title: Efficient Nef-mediated downmodulation of TCR-CD3 and CD28 is associated with high CD4+ T cell counts in viremic HIV-2 infection.
abstract: The role of the multifunctional accessory Nef protein in the immunopathogenesis of HIV-2 infection is currently poorly understood. Here, we performed comprehensive functional analyses of 50 nef genes from 21 viremic (plasma viral load, >500 copies/ml) and 16 nonviremic (<500) HIV-2-infected individuals. On average, nef alleles from both groups were equally active in modulating CD4, TCR-CD3, CD28, MHC-I, and Ii cell surface expression and in enhancing virion infectivity. Thus, many HIV-2-infected individuals efficiently control the virus in spite of efficient Nef function. However, the potency of nef alleles in downmodulating TCR-CD3 and CD28 to suppress the activation and apoptosis of T cells correlated with high numbers of CD4(+) T cells in viremic patients. No such correlations were observed in HIV-2-infected individuals with undetectable viral load. Further functional analyses showed that the Nef-mediated downmodulation of TCR-CD3 suppressed the induction of Fas, Fas-L, PD-1, and CTLA-4 cell surface expression as well as the secretion of gamma interferon (IFN-γ) by primary CD4(+) T cells. Moreover, we identified a single naturally occurring amino acid variation (I132T) in the core domain of HIV-2 Nef that selectively disrupts its ability to downmodulate TCR-CD3 and results in functional properties highly reminiscent of HIV-1 Nef proteins. Taken together, our data suggest that the efficient Nef-mediated downmodulation of TCR-CD3 and CD28 help viremic HIV-2-infected individuals to maintain normal CD4(+) T cell homeostasis by preventing T cell activation and by suppressing the induction of death receptors that may affect the functionality and survival of both virally infected and uninfected bystander cells.
authors.affiliation: Institute of Molecular Virology, University Clinic of Ulm, Ulm, Germany.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Khalid
authors.forename: Hangxing
authors.initials: H
authors.lastname: Yu
authors.forename: Daniel
authors.initials: D
authors.lastname: Sauter
authors.forename: Shariq M
authors.initials: SM
authors.lastname: Usmani
authors.forename: Jan
authors.initials: J
authors.lastname: Schmokel
authors.forename: Jerome
authors.initials: J
authors.lastname: Feldman
authors.forename: Rob A
authors.initials: RA
authors.lastname: Gruters
authors.forename: Marchina E
authors.initials: ME
authors.lastname: van der Ende
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.forename: Sarah
authors.initials: S
authors.lastname: Rowland-Jones
authors.forename: Albert D
authors.initials: AD
authors.lastname: Osterhaus
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
mesh_terms: D019943:Amino Acid Substitution; D017209:Apoptosis / Q000235:genetics; D018106:CD28 Antigens / Q000378:metabolism*; D018791:CD4 Lymphocyte Count; D002460:Cell Line; D015536:Down-Regulation / Q000276:immunology; D015870:Gene Expression; D023061:Gene Order; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015498:HIV-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D008213:Lymphocyte Activation / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D011533:Proviruses / Q000235:genetics; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014766:Viremia / Q000276:immunology / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011956:Receptors, Cell Surface; D053218:Receptors, Death Domain; D054311:nef Gene Products, Human Immunodeficiency Virus