T-cell receptor-mediated anergy of a human immunodeficiency virus (HIV) gp120-specific CD4(+) cytotoxic T-cell clone, induced by a natural HIV type-1variant peptide

Human immunodeficiency virus type 1 (HIV-1) infection triggers a cytotoxic T-lymphocyte (CTL) response mediated by CD8(+) and perhaps CD4(+) CTLs. The mechanisms by which HIV-1 escapes from this CTL response are only beginnin g to be understood. However, it is already clear that the extreme genetic v ariability of the virus is a major contributing factor. Because of the well -known ability of altered peptide ligands (APL) to induce a T-cell receptor (TCR)-mediated anergic state in CD4(+) helper T cells, we investigated the effects of HIV-1 sequence variations on the proliferation and cytotoxic ac tivation:of a human CD4(+) CTL clone (Een217) specific for an epitope compo sed of amino acids 410 to 429 of HIV-1 gp120, We report that a natural vari ant of this epitope induced a functional anergic state rendering; the T cel ls unable to respond to their antigenic ligand and preventing the prolifera tion and cytotoxic activation normally induced by the original antigenic pe ptide. Furthermore, the stimulation of Een217 cells with this APL generated altered TCR-proximal signaling events that have been associated with the i nduction of T-cell anergy in CD4(+) T cells. Importantly, the APL-induced a nergic state of the Een217 T cells could be prevented by the addition of in terleukin 2, which restored their ability to respond to their nominal antig en. Our-data therefore suggest that HIV-1 variants can induce a state of an ergy in HIV-specific CD4(+) CTLs, Such a mechanism may allow a viral varian t to not only escape the CTL response but also facilitate the persistence o f other viral strains that may otherwise be recognized and eliminated by HI V-specific CTLs.