The Role of Tissue Resident Memory CD4 T Cells in Herpes Simplex Viral and HIV Infection

Tissue-resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8(+) TRM, there has recently been increased interest in defining the phenotype and the role of CD4(+) TRM in diseases. Circulating CD4(+) T cells seed CD4(+) TRM, but there also appears to be an equilibrium between CD4(+) TRM and blood CD4(+) T cells. CD4(+) TRM are more mobile than CD8(+) TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8(+) TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4(+) and CD8(+) TRM persisting between lesions may control asymptomatic shedding through interferon-gamma secretion, although this has been more clearly shown for CD8(+) T cells. The exact role of the CD4(+)/CD8(+) TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4(+) TRM have now been shown to be a major target for productive and latent infection in the cervix. In HSV and HIV co-infections, CD4(+) TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4(+) TRM and their induction by vaccines may help control sexual transmission by both viruses.