title: Conserved Interaction of Lentiviral Vif Molecules with HIV-1 Gag and Differential Effects of Species-Specific Vif on Virus Production.
abstract: The virion infectivity factor (Vif) open reading frame is conserved among most lentiviruses. Vif molecules contribute to viral replication by inactivating host antiviral factors, the APOBEC3 cytidine deaminases. However, various species of lentiviral Vif proteins have evolved different strategies for overcoming host APOBEC3. Whether different species of lentiviral Vif proteins still preserve certain common features has not been reported. Here, we show for the first time that diverse lentiviral Vif molecules maintain the ability to interact with the human immunodeficiency virus type 1 (HIV-1) Gag precursor (Pr55Gag) polyprotein. Surprisingly, bovine immunodeficiency virus (BIV) Vif, but not HIV-1 Vif, interfered with HIV-1 production and viral infectivity even in the absence of APOBEC3. Further analysis revealed that BIV Vif demonstrated an enhanced interaction with Pr55Gagcompared to that of HIV-1 Vif, and BIV Vif defective for the Pr55Gaginteraction lost its ability to inhibit HIV-1. The C-terminal region of capsid (CA) and the p2 region of Pr55Gag, which are important for virus assembly and maturation, were involved in the interaction. Transduction of CD4+T cells with BIV Vif blocked HIV-1 replication. Thus, the conserved Vif-Pr55Gaginteraction provides a potential target for the future development of antiviral strategies.IMPORTANCEThe conserved Vif accessory proteins of primate lentiviruses HIV-1, simian immunodeficiency virus (SIV), and BIV all form ubiquitin ligase complexes to target host antiviral APOBEC3 proteins for degradation, with different cellular requirements and using different molecular mechanisms. Here, we demonstrate that BIV Vif can interfere with HIV-1 Gag maturation and suppress HIV-1 replication through interaction with the precursor of the Gag (Pr55Gag) of HIV-1 in virus-producing cells. Moreover, the HIV-1 and SIV Vif proteins are conserved in terms of their interactions with HIV-1 Pr55Gagalthough HIV-1 Vif proteins bind Pr55Gagless efficiently than those of BIV Vif. Our research not only sheds new light on this feature of these conserved lentiviral Vif proteins but also provides a formerly unrecognized target for the development of antiviral strategies. Since increasing the Vif-Pr55Gaginteraction could potentially suppress virus proliferation, this approach could offer a new strategy for the development of HIV inhibitors.
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
authors.forename: Wenwen
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Colorectal and Anal Surgery, First Hospital of Jilin University, Changchun, Jilin Province, China.
authors.forename: Limian
authors.initials: L
authors.lastname: Ling
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
authors.forename: Zhaolong
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Life Science, Tianjin University, Tianjin, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin Province, China.|Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Rui
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
authors.forename: Wenying
authors.initials: W
authors.lastname: Gao
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Wang
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin Province, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Su
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin Province, China wwei6@jlu.edu.cn xyu2@jhu.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Institute of Virology and AIDS Research, First Hospital of Jilin University, Changchun, Jilin Province, China wwei6@jlu.edu.cn xyu2@jhu.edu.|Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yu
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence; D057809:HEK293 Cells; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D016087:Immunodeficiency Virus, Bovine / Q000502:physiology*; D008958:Models, Molecular; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D013045:Species Specificity; D014779:Virus Replication; D054301:gag Gene Products, Human Immunodeficiency Virus; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: D054301:gag Gene Products, Human Immunodeficiency Virus; D054320:vif Gene Products, Human Immunodeficiency Virus
keywords: BIV Vif; HIV-1; HIV-1 Gag precursor; viral infectivity factor