Long term persistence of herpes simplex virus-specific CD8(+) CTL in persons with frequently recurring genital herpes

Herpes simplex virus (HSV) establishes a lifelong infection in humans. Reac tivation of latent virus occurs intermittently so that the immune system is frequently exposed to viral Ag, providing an opportunity to evaluate memor y T cells to a persistent human pathogen, We studied the persistence of gen ital herpes lesion-derived HSV-specific CD8(+) CTL from three Immunocompete nt individuals with frequently recurring genital HSV-2 infection. All CTL c lones were HSV-2 type specific and only one to three unique clonotypes were identified from any single biopsy specimen, The TCRBV genes utilized by th ese clonotypes were sequenced, and clonotype-specific probes were used to l ongitudinally track these clonotypes in PBMC and genital lesions. CTL clono types were consistently detected in PBMC and lesions for at least 2 and up to 7 years, and identical clonotypes infiltrated herpes lesions spaced as l ong as 7.5 years apart. Moreover, these clones were functionally lytic in v ivo over these time periods. Additionally, CTL clones killed target cells i nfected with autologous viral isolates obtained 6.5 years after CTL clones were established? suggesting that selective pressure by these CTL did not r esult in the mutation of CTL epitopes, Thus, HSV recurs in the face of pers istent CD8(+) CTL with no evidence of clonal exhaustion or mutation of CTL epitopes as mechanisms of viral persistence.