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CD8+ cytolytic T cells can suppress HIV replication by a variety of lytic and nonlytic mechanisms, and the relative clinical importance of particular CTL functions is not fully understood. Therefore studies have utilized various in vitro viral suppression assays as an indication of the antiviral efficacy. We measured antiviral activities of CD8+ lymphocytes from elite controllers who spontaneously suppress HIV without medication, from chronically infected HIV+ donors, and from HIVneg donors. Bulk CD8+ lymphocytes containing a CD56+ fraction suppressed HIV replication in autologous macrophages, even for HIVneg donors. CD56-depleted CD8 T cells from HIV+ donors also suppressed HIV replication in macrophage targets, with elite controller T cells exerting significantly greater suppression than progressor T cells. CD56-depleted CD8 T cells from HIVneg donors did not suppress but rather enhanced HIV-replication specifically in macrophages. Finally, when CD8 T cells and HIV-infected macrophages from elite controllers were separated by a transwell membrane, CD8 T cells did not suppress but rather enhanced HIV replication, indicating that HIV suppression was cell-contact dependent while soluble factors may be responsible for enhanced HIV replication. In summary CD8+CD56+ cells have innate antiviral activity in both elite controllers and uninfected donors, while CD8+ T cells have specific antiviral activity in HIV+ donors. In some cases inflammatory CTL may enhance viral replication.