title: Cytotoxic capacity of SIV-specific CD8(+) T cells against primary autologous targets correlates with immune control in SIV-infected rhesus macaques.
abstract: Although the study of non-human primates has resulted in important advances for understanding HIV-specific immunity, a clear correlate of immune control over simian immunodeficiency virus (SIV) replication has not been found to date. In this study, CD8(+) T-cell cytotoxic capacity was examined to determine whether this function is a correlate of immune control in the rhesus macaque (RM) SIV infection model as has been suggested in chronic HIV infection. SIVmac251-infected human reverse transcriptase (hTERT)-transduced CD4(+) T-cell clone targets were co-incubated with autologous macaque effector cells to measure infected CD4(+) T-cell elimination (ICE). Twenty-three SIV-infected rhesus macaques with widely varying plasma viral RNA levels were evaluated in a blinded fashion. Nineteen of 23 subjects (83%) were correctly classified as long-term nonprogressor/elite controller (LTNP/EC), slow progressor, progressor or SIV-negative rhesus macaques based on measurements of ICE (weighted Kappa 0.75). LTNP/EC had higher median ICE than progressors (67.3% [22.0-91.7%] vs. 23.7% [0.0-58.0%], p = 0.002). In addition, significant correlations between ICE and viral load (r = -0.57, p = 0.01), and between granzyme B delivery and ICE (r = 0.89, p<0.001) were observed. Furthermore, the CD8(+) T cells of LTNP/EC exhibited higher per-cell cytotoxic capacity than those of progressors (p = 0.004). These findings support that greater lytic granule loading of virus-specific CD8(+) T cells and efficient delivery of active granzyme B to SIV-infected targets are associated with superior control of SIV infection in rhesus macaques, consistent with observations of HIV infection in humans. Therefore, such measurements appear to represent a correlate of control of viral replication in chronic SIV infection and their role as predictors of immunologic control in the vaccine setting should be evaluated.
authors.affiliation: HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mendoza
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Migueles
authors.forename: Julia E
authors.initials: JE
authors.lastname: Rood
authors.forename: Bennett
authors.initials: B
authors.lastname: Peterson
authors.forename: Sarah
authors.initials: S
authors.lastname: Johnson
authors.forename: Nicole
authors.initials: N
authors.lastname: Doria-Rose
authors.forename: Douglas
authors.initials: D
authors.lastname: Schneider
authors.forename: Eva
authors.initials: E
authors.lastname: Rakasz
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Trivett
authors.forename: Charles M
authors.initials: CM
authors.lastname: Trubey
authors.forename: Vicky
authors.initials: V
authors.lastname: Coalter
authors.forename: Claire W
authors.initials: CW
authors.lastname: Hallahan
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.forename: Genoveffa
authors.initials: G
authors.lastname: Franchini
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology* / Q000821:virology; D018450:Disease Progression; D054884:Host-Pathogen Interactions; D007109:Immunity; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000473:pathology* / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology* / Q000821:virology; D014779:Virus Replication