Second, while several studies have shown that HSV-2 coinfection is associated with an increase and persistence of activated CD4+ T cells at sites of HSV-2 reactivation (local) as well as in the peripheral blood (5–7, 12), the mechanism by which the cells are activated in vivo may differ from in vitro activation with anti-CD3/CD28 and thus impact the transcriptional response. Here, CD28 is linked to coinfection.