INHIBITION OF SIMIAN IMMUNODEFICIENCY VIRUS (SIV) REPLICATION BY CD8(-LYMPHOCYTES FROM MACAQUES IMMUNIZED WITH LIVE ATTENUATED SIV() T)

Characterization of immune responses induced by live attenuated simian immunodeficiency virus (SIV) strains may yield clues to the nature of protective immunity induced by this vaccine approach. We investigated the ability of CD8+ T lymphocytes from rhesus macaques immunized with the live, attenuated SIV strain SIVmac239 Delta nef or SIVmac239 Delt a 3 to inhibit SIV replication. CD8+ T lymphocytes from immunized anim als were able to potently suppress SN replication in autologous SIV-in fected CD4+ T cells. Suppression of SIV replication by unstimulated CD 8+ T cells required direct contact and was major histocompatibility co mplex (MRC) restricted. However, CD3-stimulated CD8+ T cells produced soluble factors that inhibited SIV replication in an MHC-unrestricted fashion as much as 30-fold. Supernatants from stimulated CD8+ T cells were also able to inhibit replication of both CCR5- and CXCR4-dependen t human immunodeficiency virus type I (HIV-1) strains. Stimulation of CD8+ cells with cognate cytotoxic T-lymphocyte epitopes also induced s ecretion of soluble factors able to inhibit SIV replication. Productio n of RANTES, macrophage inhibitory protein 1 alpha (MTP-la), or MIP-IP from stimulated CD8+ T cells of vaccinated animals was almost 10-fold higher than that from stimulated CD8+ T cells of control animals. How ever, addition of antibodies that neutralize these beta-chemokines, ei ther alone or in combination, only partly blocked inhibition of SIV an d HIV replication by soluble factors produced by stimulated CD8+ T cel ls. Our results indicate that inhibition of SIV replication by CD8+ T cells from animals immunized with live attenuated SIV strains involves both MHC-restricted and -unrestricted mechanisms and that MHC-unrestr icted inhibition of SIV replication is due principally to soluble fact ors other than RANTES, MIP-1 alpha, and MIP-1 beta.