title: Magnitude and Quality of Cytokine and Chemokine Storm during Acute Infection Distinguish Nonprogressive and Progressive Simian Immunodeficiency Virus Infections of Nonhuman Primates.
abstract: Acute human immunodeficiency virus (HIV) infection represents a period of intense immune perturbation and activation of the host immune system. Study of the eclipse and viral expansion phases of infection is difficult in humans, but studies in nonprogressive and progressive nonhuman primate (NHP) infection models can provide significant insight into critical events occurring during this time. Cytokines, chemokines, and other soluble immune factors were measured in longitudinal samples from rhesus macaques infected with either SIVmac251 (progressive infection) or SIVmac239Δnef (attenuated/nonprogressive infection) and from African green monkeys infected with SIVsab9315BR (nonpathogenic infection). Levels of acute-phase peak viral replication were highest in SIVmac251 infection but correlated positively with viremia at 3 months postinfection in all three infection models. SIVmac251 infection was associated with stronger corresponding acute-phase cytokine/chemokine responses than the nonprogressive infections. The production of interleukin 15 (IL-15), IL-18, gamma interferon (IFN-γ), granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1β (MIP-1β), and serum amyloid A protein (SAA) during acute SIVmac251 infection, but not during SIVmac239Δnef or SIVsab9315BR infection, correlated positively with chronic viremia at 3 months postinfection. Acute-phase production of MCP-1 correlated with viremia at 3 months postinfection in both nonprogressive infections. Finally, a positive correlation between the acute-phase area under the curve (AUC) for IL-6 and soluble CD40 ligand (sCD40L) and chronic viremia was observed only for the nonprogressive infection models. While we observed dynamic acute inflammatory immune responses in both progressive and nonprogressive SIV infections, the responses in the nonprogressive infections were not only lower in magnitude but also qualitatively different biomarkers of disease progression.
  
  
  OBJECTIVE
  NHP models of HIV infection constitute a powerful tool with which to study viral pathogenesis in order to gain critical information for a better understanding of HIV infection in humans. Here we studied progressive and nonprogressive simian immunodeficiency virus (SIV) infection models in both natural and nonnatural host NHP species. Regardless of the pathogenicity of the virus infection and regardless of the NHP species studied, the magnitude of viremia, as measured by area under the curve, during the first 4 weeks of infection correlated positively with viremia in chronic infection. The magnitude of cytokine and chemokine responses during primary infection also correlated positively with both acute-phase and chronic viremia. However, the pattern and levels of specific cytokines and chemokines produced differed between nonprogressive and progressive SIV infection models. The qualitative differences in the early immune response in pathogenic and nonpathogenic infections identified here may be important determinants of the subsequent disease course.
authors.affiliation: Blood Systems Research Institute, San Francisco, California, USA skeating@bloodsystems.org.|Department of Laboratory Medicine, University of California, San Francisco, California, USA.
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Keating
authors.affiliation: Blood Systems Research Institute, San Francisco, California, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Heitman
authors.affiliation: Blood Systems Research Institute, San Francisco, California, USA.
authors.forename: Shiquan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Blood Systems Research Institute, San Francisco, California, USA.
authors.forename: Xutao
authors.initials: X
authors.lastname: Deng
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Stacey
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA.
authors.forename: Roland C
authors.initials: RC
authors.lastname: Zahn
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA.
authors.forename: Maurus
authors.initials: M
authors.lastname: de la Rosa
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Finstad
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: Texas Biomedical Research Institute, Department of Virology and Immunology and Southwest National Primate Research Center, San Antonio, Texas, USA.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gauduin
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.|Target Discovery Institute, University of Oxford, Oxford, United Kingdom.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.|Target Discovery Institute, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicola
authors.identifier: http://orcid.org/0000-0002-9283-0743
authors.initials: N
authors.lastname: Ternette
authors.affiliation: Department of Primate Resources, New England Primate Research Center, Southborough, Massachusetts, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Carville
authors.affiliation: Department of Immunology, New England Primate Research Center, Southborough, Massachusetts, USA.
authors.forename: R Paul
authors.initials: RP
authors.lastname: Johnson
authors.affiliation: Department of Microbiology, New England Primate Research Center, Southborough, Massachusetts, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Desrosiers
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Persephone
authors.initials: P
authors.lastname: Borrow
authors.affiliation: Blood Systems Research Institute, San Francisco, California, USA.|Department of Laboratory Medicine, University of California, San Francisco, California, USA.|Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Norris
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA.
authors.forename: Joern E
authors.initials: JE
authors.lastname: Schmitz
mesh_terms: D000208:Acute Disease; D000818:Animals; D018925:Chemokines / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D006678:HIV / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D011323:Primates; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D014766:Viremia / Q000276:immunology / Q000821:virology
chemical_list: D018925:Chemokines; D016207:Cytokines