title: R5-SHIV induces multiple defects in T cell function during early infection of rhesus macaques including accumulation of T reg cells in lymph nodes.
abstract: BACKGROUND
  HIV-1 is a pathogen that T cell responses fail to control. HIV-1gp120 is the surface viral envelope glycoprotein that interacts with CD4 T cells and mediates entry. HIV-1gp120 has been implicated in immune dysregulatory functions that may limit anti-HIV antigen-specific T cell responses. We hypothesized that in the context of early SHIV infection, immune dysregulation of antigen-specific T-effector cell and regulatory functions would be detectable and that these would be associated or correlated with measurable concentrations of HIV-1gp120 in lymphoid tissues.
  
  
  METHODS
  Rhesus macaques were intravaginally inoculated with a Clade C CCR5-tropic simian-human immunodeficiency virus, SHIV-1157ipd3N4. HIV-1gp120 levels, antigen-specificity, levels of apoptosis/anergy and frequency and function of Tregs were examined in lymph node and blood derived T cells at 5 and 12 weeks post inoculation.
  
  
  CONCLUSIONS
  We observed reduced responses to Gag in CD4 and gp120 in CD8 lymph node-derived T cells compared to the peripheral blood at 5 weeks post-inoculation. Reduced antigen-specific responses were associated with higher levels of PD-1 on lymph node-derived CD4 T cells as compared to peripheral blood and uninfected lymph node-derived CD4 T cells. Lymph nodes contained increased numbers of Tregs as compared to peripheral blood, which positively correlated with gp120 levels; T regulatory cell depletion restored CD8 T cell responses to Gag but not to gp120. HIV gp120 was also able to induce T regulatory cell chemotaxis in a dose-dependent, CCR5-mediated manner. These studies contribute to our broader understanding of the ways in which HIV-1 dysregulates T cell function and localization during early infection.
authors.affiliation: Infectious Diseases Medicine Division, Vaccine and Immunotherapy Center, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Santosuosso
authors.forename: Elda
authors.initials: E
authors.lastname: Righi
authors.forename: E David
authors.initials: ED
authors.lastname: Hill
authors.forename: Pierre R
authors.initials: PR
authors.lastname: Leblanc
authors.forename: Brett
authors.initials: B
authors.lastname: Kodish
authors.forename: Hari N
authors.initials: HN
authors.lastname: Mylvaganam
authors.forename: Nagadenahalli B
authors.initials: NB
authors.lastname: Siddappa
authors.forename: Liljana
authors.initials: L
authors.lastname: Stevceva
authors.forename: Shiu-Lok
authors.initials: SL
authors.lastname: Hu
authors.forename: Musie
authors.initials: M
authors.lastname: Ghebremichael
authors.forename: Agnes-L
authors.initials: AL
authors.lastname: Chenine
authors.forename: Avi-Hai
authors.initials: AH
authors.lastname: Hovav
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Ruprecht
authors.forename: Mark C
authors.initials: MC
authors.lastname: Poznansky
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D002633:Chemotaxis / Q000276:immunology; D015683:Gene Products, gag / Q000276:immunology / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008198:Lymph Nodes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D008253:Macaca mulatta; D009092:Mucous Membrane / Q000821:virology; D019713:Receptors, CCR5 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D015683:Gene Products, gag; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D043562:Receptors, G-Protein-Coupled; C514793:gp120 protein, Human immunodeficiency virus 1