Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation.

Cytotoxic CD8(+) T cells play a critical role in controlling herpes simplex virus (HSV) infection and reactivation. However, little is known about the spatiotemporal dynamics of CD8(+) T cells during HSV lesion evolution or about their involvement in immune surveillance after lesion resolution. Using quantum dot-conjugated peptide-major histocompatibility complex multimers, we investigated the in vivo localization of HSV-2-specific CD8(+) T cells in sequential biopsies of human genital skin during acute, resolving, and healed stages of HSV-2 reactivation. Our studies revealed that functionally active CD8(+) T cells selectively infiltrated to the site of viral reactivation. After lesion healing in concert with complete reepithelialization and loss of HSV DNA from skin biopsies, HSV-2-specific CD8(+) T cells persisted for more than two months at the dermal-epidermal junction, adjacent to peripheral nerve endings. In two out of the six sequentially studied individuals, HSV-2 DNA reappeared in clinically and histologically normal-appearing skin. Detection of viral DNA was accompanied by increased numbers of both HSV-specific and total CD8(+) T cells in the dermis. These findings indicate that the frequency and clinical course of HSV-2 reactivation in humans is influenced by virus-specific CD8(+) T cells that persist in peripheral mucosa and genital skin after resolution of herpes lesions.

Type 3 reovirus neuroinvasion after intramuscular inoculation: direct invasion of nerve terminals and age-dependent pathogenesis.

Neonatal but not adult mice are vulnerable to reovirus invasion of the central nervous system after peripheral inoculation. After hindlimb injection, type 3 reovirus travels via the sciatic nerve to replicate in spinal cord motor neurons before spread to the brain and development of lethal encephalitis. Here we provide ultrastructural evidence for direct reovirus invasion of unmyelinated neonatal motor nerve terminals within 2 h and replication in spinal cord motor neurons within 14 h after hindlimb injection of 1-day-old mice. In adult mice, resistance to reovirus lethality after intracranial (IC) injection correlates with the restriction of virus growth in cortical neurons. We found that neuroinvasion also is age dependent after intramuscular injection. Virus lethality and CNS infection decreased sharply during the first postnatal week, while lethality after IC injection continued for 2 additional weeks. Mice inoculated at 7 days of age with high virus doses suffered paralysis of the injected limb, but significant brain infection was not lethal. These results suggest that reovirus invasion of the neonatal CNS is restricted by several progressive age-dependent mechanisms.