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HIV-1) CD4 Receptor and Its Central Role in Promotion of HIV-1 Infection

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HIV-1) CD4 Receptor and Its Central Role in Promotion of HIV-1 Infection MICROBIOLOGICAL REVIEWS, Mar. 1995, p. 63–93 Vol. 59, No. 1 0146-0749/95/$04.0010 Copyright q 1995, American Society for Microbiology The Human Immunodeficiency Virus Type 1 (HIV-1) CD4 Receptor and Its Central Role in Promotion of HIV-1 Infection STEPHANE BOUR,* ROMAS GELEZIUNAS,† AND MARK A. WAINBERG* McGill AIDS Centre, Lady Davis Institute-Jewish General Hospital, and Departments of Microbiology and Medicine, McGill University, Montreal, Quebec, Canada H3T 1E2 INTRODUCTION .........................................................................................................................................................63 RETROVIRAL RECEPTORS .....................................................................................................................................64 Receptors for Animal Retroviruses ........................................................................................................................64 CD4 Is the Major Receptor for HIV-1 Infection..................................................................................................65 ROLE OF THE CD4 CORECEPTOR IN T-CELL ACTIVATION........................................................................65 Structural Features of the CD4 Coreceptor..........................................................................................................65 Interactions of CD4 with Class II MHC Determinants ......................................................................................66 CD4–T-Cell Receptor Interactions during T-Cell Activation .............................................................................67 Signal Transduction by the CD4-p56lck Complex.................................................................................................67 CD4 Can Transduce Inhibitory Signals to T Cells..............................................................................................68 STRUCTURE AND MATURATION OF HIV-1 ENVELOPE GLYCOPROTEINS.............................................69 Biosynthesis of the gp160 Polyprotein Precursor.................................................................................................69 Endoproteolytic Cleavage of gp160.........................................................................................................................69 Glycosylation and Trimming...................................................................................................................................70 Oligomeric Structure of the Envelope Glycoproteins of HIV-1..........................................................................70 MOLECULAR CHARACTERIZATION OF CD4-gp120 INTERACTIONS .........................................................70 Role of Oligosaccharides in CD4-gp120 Interactions..........................................................................................70 Binding Site for gp120 on CD4...............................................................................................................................70 The MHC II- and gp120-Binding Sites on CD4 Are Distinct but Overlapping ..............................................71 Binding Site for CD4 on gp120...............................................................................................................................72 Postentry Events Involving CD4 and Viral Envelope Glycoproteins.................................................................72 BIOLOGICAL EFFECTS OF CD4-gp120 CELL SURFACE INTERACTIONS..................................................73 Triggering of T-Cell Activation...............................................................................................................................73 Inhibition of T-Cell Activation by gp120 and Induction of Apoptosis ..............................................................74 RETROVIRAL INTERFERENCE ..............................................................................................................................75 Classification of Retroviruses in Receptor Interference Groups .......................................................................75 Retroviral Interference by HIV-1............................................................................................................................76 Cytopathology Associated with Superinfection.....................................................................................................76 Downregulation of MHC Antigens as a Means of Immune Evasion ................................................................76 INTRACELLULAR INTERACTIONS BETWEEN CD4 AND HIV-1....................................................................77 