Mucosal host immune response predicts the severity and duration of herpes simplex virus-2 genital tract shedding episodes

Abstract

Herpes simplex virus-2 (HSV-2) shedding episodes in humans vary markedly in duration and virologic titer within an infected person over time, an observation that is unexplained. To evaluate whether host or virological factors more closely accounted for this variability, we combined measures of viral replication and CD8(+) lymphocyte density in genital biopsies, with a stochastic mathematical model of HSV-2 infection. Model simulations reproduced quantities of virus and duration of shedding detected in 1,003 episodes among 386 persons. In the simulations, local CD8(+) lymphocyte density in the mucosa at episode onset predicted peak HSV DNA copy number and whether genital lesions or subclinical shedding occurred. High density of CD8(+) T cells in the mucosa correlated with decreased infected cell lifespan and fewer infected epithelial cells before episode clearance. If infected cell lifespan increased by 15 min because of CD8(+) lymphocyte decay, then there was potential for a thousandfold increase in the number of infected cells. The model suggests that the rate of containment of infected cells by the peripheral mucosal immune system is the major driver of duration and severity of HSV-2 reactivation in the immunocompetent host.

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

“…Both CD4 and CD8 T lymphocytes are key effectors in human cutaneous herpetic lesions and persist as sentinels between lesions: CD8 T lymphocytes at the dermo-epidermal junction and CD4 T lymphocytes deeper in the dermis (3,49). They show different kinetics of recruitment into clinical recurrent lesions and apparently different, but overlapping, functions.…”

“…However, they also can secrete IFN-g. Recently, the load of HSV2 shed in vaginal secretions was shown to be inversely proportional to the density of lesional CD8 T lymphocytes, although this could just represent the density of all key immune effectors (3).…”

“…In human recurrent lesions, monocytes and CD4 T lymphocytes infiltrate first, followed by CD8 T lymphocytes, which appear to clear HSV infection (1)(2)(3). HSV infection of keratinocytes in vitro and in vivo induces the secretion of a sequence of chemokines and cytokines (first IFN-b and b chemokines and then IL-12, followed by IL-1b and IL-6) (4).…”

Management of multidrug‐resistant viruses in the immunocompromised host

“…Herpetic ulcers are accompanied by dense CD8 + T cell infiltration as well as by large numbers of CD4 + lymphocytes and dendritic cells, and host immune responses are critical determinants in the clearance of these lesions (Schiffer et al, 2010). HSV infections in patients with haematological malignancies are predominantly 'reactivations' (i.e.…”

Evidence for clinical activity of artesunate in multidrug-resistant herpes simplex infection following HSCT

“…Host immune responses are critical determinants in the clearance of herpetic lesions. 1 The corollary of this is that immunocompromised hosts, who lack such a response, may develop either high frequency of viral shedding or persistent, poorly healing genital lesions.…”