title: The V3 Loop of HIV-1 Env Determines Viral Susceptibility to IFITM3 Impairment of Viral Infectivity.
abstract: Interferon-inducible transmembrane proteins (IFITMs) inhibit a broad spectrum of viruses, including HIV-1. IFITM proteins deter HIV-1 entry when expressed in target cells and also impair HIV-1 infectivity when expressed in virus producer cells. However, little is known about how viruses resist IFITM inhibition. In this study, we have investigated the susceptibilities of different primary isolates of HIV-1 to the inhibition of viral infectivity by IFITMs. Our results demonstrate that the infectivity of different HIV-1 primary isolates, including transmitted founder viruses, is diminished by IFITM3 to various levels, with strain AD8-1 exhibiting strong resistance. Further mutagenesis studies revealed that HIV-1 Env, and the V3 loop sequence in particular, determines the extent of inhibition of viral infectivity by IFITM3. IFITM3-sensitive Env proteins are also more susceptible to neutralization by soluble CD4 or the 17b antibody than are IFITM3-resistant Env proteins. Together, data from our study suggest that the propensity of HIV-1 Env to sample CD4-bound-like conformations modulates viral sensitivity to IFITM3 inhibition.IMPORTANCEResults of our study have revealed the key features of the HIV-1 envelope protein that are associated with viral resistance to the IFITM3 protein. IFITM proteins are important effectors in interferon-mediated antiviral defense. A variety of viruses are inhibited by IFITMs at the virus entry step. Although it is known that envelope proteins of several different viruses resist IFITM inhibition, the detailed mechanisms are not fully understood. Taking advantage of the fact that envelope proteins of different HIV-1 strains exhibit different degrees of resistance to IFITM3 and that these HIV-1 envelope proteins share the same domain structure and similar sequences, we performed mutagenesis studies and determined the key role of the V3 loop in this viral resistance phenotype. We were also able to associate viral resistance to IFITM3 inhibition with the susceptibility of HIV-1 to inhibition by soluble CD4 and the 17b antibody that recognizes CD4-binding-induced epitopes.
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.|Department of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Yimeng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Centre de Recherche du CHUM, Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Shilei
authors.initials: S
authors.lastname: Ding
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.|Department of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Jingyou
authors.initials: J
authors.lastname: Yu
authors.affiliation: Centre de Recherche du CHUM, Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.|Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
authors.affiliation: Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Shan-Lu
authors.initials: SL
authors.lastname: Liu
authors.affiliation: Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada chen.liang@mcgill.ca.|Department of Medicine, McGill University, Montreal, QC, Canada.|Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
mesh_terms: D020816:Amino Acid Motifs; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D057131:Immune Evasion; D008565:Membrane Proteins / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000502:physiology*; D014771:Virion
chemical_list: D015699:HIV Envelope Protein gp120; C080082:IFITM3 protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: IFITM; envelope protein; human immunodeficiency virus