Department of Medicine, University of Washington, Seattle, Washington, USA.
J Virol. 2014 May;88(9):4921-31. doi: 10.1128/JVI.03285-13. Epub 2014 Feb 19.
Genital herpes simplex virus (HSV) reactivation is thought to be anatomically and temporally localized, coincident with limited ganglionic infection. Short, subclinical shedding episodes are the most common form of HSV-2 reactivation, with host clearance mechanisms leading to rapid containment. The anatomic distribution of shedding episodes has not been characterized. To precisely define patterns of anatomic reactivation, we divided the genital tract into a 22-region grid and obtained daily swabs for 20 days from each region in 28 immunocompetent, HSV-2-seropositive persons. HSV was detected via PCR, and sites of asymptomatic HSV shedding were subjected to a biopsy procedure within 24 h. CD4(+) and CD8(+) T cells were quantified by immunofluorescence, and HSV-specific CD4(+) T cells were identified by intracellular cytokine cytometry. HSV was detected in 868 (7%) of 11,603 genital swabs at a median of 12 sites per person (range, 0 to 22). Bilateral HSV detection occurred on 83 (67%) days with shedding, and the median quantity of virus detected/day was associated with the number of sites positive (P < 0.001). In biopsy specimens of asymptomatic shedding sites, we found increased numbers of CD8(+) T cells compared to control tissue (27 versus 13 cells/mm(2), P = 0.03) and identified HSV-specific CD4(+) T cells. HSV reactivations emanate from widely separated anatomic regions of the genital tract and are associated with a localized cellular infiltrate that was demonstrated to be HSV specific in 3 cases. These data provide evidence that asymptomatic HSV-2 shedding contributes to chronic inflammation throughout the genital tract.
This detailed report of the anatomic patterns of genital HSV-2 shedding demonstrates that HSV-2 reactivation can be detected at multiple bilateral sites in the genital tract, suggesting that HSV establishes latency throughout the sacral ganglia. In addition, genital biopsy specimens from sites of asymptomatic HSV shedding have increased numbers of CD8(+) T cells compared to control tissue, and HSV-specific CD4(+) T cells are found at sites of asymptomatic shedding. These findings suggest that widespread asymptomatic genital HSV-2 shedding is associated with a targeted host immune response and contributes to chronic inflammation throughout the genital tract.
生殖器单纯疱疹病毒 (HSV) 再激活被认为在解剖学和时间上是局部的，与有限的神经节感染一致。短暂的亚临床脱落期是 HSV-2 再激活的最常见形式，宿主清除机制导致快速遏制。脱落期的解剖分布尚未确定。为了准确确定解剖再激活的模式，我们将生殖道分为 22 个区域网格，并在 28 名免疫功能正常的 HSV-2 血清阳性者的每个区域每天采集 20 天的拭子。通过 PCR 检测 HSV，在无症状 HSV 脱落的部位在 24 小时内进行活检。通过免疫荧光定量 CD4(+)和 CD8(+)T 细胞，并通过细胞内细胞因子细胞术鉴定 HSV 特异性 CD4(+)T 细胞。在 11603 个生殖道拭子中，有 868 个（7%）检测到 HSV，中位数为每人 12 个部位（范围 0 至 22 个）。在有脱落的 83 天（67%）出现双侧 HSV 检测，每日检测到的病毒量中位数与阳性部位数量相关（P<0.001）。在无症状脱落部位的活检标本中，与对照组织相比，我们发现 CD8(+)T 细胞数量增加（27 个细胞/mm(2)与 13 个细胞/mm(2)，P=0.03），并鉴定出 HSV 特异性 CD4(+)T 细胞。HSV 再激活源于生殖道广泛分离的解剖区域，与局部细胞浸润有关，在 3 例中证明该细胞浸润是 HSV 特异性的。这些数据提供了证据表明，无症状的 HSV-2 脱落会导致整个生殖道的慢性炎症。
本报告详细描述了生殖器单纯疱疹病毒 2 型脱落的解剖模式，表明生殖器单纯疱疹病毒 2 型再激活可在生殖道的多个双侧部位检测到，这表明单纯疱疹病毒在骶神经节中建立了潜伏。此外，与对照组织相比，无症状 HSV 脱落部位的生殖器活检标本中 CD8(+)T 细胞数量增加，并且在无症状脱落部位发现 HSV 特异性 CD4(+)T 细胞。这些发现表明，广泛的无症状生殖器单纯疱疹病毒 2 型脱落与针对宿主的免疫反应有关，并导致整个生殖道的慢性炎症。