HIV-1 Infection Downregulates CD4 Transcription ............................................................................................77 Formation of Intracellular Complexes between CD4 and gp160 .......................................................................77 Regulation of CD4-gp160 Complexes and CD4 Degradation by Vpu ...............................................................78 Vpu Induces Degradation of ER-Resident CD4 ...................................................................................................78 Receptor Interference by the Nef Protein..............................................................................................................80 CONCLUSION..............................................................................................................................................................82 ACKNOWLEDGMENTS .............................................................................................................................................82 REFERENCES ..............................................................................................................................................................82 INTRODUCTION the surface (SU) envelope glycoprotein of HIV-1 (gp120) ini- tiate infection and viral entry (232, 296). HIV infection com- Infection of target cells by human immunodeficiency virus monly leads to progressive loss of CD4-expressing cells, includ- type 1 (HIV-1) is dependent on surface representation of clus- ing CD41 T lymphocytes (26). This is correlated with the ter determinant 4 (CD4), which serves as a specific virus re- occurrence of opportunistic infections and development of ceptor (232, 276). High-affinity interactions between CD4 and AIDS (119). In addition to peripheral blood lymphocytes, HIV-1 targets CD41 cells in the thymus, the primary site of CD41 T-cell * Corresponding author. Mailing address for Stephane Bour: Lab- selection (40, 437), and lymph nodes, a major HIV reservoir in oratory of Molecular Microbiology, National Institute of Allergy and asymptomatic infected individuals (346). HIV can induce cy- Infectious Diseases, Bethesda, MD 20892-0460. Mailing address for topathic effects, including syncytium formation and cell death Mark A. Wainberg: Lady Davis Institute-Jewish General Hospital, 1 3755 Cote-Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2. (270). It can also persistently infect CD4 cells both in vivo Phone: (514) 340-8260. Fax: (514) 340-7537. and in cell culture (193, 363, 405), leading to immunological † Present address: Gladstone Institute of Virology and Immunology, dysregulation and a loss of immune competence in infected San Francisco, CA 94110. individuals (120). 63 64 BOUR ET AL. MICROBIOL.REV. TABLE 1. Biological characteristics of known receptors for animal retroviruses Chromosome Biochemical Structural Receptor Virusa containing receptor characteristics of Cellular function of receptor homology of name Mouse Human receptor receptor ALSV-A tv-a 101–138-aa protein LDL receptor MuLV-E Rec1 (Atrc1) 5 622-aa protein Amino acid transporter Tea, H13 MuLV-A Ram1 8 8 656-aa protein Phosphate permease GLVR-1 MuLV-P (MCFF) Rmc1 1 Sxv MuLV-X Sxv 1 Rmc1 MMTV Mtvr1 16 M813 (asian MuLV) Rec2 2 FeLV-A 70-kDa protein BLV BLVR-1 729-aa protein GALV FeLV-B GLVR-1 2 2q 629-aa protein Phosphate permease pho41 permease MuLV-XCaroli SRV-D FEV-C (RD114) BaEV-C 19q 60-kDa protein REV HTLV-I HTLV-II HTLV-R 17q 31–70-kDa proteins STLV HIV-1 HIV-2 CD4 6 12 433-aa glycoprotein T-lymphocyte coreceptor IgG superfamily SIV a Abbreviations: ASLV, avian leukosis and sarcoma virus; MMTV, mouse mammary tumor virus; FeLV, feline leukemia virus; BLV, bovine leukemia virus; SRV, simian retrovirus; FEV, feline endogenous virus; BaEV, baboon endogenous virus; REV, reticuloendotheliosis virus; STLV, simian T-cell leukemia virus; MCFF, mink cell focus-forming virus; aa, amino acid; LDL, low-density lipoprotein. This review deals with molecular mechanisms that underlie tion as a basic amino acid transporter (66, 229, 484). The perturbation of CD41 cell function and maintenance of HIV selectivity and electrochemical properties of the EcoR trans- infection; most such changes involve alterations of both expres- porter are identical to those of the previously identified y1 sion and function of the CD4 molecule. cationic L-amino acid transporter, found at the plasma mem- brane of mammalian cells (359, 496, 497). RETROVIRAL RECEPTORS A human gene homologous to EcoR (H13) has been iden- tified and mapped to chromosome 13 (514). Although H13 is Receptors for Animal Retroviruses unable to serve as a receptor for MuLV infection, it has a 87.6% amino acid homology with EcoR and shares 14 trans- Retroviral envelope proteins bind to specific receptor mol- membrane-spanning regions with its mouse homolog (514). ecules expressed
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