title: Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV.
abstract: Natural-host sooty mangabeys (SM) infected with simian immunodeficiency virus (SIV) exhibit high viral loads but do not develop disease, whereas infection of rhesus macaques (RM) causes CD4(+) T cell loss and AIDS. Several mechanisms have been proposed to explain these divergent outcomes, including differences in cell targeting, which have been linked to low expression of the canonical SIV entry receptor CCR5 on CD4(+) T cells of SM and other natural hosts. We previously showed that infection and high-level viremia occur even in a subset of SM that genetically lack functional CCR5, which indicates that alternative entry coreceptors are used by SIV in vivo in these animals. We also showed that SM CXCR6 is a robust coreceptor for SIVsmm in vitro. Here we identify CXCR6 as a principal entry pathway for SIV in SM primary lymphocytes. We show that ex vivo SIV infection of lymphocytes from CCR5 wild-type SM is mediated by both CXCR6 and CCR5. In contrast, infection of RM lymphocytes is fully dependent on CCR5. These data raise the possibility that CXCR6-directed tropism in CCR5-low natural hosts may alter CD4(+) T cell subset targeting compared with that in nonnatural hosts, enabling SIV to maintain high-level replication without leading to widespread CD4(+) T cell loss.
  
  
  OBJECTIVE
  Natural hosts of SIV, such as sooty mangabeys, sustain high viral loads but do not develop disease, while nonnatural hosts, like rhesus macaques, develop AIDS. Understanding this difference may help elucidate mechanisms of pathogenesis. Natural hosts have very low levels of the SIV entry coreceptor CCR5, suggesting that restricted entry may limit infection of certain target cells, although it is unclear how the virus replicates so robustly. Here we show that in sooty mangabey lymphocytes, infection is mediated by the alternative entry coreceptor CXCR6, as well as CCR5. In rhesus macaque lymphocytes, however, infection occurs entirely through CCR5. The use of CXCR6 for entry, combined with very low CCR5 levels, may redirect the virus to different cell targets in natural hosts. It is possible that differential targeting may favor infection of nonessential cells and limit infection of critical cells in natural hosts, thus contributing to benign outcome of infection.
authors.affiliation: Departments of Medicine and Microbiology and the Penn Center for AIDS Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Sarah T C
authors.initials: ST
authors.lastname: Elliott
authors.affiliation: Departments of Medicine and Microbiology and the Penn Center for AIDS Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Wetzel
authors.affiliation: Departments of Medicine and Microbiology and the Penn Center for AIDS Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Francella
authors.affiliation: Departments of Medicine and Microbiology and the Penn Center for AIDS Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Bryan
authors.affiliation: Departments of Medicine and Microbiology and the Penn Center for AIDS Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Dino C
authors.initials: DC
authors.lastname: Romero
authors.affiliation: Departments of Medicine and Microbiology and the Penn Center for AIDS Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Nadeene E
authors.initials: NE
authors.lastname: Riddick
authors.affiliation: Departments of Medicine and Microbiology and the Penn Center for AIDS Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Farida
authors.initials: F
authors.lastname: Shaheen
authors.affiliation: Department of Pathology and Laboratory Medicine and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vanderford
authors.affiliation: Department of Pathology and Laboratory Medicine and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
authors.affiliation: Department of Pathology and Laboratory Medicine and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.affiliation: Department of Pathology and Laboratory Medicine and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Mirko
authors.initials: M
authors.lastname: Paiardini
authors.affiliation: Departments of Medicine and Microbiology and the Penn Center for AIDS Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA collmanr@upenn.edu.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Collman
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D016665:Cercocebus atys; D057809:HEK293 Cells; D006801:Humans; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000378:metabolism*; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D056189:Viral Tropism / Q000502:physiology; D053586:Virus Internalization
chemical_list: D019713:Receptors, CCR5; D054387:Receptors, CXCR