Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8 (HHV8), is a double-stranded DNA virus that causes Kaposi's sarcoma, primary effusion lymphomas, and multicentric Castleman's disease (1-3). Like other herpesviruses, KSHV exhibits both latent and lytic modes of infection, persisting predominantly in the latent state in which only a subset of the viral proteins are expressed, including the latency-associated nuclear antigen (LANA) protein (4-8). Although the expression of latent proteins plays a critical role in inducing and maintaining KSHV latency, the infected cells are primed early during the primary infection to retain the viral genomes and induce tumors (9). During the primary infection, KSHV undergoes a short lytic replication cycle that transcribes an array of viral genes, which have been shown to modulate various pathways for establishing the latent infection (9). In addition, a small fraction (1 to 5%) of the infected cells spontaneously undergo lytic reactivation to produce infectious virions, which is likely to be essential for increasing the population of infected cells and inducing viral pathogenesis (10-13).The infection of target cells with KSHV is a complex multistep process involving a variety of host cell surface receptors and multiple viral glycoproteins. Irrespective of its mechanism of entry, for a successful infection, KSHV must overcome the obstacles it encounters during the transportation of viral capsids from the plasma membrane into the nucleus. The main obstacles include

Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpes virus 8 (HHV-8) is one of the several carcinogenic viruses that infect humans. KSHV infection has been implicated in the development of Kaposi’s sarcoma (KS), primary effusion lymphoma, and multicentric Castleman’s Disease. While KSHV infection is necessary for the development of KSHV associated malignancies, it is not sufficient to induce tumorigenesis. Evidently, other co-factors are essential for the progression of KSHV induced malignancies. One of the most important co-factors, necessary for the progression of KSHV induced tumors, is immune suppression that frequently arises during co-infection with HIV and also by other immune suppressants. In this mini-review, we discuss the roles of co-infection with HIV and other pathogens on KSHV infection and pathogenesis.

Major histocompatibility complex class II (MHC-II Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus that causes several malignancies, such as Kaposi's sarcoma (KS), primary effusion lymphomas (PELs), and multicentric Castleman's disease (MCD), in immunocompromised individuals (1, 2). The life cycle of KSHV consists of a predominant latent phase marked by restricted gene expression and a transient lytic replication phase characterized by the production of functional virions. KSHV maintains a lifelong persistent infection in susceptible hosts after primary infection (3, 4). One of the main factors contributing to the successful lifelong persistence of KSHV is its astounding ability to hide from host immune surveillance. During the course of evolution, KSHV has evolved multiple mechanisms to evade and modulate nearly all aspects of both the innate and adaptive immunities of infected hosts (5-7).Latency-associated nuclear antigen (LANA or LANA-1) is the most abundantly expressed protein in all KSHV-infected cells (8-10). LANA is a large multifunctional protein that plays diverse Citation Thakker S, Purushothaman P, Gupta N, Challa S, Cai Q, Verma SC. 2015. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen inhibits major histocompatibility complex class II expression by disrupting enhanceosome assembly through binding with the regulatory factor X complex.

The establishment of latency is an essential for lifelong persistence and pathogenesis of Kaposi’s sarcoma-associated herpesvirus (KSHV). Latency-associated nuclear antigen (LANA) is the most abundantly expressed protein during latency and is important for viral genome replication and transcription. Replication-coupled nucleosome assembly is a major step in packaging the newly synthesized DNA into chromatin, but the mechanism of KSHV genome chromatinization post-replication is not understood. Here, we show that nucleosome assembly protein 1-like protein 1 (NAP1L1) associates with LANA. Our binding assays revealed an association of LANA with NAP1L1 in KSHV-infected cells, which binds through its amino terminal domain. Association of these proteins confirmed their localization in specific nuclear compartments of the infected cells. Chromatin immunoprecipitation assays from NAP1L1-depleted cells showed LANA-mediated recruitment of NAP1L1 at the terminal repeat (TR) region of the viral genome. Presence of NAP1L1 stimulated LANA-mediated DNA replication and persistence of a TR-containing plasmid. Depletion of NAP1L1 led to a reduced nucleosome positioning on the viral genome. Furthermore, depletion of NAP1L1 increased the transcription of viral lytic genes and overexpression decreased the promoter activities of LANA-regulated genes. These results confirmed that LANA recruitment of NAP1L1 helps in assembling nucleosome for the chromatinization of newly synthesized viral DNA.

Kaposi’s sarcoma (KS) is a highly-vascularized tumor characterized by inflammation and extensive neo-angiogenesis. The KS tumor microenvironment is rich in inflammatory and pro-angiogenic cytokines. Here, we report that the expression of Epidermal growth factor-like domain 7 (EGFL7) is upregulated in Kaposi’s sarcoma-associated herpes virus (KSHV) infected cells. EGFL7 is a secreted pro-angiogenic cytokine that has been implicated in angiogenesis and the proliferation of endothelial cells during many pathological conditions. Our data show that KS tumors as well as primary effusion lymphoma cells have increased levels of EGFL7 compared to the uninfected cells. We determined that the expression of a KSHV latent protein, LANA (latency-associated nuclear antigen), is the main viral factor responsible for this upregulation. The modulation of EGFL7 expression by LANA involves sequestration of death domain-associated protein 6 (Daxx) from the EGFL7 promoter. Daxx acts as a suppressor of promoter activity by binding to the avian erythroblastosis virus E26 oncogene homolog 1 (Ets-1), which is the core transcription factor required for the expression of EGFL7. We additionally show that the upregulation of EGFL7 by LANA contributes to the promotion of angiogenesis since siRNA-mediated knockdown of EGFL7 reduced in vitro tubulogenesis in LANA-expressing HUVEC cells. EGFL7 promotes angiogenesis through autocrine as well as paracrine mechanisms as the supernatant from LANA expressing cells depleted of EGFL7 showed reduced tubulogenesis. This study for the first time demonstrates EGFL7 to be an important angiogenic molecule secreted during KSHV infection that could be exploited for blocking KSHV associated malignancies in conjugation with other anti-angiogenic therapies.