title: Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control.
abstract: Virus-specific CD8+ T cells probably mediate control over HIV replication in rare individuals, termed long-term nonprogressors (LTNPs) or elite controllers. Despite extensive investigation, the mechanisms responsible for this control remain incompletely understood. We observed that HIV-specific CD8+ T cells of LTNPs persisted at higher frequencies than those of treated progressors with equally low amounts of HIV. Measured on a per-cell basis, HIV-specific CD8+ T cells of LTNPs efficiently eliminated primary autologous HIV-infected CD4+ T cells. This function required lytic granule loading of effectors and delivery of granzyme B to target cells. Defective cytotoxicity of progressor effectors could be restored after treatment with phorbol ester and calcium ionophore. These results establish an effector function and mechanism that clearly segregate with immunologic control of HIV. They also demonstrate that lytic granule contents of memory cells are a critical determinant of cytotoxicity that must be induced for maximal per-cell killing capacity.
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Migueles
authors.forename: Christine M
authors.initials: CM
authors.lastname: Osborne
authors.forename: Cassandra
authors.initials: C
authors.lastname: Royce
authors.forename: Alex A
authors.initials: AA
authors.lastname: Compton
authors.forename: Rohan P
authors.initials: RP
authors.lastname: Joshi
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Weeks
authors.forename: Julia E
authors.initials: JE
authors.lastname: Rood
authors.forename: Amy M
authors.initials: AM
authors.lastname: Berkley
authors.forename: Jonah B
authors.initials: JB
authors.lastname: Sacha
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Cogliano-Shutta
authors.forename: Margaret
authors.initials: M
authors.lastname: Lloyd
authors.forename: Gregg
authors.initials: G
authors.lastname: Roby
authors.forename: Richard
authors.initials: R
authors.lastname: Kwan
authors.forename: Mary
authors.initials: M
authors.lastname: McLaughlin
authors.forename: Sara
authors.initials: S
authors.lastname: Stallings
authors.forename: Catherine
authors.initials: C
authors.lastname: Rehm
authors.forename: Marie A
authors.initials: MA
authors.lastname: O'Shea
authors.forename: JoAnn
authors.initials: J
authors.lastname: Mican
authors.forename: Beverly Z
authors.initials: BZ
authors.lastname: Packard
authors.forename: Akira
authors.initials: A
authors.lastname: Komoriya
authors.forename: Sarah
authors.initials: S
authors.lastname: Palmer
authors.forename: Ann P
authors.initials: AP
authors.lastname: Wiegand
authors.forename: Frank
authors.initials: F
authors.lastname: Maldarelli
authors.forename: John M
authors.initials: JM
authors.lastname: Coffin
authors.forename: John W
authors.initials: JW
authors.lastname: Mellors
authors.forename: Claire W
authors.initials: CW
authors.lastname: Hallahan
authors.forename: Dean A
authors.initials: DA
authors.lastname: Follman
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D015550:Cell Degranulation / Q000276:immunology; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D054353:Perforin / Q000276:immunology / Q000378:metabolism; D012367:RNA, Viral / Q000276:immunology
chemical_list: D012367:RNA, Viral; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes