Immunity，doi:10.1016/j.immuni.2008.10.010，Stephen A. Migueles，Mark Connors
Lytic Granule Loading of CD8+ T Cells Is Required for HIV-Infected Cell Elimination Associated with Immune Control
Stephen A. Migueles1,Christine M. Osborne1,Cassandra Royce1,Alex A. Compton1,Rohan P. Joshi1,Kristin A. Weeks1,Julia E. Rood1,Amy M. Berkley1,Jonah B. Sacha2,Nancy A. Cogliano-Shutta1,Margaret Lloyd1,Gregg Roby1,Richard Kwan1,Mary McLaughlin1,Sara Stallings1,Catherine Rehm1,Marie A. O'Shea1,JoAnn Mican1,Beverly Z. Packard3,Akira Komoriya3,Sarah Palmer4,Ann P. Wiegand4,Frank Maldarelli4,John M. Coffin4,John W. Mellors5,Claire W. Hallahan1,Dean A. Follman1andMark Connors1,,
1 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
2 Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53719, USA
3 OncoImmunin, Gaithersburg, MD 20877, USA
4 HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702, USA
5 Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
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.