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.

To determine the safety, immunogenicity, and efficacy of a recombinant herpes simplex virus type 2 glycoprotein D and B vaccine in the treatment of recurrent genital herpes, a randomized, placebo-controlled trial was held at two referral centers. Healthy patients with 4-14 recurrences per year received injections of both glycoproteins in MF59 adjuvant or of MF59 alone at 0, 2, 12, and 14 months. For 18 study months, the rate and number of recurrences, the duration and severity of the first confirmed recurrence, vaccine immunogenicity, and rates of local and systemic reactions were determined. The monthly rate of recurrences was not significantly improved, but the duration and severity of the first study outbreak was reduced significantly by vaccination. Glycoprotein-specific and neutralizing antibodies were boosted by vaccination for the duration of the study. This vaccine is safe and immunogenic and ameliorated an observed first postvaccination genital recurrence, but it does not reduce recurrence frequency.

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CD8-only vaccines can be protective on some mouse models. HSV-1-specific CD8s localize to sites of lesion and healed skin, and to chronically infected ganglion. We enriched polyclonal HSV-1-specific CD8s from human blood using a novel cross-presentation/activation marker-based protocol. After expansion, these cell populations were quite oligoclonal as assessed by TCR beta chain CDR3 deep sequencing. To query fine specificity, artificial APC were created by transfecting Cos-7 cells with each HLA A or B heavy chain from the subject. Each HSV-1 ORF was cloned into an expression vector and separately co-transfected with each HLA allele. Activation of CD8+ cells in the polyclonal T-cell population to specific ORFs was detected by interferon-gamma ELISA. The complexity of the response ranged from 7 to 23 reactive ORF/HLA combinations per subject. Most such epitopes are HSV-1 type-specific, but some are identical within the related pathogen HSV-2. One type-common epitope was studied in HLA A*0201-transgenic mice, in which DNA vaccination with the HSV-1 full-length ORF lead to very strong epitope-specific responses. Overall, we observed a remarkably similar complexity for the CD8 response to HSV-1 by using either the deep TCR sequencing or antigenic specificity method. Novel candidate immunodominant HSV-1 CD8 antigens were identified, and no apparent skewing to virion input or immediate early proteins due to TAP inhibition was detected.