The epidemical studies shown that interaction between the STIs was complex. The relationship of HSV-2 and KSHV remains quite controversial. Studies from three groups demonstrated that HSV-2 and KSHV were associated in the prisoners of Italian and some areas in Africa, which suggest that HSV-2 infection contributed to sexual transmission of KSHV infection 
. However, Malope et al have shown that in a heterosexual South African population there was no evidence of sexual transmission of KSHV 
The present work demonstrated that HSV-2 infection of BCBL-1 cells induced KSHV replication and provided the direct laboratory evidence that HSV-2 was a potential cofactor for KSHV reactivation. KSHV was necessary but not sufficient in KS development and the cofactors played an important role in the pathogenesis of KS 
. For instance, HIV-1 infection of PEL cell lines induced the reactivation of KSHV through directly activating the promoter of KSHV Rta 
. HSV-1 could activate KSHV replication partially by elevating the level of IL-10 and IL-4 
. Here we have further demonstrated that HSV-2 was also a critical factor responsible for the induction of KSHV replication, suggesting that HSV-2 might promote KS progression by increasing viral load. However, whether some soluble factors produced in response to HSV-2 infection might also be involved in this procedure is still unknown.
The role of NF-κB pathway during the reactivation of KSHV is still a highly controversial and arguable subject. We and other five groups consistently demonstrated that NF-κB signaling displayed an inhibitory effect on KSHV reactivation 
. However, one group showed that activation of NF-κB was required for KSHV replication and the production of replication-competent KSHV virions 
. Actually, Grossmann and colleagues indicated that the relationship between NF-κB and spontaneous KSHV reactivation was complex, non-uniform and dependent on the cellular context. Even though NF-κB activation is inhibitory to lytic gene expression in some contexts, such inhibition is at least partially bypassed or overridden during lytic growth. In this study, we indicated that HSV-2 infection of BCBL-1 cells led to dramatic activation of the NF-κB signaling, which was consistent with previous reports 
. Furthermore, inhibition of NF-κB significantly promoted KSHV lytic replication; elevating NF-κB signaling remarkably repressed KSHV replication, which was in agreement with the reports of six groups above mentioned. These observations also implied that other signal pathways might exist together with activated NF-κB in HSV-2-infected BCBL-1 cells during KSHV reactivation. When HSV-2 infected BCBL-1 cells, it must lead to alternation of multiple signal pathways. Some activated signals facilitated KSHV replication; inversely, others exerted an inhibitory effect, such as NF-κB. If signals whose activation can promote KSHV replication are always predominated, they may compensate the inhibitory effect of NF-κB. Therefore, our results never eliminate the possibility that some other signals produced in response to HSV-2 infection might also be involved in this procedure.
The Tat protein of HIV-1 functioned as a transacting transcriptional activator and was of great interest in the studies of KS. Our previous studies demonstrated that Tat not only induced KSHV replication, but also accelerated the tumorigenesis by KSHV Kaposin A in vitro
and in vivo
. In the current study, we showed that Tat could enhance the HSV-2-induced lytic replication of KSHV. Interestingly, Tat also accelerated HSV-2 replication in BCBL-1 cells. Given the fact that HSV-1 and its immediate-early genes ICP0 and ICP4 greatly stimulated the expression of HIV-1 LTR-directed viral gene expression collaborated with Tat 
, and Tat increased the transcriptional activity of HSV-1 ICP0 
. We speculated that, with high homology to ICP0 and ICP4 of HSV-1 
, the cooperation of Tat and ICP0 and ICP4 of HSV-2 stimulated the transcript and replication of HSV-2, which indirectly induced KSHV replication. However, the mechanism still needs to be elucidated.
In summary, we showed that HSV-2 was a potentially important factor in the pathogenesis of KS and NF-κB signal exerted an inhibitory effect in HSV-2-induced KSHV replication. We also revealed that Tat could enhance HSV-2-induced KSHV replication. Because HSV-2 infection of cells stimulated multiple downstream effects 
and intracellular Tat activated the KSHV replication partially through JAK/STAT pathways 
, further studies are needed to better understand the signaling involved in Tat increasing HSV-2-induced KSHV reactivation from latency.