HIV-associated cancers and lymphoproliferative disorders caused by Kaposi sarcoma herpesvirus and Epstein-Barr virus

Abstract

SUMMARYWithin weeks of the first report of acquired immunodeficiency syndrome (AIDS) in 1981, it was observed that these patients often had Kaposi sarcoma (KS), a hitherto rarely seen skin tumor in the USA. It soon became apparent that AIDS was also associated with an increased incidence of high-grade lymphomas caused by Epstein-Barr virus (EBV). The association of AIDS with KS remained a mystery for more than a decade until Kaposi sarcoma-associated herpesvirus (KSHV) was discovered and found to be the cause of KS. KSHV was subsequently found to cause several other diseases associated with AIDS and human immunodeficiency virus (HIV) infection. People living with HIV/AIDS continue to have an increased incidence of certain cancers, and many of these cancers are caused by EBV and/or KSHV. In this review, we discuss the epidemiology, virology, pathogenesis, clinical manifestations, and treatment of cancers caused by EBV and KSHV in persons living with HIV.

Keywords: AIDS; Castleman; EBV; HIV; KSHV; Kaposi; gammaherpesvirus; lymphoma.

Fig 1

The biphasic lifecycle of the human gammaherpesviruses Epstein-Barr virus and Kaposi sarcoma herpesvirus. Infection initiates with the engagement of viral glycoproteins of the enveloped particle with cell surface receptors to mediate attachment (1) and entry via direct membrane fusion or endocytic mechanisms (2). Tegument proteins are released and capsids are transported via microtubules (3), leading to docking of the capsid portal at nuclear pores and deposition of linear viral genomes into the nucleus (4). The viral genomes are quickly circularized and undergo chromatin-like epigenetic modifications. Multiple factors lead to a decision of productive lytic infection (5a) or a restricted phase of limited gene expression termed latency which is mediated by a viral tethering and maintenance protein (5b) that can be reverted back to a productive phase via reactivation (5c). In lytic replication, an ordered cascade of viral gene expression (6a) is initiated by immediate early viral transactivator proteins to drive expression of early genes that encode proteins that manipulate the host and the viral proteins that mediate viral DNA replication (6b). The viral DNA replication machinery generates linear head-to-tail concatemers of viral DNA genomes (6c) that license late gene expression (6d) to produce the structural components of the virion (6e). Unit-length viral genomes are -packaged into icosahedral caspids (7). The capsid traffics through the nuclear envelope and endoplasmic reticulum/trans-Golgi network to sequentially acquire the tegument layer and then the envelope, a host-derived lipid bilayer studded with viral glycoproteins (8) prior to release as a particle that is infectious for transmission (9).

Fig 2

Gene products of gammaherpesviruses with functions consistent with hallmarks of cancer. Genes of KSHV and EBV are listed below each hallmark. Bold text in blue for KSHV and bold text in red for EBV indicate genes expressed during latency, while the text in black font are lytic cycle-associated genes. The functions ascribed are a compilation of previous reports (6, 79, 83, 88, 90, 94–100).

Fig 3

Selected reported and potential ncRNA interactions. (A) An mRNA is shown (green line) to be targeted by multiple microRNAs (miRNAs), depicted in red and blue. These could be viral miRNAs targeting a human mRNA or human miRNAs targeting a viral miRNA. (B) A circular RNA (circRNA) is depicted (green circle) to be sequestering multiple miRNAs and preventing the miRNAs from performing their normal function of targeting mRNAs. Again, these could be human or viral miRNAs. (C) A circRNA is represented to be binding to multiple RNA-binding proteins (RBPs) and disrupting the usual function of the RBP.

Fig 4

Clinical presentation, radiographic imaging, and pathology findings in KSHV-associated disorders. Created with Biorender.com.

Fig 5

Pathological examination of a typical KSHV-MCD lymph node. Photomicrograph showing hyaline vascular changes of the follicles and plasmacytosis by hematoxylin and eosin (H&E) staining, and KSHV-infected plasmablasts in the mantle zone, with lambda restriction (arrow) and expression of LANA and vIL-6.

Fig 6

KSHV MCD lymph node with concomitant KS. Photomicrograph of a KSHV-MCD lymph node showing concomitant KS (top panels) composed of spindle cell proliferation expressing LANA, and MCD (bottom panels) with KSHV-infected plasmablasts residing in the mantle zone of regressed hyaline vascular follicles.

Fig 7

KSHV-infected plasmablasts in the pleural fluid of a patient with KSHV-MCD. KSHV-infected lambda-restricted plasmablasts in the pleural fluid of a patient with KSHV-MCD identified by cytomorphologic features including enlarged nuclei and basophilic cytoplasm (arrow), expression of LANA, and a distinct immunophenotype by flow cytometric analyses (red: KSHV-infected lambda-restricted plasmablasts; blue: normal polyclonal plasma cells).

Fig 8

Photomicrographs of typical and extracellular PEL. Photomicrographs of typical PEL (A) and extracavitary PEL (B) showing cytologic atypia including nuclear pleomorphism with prominent nucleoli and frequent mitoses by Dif-Quik and hematoxylin and eosin (H&E) staining, with co-infection of EBV and KSHV shown in (B) as demonstrated by EBER in situ hybridization and LANA stain.

Fig 9

¹⁸FDG-PET scan of patient with EBV-associated plasmablastic lymphoma. PET scan of patient with EBV-associated plasmablastic lymphoma showing involvement of the bladder, ureters, and retroperitoneal lymph nodes before and after treatment with six cycles of infusional EPOCH.