of SFTSV infection, highlighting the potential of clinical intervention on SFTS disease.

African swine fever virus (ASFV) causes a highly contagious and deadly disease in domestic pigs and European wild boars, posing a severe threat to the global pig industry. ASFV CP204L, a highly immunogenic protein, is produced during the early stages of ASFV infection. However, the impact of CP204L protein-interacting partners on the outcome of ASFV infection is poorly understood. To accomplish this, coimmunoprecipitation and mass spectrometry analysis were conducted in ASFV-infected porcine alveolar macrophages (PAMs). We have demonstrated that sorting nexin 32 (SNX32) is a CP204L-binding protein and that CP204L interacted and colocalized with SNX32 in ASFV-infected PAMs. ASFV growth and replication were promoted by silencing SNX32 and suppressed by overexpressing SNX32. SNX32 degraded CP204L by recruiting the autophagy-related protein Ras-related protein Rab-1b (RAB1B). RAB1B overexpression inhibited ASFV replication, while knockdown of RAB1B had the opposite effect. Additionally, RAB1B, SNX32, and CP204L formed a complex upon ASFV infection. Taken together, this study demonstrates that SNX32 antagonizes ASFV growth and replication by recruiting the autophagy-related protein RAB1B. This finding extends our understanding of the interaction between ASFV CP204L and its host and provides new insights into exploring the relationship between ASFV infection and autophagy.IMPORTANCEAfrican swine fever (ASF) is a highly contagious and acute hemorrhagic viral disease with a high mortality near 100% in domestic pigs. ASF virus (ASFV), which is the only member of the family Asfarviridae, is a dsDNA virus of great complexity and size, encoding more than 150 proteins. Currently, there are no available vaccines against ASFV. ASFV CP204L represents the most abundantly expressed viral protein early in infection and plays an important role in regulating ASFV replication. However, the mechanism by which the interaction between ASFV CP204L and host proteins affects ASFV replication remains unclear. In this study, we demonstrated that the cellular protein SNX32 interacted with CP204L and degraded CP204L by upregulating the autophagy-related protein RAB1B. In summary, this study will help us understand the interaction mechanism between CP204L and its host upon infection and provide new insights for the development of vaccines and antiviral drugs.

Herpes simplex virus 1 (HSV-1) is a neurotropic virus that remains latent in neuronal cell bodies but reactivates throughout an individual\'s life, causing severe adverse reactions, such as herpes simplex encephalitis (HSE). Recently, it has also been implicated in the etiology of Alzheimer\'s disease (AD). The absence of an effective vaccine and the emergence of numerous drug-resistant variants have called for the development of new antiviral agents that can tackle HSV-1 infection. Host-targeting antivirals (HTAs) have recently emerged as promising antiviral compounds that act on host-cell factors essential for viral replication. Here we show that a new class of HTAs targeting peptidylarginine deiminases (PADs), a family of calcium-dependent enzymes catalyzing protein citrullination, exhibits a marked inhibitory activity against HSV-1. Furthermore, we show that HSV-1 infection leads to enhanced protein citrullination through transcriptional activation of three PAD isoforms: PAD2, PAD3, and PAD4. Interestingly, PAD3-depletion by specific drugs or siRNAs dramatically inhibits HSV-1 replication. Finally, an analysis of the citrullinome reveals significant changes in the deimination levels of both cellular and viral proteins, with the interferon (IFN)-inducible proteins IFIT1 and IFIT2 being among the most heavily deiminated ones. As genetic depletion of IFIT1 and IFIT2 strongly enhances HSV-1 growth, we propose that viral-induced citrullination of IFIT1 and 2 is a highly efficient HSV-1 evasion mechanism from host antiviral resistance. Overall, our findings point to a crucial role of citrullination in subverting cellular responses to viral infection and demonstrate that PAD inhibitors efficiently suppress HSV-1 infection in vitro, which may provide the rationale for their repurposing as HSV-1 antiviral drugs.

