Saturday, May 17, 2025
5/17/2025
KSHV Infection And Persistence - Kaposi's sarcoma (KS) herpesvirus (KSHV) is the etiologic agent of KS and primary effusion lymphoma (PEL), and is tightly linked with multicentric Castleman's disease (MCD). These tumors are most common in immune suppressed individuals, especially those with AIDS. There are no specific therapies for KSHV malignancies. KS is a leading AIDS malignancy, and is epidemic in sub-Saharan Africa. KS often involves the oral cavity and can disseminate to visceral organs. Saliva is the KSHV vehicle of transmission. For unknown reasons, and in contrast to other herpesviruses, which are ubiquitous, KSHV epidemiology mirrors that of P. falciparum malaria and certain helminth infections. Accordingly, seroprevalence is high in sub-Saharan Africa (~80%) and much lower in western nations (~5%) that lack similar endemic infections. KSHV seroprevalence is also elevated (30-60%) in men who have sex with men. Latency is the hallmark of KSHV and gammaherpesvirus infection during which only several of its ~100 genes are expressed. KSHV latently infects cells, including tumor cells, and viral genomes persist as extrachromosomal, circularized, multi-copy, episomes. KSHV establishes lifelong infection, and persists in latently infected B cells. Paradoxically, however, in vitro infection of B cells is inefficient, and cells are short lived, suggesting absence of necessary factor(s). MCD infected cells exhibit B cell plasmablast characteristics, and PEL cells those of plasma cells, suggesting these diseases derive from aberrant development at different stages of B cell infection. B cells may differentiate to plasmablasts and long-lived plasma cells by proceeding through a germinal center reaction, in which they undergo somatic hypermutation, thus producing high affinity antibody. Alternatively, B cells may progress through an extra-follicular pathway to generate plasma cells. In this case, somatic hypermutation is typically absent, with low affinity antibody produced. MCD and KSHV (alone, without coinfecting EBV) PEL cells lack somatic hypermutation suggesting development from an extra-follicular pathway. We recently found KSHV infects mononuclear phagocytes (monocytes, macrophages) with high efficiency, and that these cells drive latently infected B cell differentiation to plasmablasts and then long lived plasma cells, thereby promoting long term KSHV B cell latency. Monocytes are elevated in malaria and in the helminth infections KSHV is associated with, suggesting increased phagocyte abundance in those parasitic diseases may underlie KSHV’s geographic disparity. These findings therefore demonstrate a key role for mononuclear phagocytes in B cell latency, providing a new paradigm for KSHV B cell latency establishment. Here, we use rigorous, detailed, in depth approaches to investigate the interactions occurring between KSHV, mononuclear phagocytes, and B cells that lead to long term KSHV B cell latency.
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