IL-15 treatment during acute simian immunodeficiency virus (SIV) infection increases viral set point and accelerates disease progression despite the induction of stronger SIV-specific CD8+ T cell responses.
In this study, we examined the effect of in vivo treatment of acutely SIV-infected Mamu-A*01+ rhesus macaques with IL-15. IL-15 treatment during acute infection increased viral set point by 3 logs and accelerated the development of simian AIDS in two of six animals with one developing early minimal lesion SIV meningoencephalitis. Although IL-15 induced a 2- to 3-fold increase in SIV-specific CD8+ T cell and NK cell numbers at peak viremia and reduced lymph node (LN) SIV-infected cells, this had no impact on peak viremia and did not lower viral set point. At viral set point, however, activated SIV-specific CD8+ T cells and NK cells were reduced in the blood of IL-15-treated animals and LN SIV-infected cells were increased. Week 30 LN from IL-15-treated animals had significantly increased Gag-specific CD8+ T cell numbers, whereas total cell, lymphocyte, and CD4+ T cell numbers were reduced. IL-15 treatment significantly reduced anti-SIV Ab concentrations at week 3 and viral set point. IL-15 increased Ki-67+CD4+ T cells at week 1 of treatment and reduced blood CCR5+ and CD45RA-CD62L- CD4+ T cells. The frequency of day 7 Ki-67+CD4+ T cells strongly correlated with viral set point. These findings suggest that CD4+ T cell activation during acute infection determines subsequent viral set point and IL-15 treatment by increasing such activation elevates viral set point. Finally, IL-15-treated acutely SIV-infected primates may serve as a useful model to investigate the poorly understood mechanisms that control viral set point and disease progression in HIV infection.
Mueller
Yvonne M
YM
Department of Microbiology and Immunology, and Center for Immunology and Vaccine Science, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Do
Duc H
DH
Altork
Susan R
SR
Artlett
Carol M
CM
Gracely
Edward J
EJ
Katsetos
Christos D
CD
Legido
Agustin
A
Villinger
Francois
F
Altman
John D
JD
Brown
Charles R
CR
Lewis
Mark G
MG
Katsikis
Peter D
PD
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D015683:Gene Products, gag / Q000032:analysis; D019409:Interleukin-15 / Q000494:pharmacology*; D019394:Ki-67 Antigen / Q000032:analysis; D007694:Killer Cells, Natural / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000032:analysis; D008198:Lymph Nodes / Q000276:immunology / Q000821:virology; D008213:Lymphocyte Activation / Q000187:drug effects; D008253:Macaca mulatta; D008590:Meningoencephalitis / Q000276:immunology / Q000473:pathology / Q000821:virology; D019713:Receptors, CCR5 / Q000032:analysis; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000502:physiology; D019562:Viral Load; D014766:Viremia / Q000276:immunology / Q000821:virology; D014779:Virus Replication
D000914:Antibodies, Viral; D017252:CD3 Complex; D015704:CD4 Antigens; D015683:Gene Products, gag; D019409:Interleukin-15; D019394:Ki-67 Antigen; D019713:Receptors, CCR5; D017493:Leukocyte Common Antigens