Toll-like Receptor 4 Mediates Innate Immunity to Kaposi Sarcoma Herpesvirus

Abstract

The involvement of Toll-like receptor 4 (TLR4) in immunity against human herpesviruses has not been previously demonstrated. We show that infection of endothelial cells with Kaposi sarcoma herpesvirus (KSHV), a human oncogenic virus, leads to rapid suppression of TLR4 expression. This is a mechanism of immune escape as TLR4 mediates innate immunity against KSHV. In vitro, cells lacking TLR4 are more susceptible to KSHV infection, whereas activation of TLR4 protects cells from infection. In vivo, HIV-1-infected individuals carrying a mutant TLR4 allele appear more likely to have multicentric Castleman's disease, a lymphoproliferation associated with enhanced KSHV replication. ERK activation by KSHV structural proteins and the KSHV-encoded vGPCR plays a key role in the TLR4 downregulation, whereas the KSHV vIRF1 also contributes to this effect. Our findings reveal a role for TLR4 in innate immunity against herpesviruses and suggest the potential use of TLR4 agonists for the treatment of KSHV-related neoplasms.

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

“…Activation of either TLR results in interferon production and upregulation of cytokines and chemokines. KSHV also activates TLR4 signaling that likely occurs through recognition of the viral glycoproteins gB and K8.1 (37). Stimulation of TLR7/8 in PEL cells has been shown to lead to reactivation from latency (38).…”

“…KSHV vIRFs have been shown to inhibit IFN production that lies downstream of TLR3 activation (49), MAVS activation (50), and cGAS-STING activation (45). KSHV vIRF1 also inhibits the function of IFN-induced genes such as ISG15 (51) and the transcription of TLR4 (37).…”

Kaposi Sarcoma-associated Herpesvirus Degrades Cellular Toll-Interleukin-1 Receptor Domain-containing Adaptor-inducing β-Interferon (TRIF)

“…TLR-4 has been identified as an important molecule against KSHV infection, and KSHV has developed a mechanism to rapid suppression of TLR-4 expression (37). Also, murine ␥-herpesvirus 68 (MHV68) is another herpesvirus with significant similarities to KSHV.…”

HSHV-HIV, not just molecular interaction, but also interfere with the fate-Re “Claudin-2 downregulation by KSHV infection is involved in the regulation of endothelial barrier function”

“…Further, the study of the effect of KSHV-HIV co-infection on the fate of infected cells, or of patients, in the meantime, provided a novel model to study KSHV-HIV interaction, or DNA-RNA interaction. KSHV decreases the expression of toll-like receptor 4 (TLR4) [23], however, HIV infection stimulates its expression [24]. Infection of KSHV can interfere with the expression of TLR4 induced by HIV infection, further sensing the presence of LPS [25].…”