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Immunotherapy for KSHV-associated diseases.

ABSTRACT: Kaposi sarcoma herpesvirus (KSHV)-associated diseases (Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, and KSHV inflammatory cytokine syndrome) are associated with immune suppression and dysregulation and loss of KSHV-specific immunity. These diseases are most frequent in people living with HIV as well as those with primary or iatrogenic immune deficiencies. KSHV itself can modulate the immune system via viral homologs of host cytokines or downregulation of immune-surface markers altering host immune surveillance. These factors make KSHV-associated diseases prime targets for immunotherapy approaches. Several agents have been studied or are under investigation in KSHV-associated diseases, including monoclonal antibodies, immunomodulatory agents, and therapeutic cytokines. Here, we review the role of immunotherapies in KSHV-associated diseases.

SUBMITTER: Lurain K

PROVIDER: S-EPMC9464688 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Immunotherapy for KSHV-associated diseases.

Lurain Kathryn K Yarchoan Robert R Ramaswami Ramya R

Current opinion in virology 20220705

Kaposi sarcoma herpesvirus (KSHV)-associated diseases (Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, and KSHV inflammatory cytokine syndrome) are associated with immune suppression and dysregulation and loss of KSHV-specific immunity. These diseases are most frequent in people living with HIV as well as those with primary or iatrogenic immune deficiencies. KSHV itself can modulate the immune system via viral homologs of host cytokines or downregulation of immune-surf ...[more]

PMID: 35803203

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Project description:Kaposi sarcoma (KS)-associated herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a relapsing and remitting systemic lymphoproliferative disorder characterized by severe inflammatory symptoms most common among people living with HIV (PLWH). Patients with KSHV-MCD may present with concurrent KSHV-associated diseases, such as KS and/or primary effusion lymphoma (PEL). We evaluated clinical and immunologic characteristics, the effects of concurrent KSHV malignancies, and treatments from the largest prospective natural history study of participants with KSHV-MCD within the United States. Treatment options administered at investigator discretion included high-dose zidovudine with valganciclovir (AZT/VGC), rituximab, or rituximab with liposomal doxorubicin (R-Dox) during KSHV-MCD flares. Survival analyses and prognostic factors were explored for all participants. Sixty-two participants with HIV were enrolled, including 20 with KSHV-MCD alone, 34 with KSHV-MCD and KS, 1 with KSHV-MCD and PEL, and 7 with all KSHV-associated diseases. Forty-four percent of KSHV-MCD diagnoses were made at our institution. Forty-four participants received rituximab-based therapies, 20 of whom had maintenance AZT/VGC or interferon. Participants receiving R-Dox and then maintenance AZT/VGC had the highest 5-year progression-free survival (89%). Cytokine profiles during KSHV-MCD flares did not differ by the presence of concurrent KSHV-associated diseases. The 10-year survival was 71% (95% confidence interval [CI], 56% to 82%) for all participants. A concurrent diagnosis of PEL negatively impacted survival (PEL hazard ratio, 5.4; 95% CI, 1.8 to 16.8). KSHV-MCD is an underdiagnosed condition among PLWH, including those with KS. KSHV-MCD has an excellent prognosis with appropriate treatment. Physicians should be alert for patients with multiple KSHV diseases, which impact optimal treatment and survival outcomes. This study was registered at www.clinicaltrials.gov as #NCT00099073.

Project description:Recently published near full-length KSHV genomes from a Cameroon Kaposi sarcoma case-control study showed strong evidence of viral recombination and mixed infections, but no sequence variations associated with disease. Using the same methodology, an additional 102 KSHV genomes from 76 individuals with KSHV-associated diseases have been sequenced. Diagnoses comprise all KSHV-associated diseases (KAD): Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated large cell lymphoma (KSHV-LCL), a type of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). Participants originated from 22 different countries, providing the opportunity to obtain new near full-length sequences of a wide diversity of KSHV genomes. These include near full-length sequence of genomes with KSHV K1 subtypes A, B, C, and F as well as subtype E, for which no full sequence was previously available. High levels of recombination were observed. Fourteen individuals (18%) showed evidence of infection with multiple KSHV variants (from two to four unique genomes). Twenty-six comparisons of sequences, obtained from various sampling sites including PBMC, tissue biopsies, oral fluids, and effusions in the same participants, identified near complete genome conservation between different biological compartments. Polymorphisms were identified in coding and non-coding regions, including indels in the K3 and K15 genes and sequence inversions here reported for the first time. One such polymorphism in KSHV ORF46, specific to the KSHV K1 subtype E2, encoded a mutation in the leucine loop extension of the uracil DNA glycosylase that results in alteration of biochemical functions of this protein. This confirms that KSHV sequence variations can have functional consequences warranting further investigation. This study represents the largest and most diverse analysis of KSHV genome sequences to date among individuals with KAD and provides important new information on global KSHV genomics.

Dataset Information

Immunotherapy for KSHV-associated diseases.

Publications

Immunotherapy for KSHV-associated diseases.

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