Abstract
During evolution, herpesviruses have developed numerous, and often very ingenious, strategies to counteract efficient host immunity. Specifically, Kaposi's sarcoma-associated herpesvirus (KSHV) eludes host immunity by undergoing a dormant stage, called latency wherein it expresses a minimal number of viral proteins to evade host immune activation. Here, we show that during latency, KSHV hijacks the complement pathway to promote cell survival. We detected strong deposition of complement membrane attack complex C5b-9 and the complement component C3 activated product C3b on Kaposi's sarcoma spindle tumor cells, and on human endothelial cells latently infected by KSHV, TIME-KSHV and TIVE-LTC, but not on their respective uninfected control cells, TIME and TIVE. We further showed that complement activation in latently KSHV-infected cells was mediated by the alternative complement pathway through down-regulation of cell surface complement regulatory proteins CD55 and CD59. Interestingly, complement activation caused minimal cell death but promoted the survival of latently KSHV-infected cells grown in medium depleted of growth factors. We found that complement activation increased STAT3 tyrosine phosphorylation (Y705) of KSHV-infected cells, which was required for the enhanced cell survival. Furthermore, overexpression of either CD55 or CD59 in latently KSHV-infected cells was sufficient to inhibit complement activation, prevent STAT3 Y705 phosphorylation and abolish the enhanced survival of cells cultured in growth factor-depleted condition. Together, these results demonstrate a novel mechanism by which an oncogenic virus subverts and exploits the host innate immune system to promote viral persistent infection.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV), known as human herpesvirus 8 (HHV8), is a DNA tumor virus associated with the development of Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and a subset of multicentric Castleman’s disease [1,2,3]
KSHV encodes a number of viral proteins to counter host immune responses during productive lytic replication
We have found that the complement system is unexpectedly activated in latently KSHV-infected endothelial cells and in KS tumor cells wherein KSHV downregulates the expression of CD55 and CD59 complement regulatory proteins
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV), known as human herpesvirus 8 (HHV8), is a DNA tumor virus associated with the development of Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and a subset of multicentric Castleman’s disease [1,2,3]. The life cycle of KSHV consists of latency and lytic replication phases [6]. KSHV replicates in the episome form expressing only a limited number of viral latent proteins. KSHV latency is an effective strategy for evading host immune surveillance and maintaining persistent infection [6,7]. During lytic replication, KSHV replicates as a linear genome expressing cascades of viral proteins and producing infectious virions, which are exposed to host immune surveillance [6,7]. In KSHV-related tumors, KSHV sustains a persistent infection with most tumor cells in latency and a small number of them undergoing lytic replication [5]. KSHV latency is paramount to persistent infection in hosts with and without pathological manifestations
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