IMMUNOBIOLOGY Differences in the frequency and function of HHV8-specific CD8 T cells between asymptomatic HHV8 infection and Kaposi sarcoma

It is unclear how the immune response controls human herpesvirus 8 (HHV8; also known as Kaposi sarcoma–associated herpesvirus [KSHV]) replication and thereby prevents Kaposi sarcoma (KS). We compared CD8 T-cell responses to HHV8 latent (K12) and lytic (glycopro-tein B, ORF6, ORF61, and ORF65) anti-gens in patients who spontaneously con-trolled the infection and in patients with posttransplantation, AIDS-related, or clas-sical KS. We found that anti-HHV8 re-sponses were frequent, diverse, and strongly differentiated toward an effector phenotype in patients who controlled the infection. Conversely, HHV8-specific CD8 cells were very rare in patients who pro-gressed to KS, and were not recruited to the tumoral tissue, as visualized by in situ tetramer staining of KS biopsies. Last, HHV8-specific CD8 T cells were observed in a seronegative recipient of an HHV8-infected graft who remained persistently aviremic and antibody negative, suggest-ing that specific cytotoxic T lymphocytes (CTLs) may provide protection from per-sistent HHV8 infection. These results sup-port the crucial role of cellular immune responses in controlling HHV8 replica-tion, in preventing malignancies in la-tently infected subjects, and in conferring genuine resistance to persistent infec-tion. They may also have important impli-cations for the design of prophylactic and therapeutic HHV8 vaccines, and for adop