Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment

Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment

Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma (KS)–associated herpesvirus, is the etiologic agent responsible for all types of KS. A 90-year-old man and an 87-year-old woman were hospitalized because of pleural effusions. This reactivation has been associated with a number of different clinical endpoints in HCT recipients, including central nervous system (CNS) disease. Finally, novel approaches to treatment and prevention are described, including antiviral agents, targeted molecular therapy and a combination of these modalities. Any drop in the immunity of the individual leads to recurrent herpes labialis. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Considering the absence of systematic screening of organ donors/recipients for HHV-8 infection, HHV-8-related illness should be suspected in transplant recipients who present with acute febrile illness, systemic symptoms, lymphadenopathies, and/or multiorgan failure to rapidly document the diagnosis and provide timely an adequate treatment.

Based on these observations, we hypothesize that differences in HHV-8 replication and lytic gene expression at oral, blood, and tissue sites contribute to the heterogeneous clinical manifestations of KS and variability in treatment response. The secondary endpoint was to assess the efficacy of preemptive administration of PFA in preventing the development of limbic encephalitis, as well as in reducing the amount of plasma HHV-6 DNA. The researchers analyzed daily mouth and throat swabs collected from 58 study participants who were dually infected with HIV-1 and HHV-8, for a total of 6036 swabs. We will then test whether levels of HHV-8 replication in these various anatomic sites are associated with clinical presentation or predict treatment response. This proposed study will advance our understanding of the biologic role of replicating HHV-8 and lytic gene expression in established KS disease and could make significant contributions to KS care. If we find that levels of HHV-8 replication predict treatment response or relapse, HHV-8 may be a useful biomarker and could improve current KS staging. If we find that HHV-8 replication is associated with disease presentation and response, our study would also provide a biologic rationale to pursue inhibition of HHV-8 as a KS treatment strategy in future studies.
Human Herpesvirus-8 Replication and Kaposi Sarcoma Response to Treatment

A description of the 4 different types of KS is as follows and can be found in Table 1: classical, endemic, iatrogenic/transplant, and AIDS-associated/epidemic KS. Corey Casper, Larry Corey, and Anna Wald, who provide unparalleled expertise in herpesvirus virology and infection-related cancers. The proposed study will also receive laboratory support from internationally-recognized PCR experts at the UW Molecular Diagnostics Laboratory and biostatistical support from faculty at the UW and the Statistical Center for HIV/AIDS Research &Prevention (SCHARP) at FHCRC. Our group’s collaboration with investigators at the UCI has also established the research infrastructure needed to complete the proposed studies in Uganda, including an experienced study staff, a specimen repository, and an on-site PCR lab. The first attack of herpes genitalis is pretty violent, following which the virus remains dormant within the neuronal cells of the dorsal root ganglion and then gives rise to recurrent lesions but milder in intensity as compared to the primary attack. My planned activities include didactic coursework in advance biostatistics, cancer epidemiology, and molecular virology. I will also pursue practical laboratory experiences in PCR methodology and cancer pathology to help me grow as a translational researcher.

In order to participate in coursework and other career development activities in both Seattle and Uganda, I will split my time between the two sites during the award period, making 2-3 roundtrips annually. The following variables related to patients and their clinical data were compared among the groups using Fisher’s exact probability test or the Mann–Whitney U-test: gender (male versus female), HHV-6 IgG titer before HSCT, intensity of the conditioning regimen (myeloablative versus reduced-intensity conditioning), prophylactic regimens for GVHD (cyclosporine-based versus tacrolimus-based), transplanted cell number, type of HSCT (UCBT versus haploidentical HSCT), date of WBCs >0.1 × 109/L, date of neutrophils >0.5 × 109/L, date of developing HHV-6 DNAemia (defined as the state characterized by the presence of HHV-6 DNA greater than 1 × 102 copies/mL in plasma), duration of HHV-6 DNAemia and development of CMV antigenemia (positive versus negative). In the near term, my goal is to build a productive research program in HHV-8 and KS in Uganda. Based of the findings of my K23 study, I anticipate conducting an HHV-8 biomarker validation study and a trial of anti-HHV-8 therapeutics, such as ganciclovir, in KS treatment. Ultimately, I hope to develop a research program aimed at integrating an understanding of virologic mechanisms of disease pathogenesis with the development of new approaches to KS treatment and prevention that will establish my career as an independent investigator in the field of HIV-associated malignancies. Kaposi sarcoma (KS) is the most common HIV-associated cancer worldwide. The proposed study will evaluate whether detection of the virus that causes KS, human herpesvirus-8, can predict treatment response in persons with KS.

The “KS belt” is a region in equatorial Africa where even before HIV, the progression of HHV-8 to endemic KS was particularly high [16].

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