title: Dengue virus-specific CD4+ and CD8+ T lymphocytes target NS1, NS3 and NS5 in infected Indian rhesus macaques.
abstract: Every year, Dengue virus (DENV) infects approximately 100 million people. There are currently several vaccines undergoing clinical studies, but most target the induction of neutralizing antibodies. Unfortunately, DENV infection can be enhanced by subneutralizing levels of antibodies that bind virions and deliver them to cells of the myeloid lineage, thereby increasing viral replication (termed antibody-dependent enhancement [ADE]). T lymphocyte-based vaccines may offer an alternative that avoids ADE. The goal of our study was to describe the cellular immune response generated after primary DENV infection in Indian rhesus macaques. We infected eight rhesus macaques with 10⁵ plaque-forming units (PFU) of DENV serotype 2 (DENV2) New Guinea C (NGC) strain, and monitored viral load and the cellular immune response to the virus. Viral replication peaked at day 4 post-infection and was resolved by day 10. DENV-specific CD4+ and CD8+ T lymphocytes targeted nonstructural (NS) 1, NS3 and NS5 proteins after resolution of peak viremia. DENV-specific CD4+ cells expressed interferon-gamma (IFN-γ) along with tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), and macrophage inflammatory protein-1 beta (MIP-1β). In comparison, DENV-specific CD8+ cells expressed IFN-γ in addition to MIP-1β and TNF-α and were positive for the degranulation marker CD107a. Interestingly, a fraction of the DENV-specific CD4+ cells also stained for CD107a, suggesting that they might be cytotoxic. Our results provide a more complete understanding of the cellular immune response during DENV infection in rhesus macaques and contribute to the development of rhesus macaques as an animal model for DENV vaccine and pathogenicity studies.
authors: Microbiology Doctoral Training Program, University of Wisconsin-Madison, 1326 Microbial Sciences, 1550 Linden Drive, Madison, WI 53706, USA.
authors: Katherine M
authors: KM
authors: Mladinich
authors: Shari M
authors: SM
authors: Piaskowski
authors: Richard
authors: R
authors: Rudersdorf
authors: Christopher M
authors: CM
authors: Eernisse
authors: Kim L
authors: KL
authors: Weisgrau
authors: Mauricio A
authors: MA
authors: Martins
authors: Jessica R
authors: JR
authors: Furlott
authors: Charalambos D
authors: CD
authors: Partidos
authors: Joseph N
authors: JN
authors: Brewoo
authors: Jorge E
authors: JE
authors: Osorio
authors: Nancy A
authors: NA
authors: Wilson
authors: Eva G
authors: EG
authors: Rakasz
authors: David I
authors: DI
authors: Watkins
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003715:Dengue / Q000276:immunology* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D007111:Immunity, Cellular; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology; D008253:Macaca mulatta; D020365:RNA Helicases / Q000276:immunology; D012697:Serine Endopeptidases / Q000276:immunology; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D016207:Cytokines; D052118:Lysosomal-Associated Membrane Protein 1; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C079340:NS1 protein, Dengue virus type 2; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C096041:NS5 protein, flavivirus