Intracellular innate immunity involves co-evolved antiviral restriction factors that specifically inhibit infecting viruses. Studying these restrictions has increased our understanding of viral replication, host-pathogen interactions, and pathogenesis, and represent potential targets for novel antiviral therapies. Lentiviral restriction 2 (Lv2) was identified as an unmapped early-phase restriction of HIV-2 and later shown to also restrict HIV-1 and simian immunodeficiency virus. The viral determinants of Lv2 susceptibility have been mapped to the envelope and capsid proteins in both HIV-1 and HIV-2, and also viral protein R (Vpr) in HIV-1, and appears dependent on cellular entry mechanism. A genome-wide screen identified several likely contributing host factors including members of the polymerase-associated factor 1 (PAF1) and human silencing hub (HUSH) complexes, and the newly characterized regulation of nuclear pre-mRNA domain containing 2 (RPRD2). Subsequently, RPRD2 (or RNA-associated early-stage antiviral factor) has been shown to be upregulated upon T cell activation, is highly expressed in myeloid cells, binds viral reverse transcripts, and potently restricts HIV-1 infection. RPRD2 is also bound by HIV-1 Vpr and targeted for degradation by the proteasome upon reverse transcription, suggesting RPRD2 impedes reverse transcription and Vpr targeting overcomes this block. RPRD2 is mainly localized to the nucleus and binds RNA, DNA, and DNA:RNA hybrids. More recently, RPRD2 has been shown to negatively regulate genome-wide transcription and interact with the HUSH and PAF1 complexes which repress HIV transcription and are implicated in maintenance of HIV latency. In this review, we examine Lv2 restriction and the antiviral role of RPRD2 and consider potential mechanism(s) of action.

Equine infectious anemia virus (EIAV) is a member of the lentivirus genus in the Retroviridae family and is considered an animal model for HIV/AIDS research. An attenuated EIAV vaccine, which was successfully developed in the 1970s by classical serial passage techniques, is the first and only lentivirus vaccine that has been widely used to date. Restriction factors are cellular proteins that provide an early line of defense against viral replication and spread by interfering with various critical steps in the viral replication cycle. However, viruses have evolved specific mechanisms to overcome these host barriers through adaptation. The battle between the viruses and restriction factors is actually a natural part of the viral replication process, which has been well studied in human immunodeficiency virus type 1 (HIV-1). EIAV has the simplest genome composition of all lentiviruses, making it an intriguing subject for understanding how the virus employs its limited viral proteins to overcome restriction factors. In this review, we summarize the current literature on the interactions between equine restriction factors and EIAV. The features of equine restriction factors and the mechanisms by which the EIAV counteract the restriction suggest that lentiviruses employ diverse strategies to counteract innate immune restrictions. In addition, we present our insights on whether restriction factors induce alterations in the phenotype of the attenuated EIAV vaccine.

Mitochondrial antiviral signaling protein (MAVS) is an essential articulatory protein in immune responses against most RNA viruses. Whether bats, the natural hosts of numerous zoonotic RNA viruses, utilize conserved signaling pathways involving MAVS-mediated interferon (IFN) responses remains elusive. In this study, we performed the cloning and functional analysis of bat MAVS (BatMAVS). Amino acid sequence analysis revealed that BatMAVS was poorly conserved among species and evolutionarily closer to other mammals. Overexpression of BatMAVS significantly inhibited the replication of green fluorescent protein (GFP)-tagged VSV (VSV-GFP) and GFP-tagged Newcastle disease virus (NDV) (NDV-GFP) by activating the type I IFN pathway, and its expression at the transcriptional level was upregulated at the late stage of VSV-GFP infection. We further demonstrated that the CARD_2 and TM domains occupy a large proportion in the ability of BatMAVS to activate IFN-β. These results suggest that BatMAVS acts as an important regulatory molecule in IFN-induction and anti-RNA viruses in bats.

Mammalian DDX23 is involved in multiple biological processes, such as RNA processing and antiviral responses. However, the function of teleost DDX23 still remains unclear. In this paper, we have cloned the DDX23 homologue of black carp (Mylopharyngodon piceus) (bcDDX23) and elucidated its role in the antiviral innate immunity. The coding region of bcDDX23 comprises 2427 nucleotides and encodes 809 amino acids. The transcription of bcDDX23 was promoted by the stimulation of LPS, poly(I:C), and SVCV; and immunoblotting (IB) assay showed that bcDDX23 migrated aground 94.5 kDa. Immunofluorescence (IF) assay revealed that bcDDX23 was mainly distributed in the nucleus, and the amount of cytosolic bcDDX23 was significantly increased after SVCV infection. The reporter assay showed that bcDDX23 inhibited bcMAVS-mediated transcription of the IFN promoter. And the co-immunoprecipitation (co-IP) assays identified the interaction between bcDDX23 and bcMAVS. Furthermore, co-expressed bcDDX23 significantly inhibited bcMAVS-mediated antiviral ability against SVCV in EPC cells, and knockdown of bcDDX23 enhanced the resistance of host cells against SVCV. Overall, our results conclude that bcDDX23 targets bcMAVS and suppresses MAVS-mediated IFN signaling, which sheds light on the regulation of IFN signaling in teleost fish.