Saturday, March 25, 2023
This activity is intended for scientists, physicians, and other allied health professionals working in the fields of HIV, hematology, oncology, immunology, infectious diseases, virology, and molecular & cellular biology.
The goal of this activity is to enhance the quality of clinical practice by healthcare professionals involved in the care of individuals with HIV/AIDS by reporting state-of-the-art treatment approaches and clinical strategies for the management of HIV/AIDS.
Upon completion of this activity, participants should be able to:
The National Institutes of Health/Foundation for Advanced Education in the Sciences (NIH/FAES) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The NIH/FAES designates this educational activity for a maximum of 1 hour in category 1 credit towards the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity.
For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]
There are no fees for participating in or receiving credit for this online educational activity. For information on applicability
and acceptance of continuing education credit for this activity, please consult your professional licensing board.
This activity is designed to be completed within the time designated on the title page; physicians should claim only those
credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the
activity online during the valid credit period that is noted on the title page.
Follow these steps to earn CME/CE credit:
You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it.
Credits will be tallied in your CME/CE Tracker and archived for 5 years; at any point within this time period you can print
out the tally as well as the certificates by accessing "Edit Your Profile" at the top of your Medscape homepage.
The credit that you receive is based on your user profile.
processing....
The session "Viral Transformation and Oncogenesis" focused on how viral-encoded gene products contribute to the establishment and maintenance of viral-induced malignancies. Three DNA tumor viruses involved in AIDS-related cancers were discussed: human papillomavirus (HPV), Epstein-Barr virus (EBV) and human herpesvirus type 8 (HHV-8).
Topics presented included viral oncoproteins, viral latency-associated proteins and RNAs, and upregulation of cellular oncogenes during viral transformation. Furthermore, activation of key cellular signaling pathways by viral proteins was also discussed.
Androphy and colleagues[1] at the University of Massachusetts Medical School, Worcester, presented data on how the HPV-16 E6 oncoprotein immortalizes human mammary epithelial cells. They identified a 2-step process involving (1) methylation of the p16 promoter, which prevented p16 from being transcribed in the E6-expressing cell, and (2) E6 induction of human telomerase activity. HPV E6-immortalized mammary epithelial cells showed an elevated level of the transcription factor HLTF, which belongs to the Swi/Snf family of transcription factors and is capable of activating telomerase gene expression. HLTF along with a mutant p53 protein were able to efficiently immortalize mammary epithelial cells, suggesting that E6 is affecting 1 pathways in these cells: one involving the p53 pathway, and the other involving stimulation of HLTF which results in the upregulation of telomerase activity in these cells. Of interest, the E6 viral oncoprotein was also required for papillomavirus replication since mutant E6 proteins that were incapable of degrading p53 were also replication-defective. Thus, multiple functions of HPV-16 E6 contribute to the immortalization of mammary epithelial cells.[2]
Presentations on EBV explored the role of EBV gene products in Burkitt lymphomas and lymphocyte growth transformation, the role of EBV in the survival and differentiation of human B cells, maintenance of the EBV episome during latency, and activation of cellular signaling pathways by EBV-encoded proteins.
Sample and Ruf[3] from St. Jude Children's Research Hospital, Memphis, Tennessee, presented data indicating that the tumorigenic potential of EBV-negative Burkitt lymphoma cells was enhanced by EBV-encoded RNAs (EBERs), but not by EBV nuclear antigen 1 (EBNA-1). However, this enhancement was lower than that seen in EBV-positive Burkitt lymphomas, implicating the contribution of other EBV genes in the establishment and maintenance of EBV-positive Burkitt lymphomas (Figure 1). The EBERs could potentiate the tumorigenicity of Burkitt lymphoma cells independently of an effect on apoptosis.[4,5] Microarray analysis indicated that the STAT pathway is activated in both EBV-negative and EBV-positive Burkitt lymphoma cells.
Figure 1. EBV induces a proliferative signal in Burkitt lymphomas.
Maruo and colleagues,[6] of the Channing Laboratory, a multidisciplinary research division of Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, analyzed the role of the EBV EBNA3A protein in maintaining lymphoblastoid cell line (LCL) proliferation by using EBV recombinants carrying an EBNA3A-HTER fusion gene, so that EBNA3A expression was dependent on 4-hydroxytamoxifen (4-HT). The growth of these EBNA3A-HTER-recombinant EBV-containing cells is dependent on the continuous presence of OH-Tamoxifen (HT), which targets the EBNA 3A-HTER fusion gene in the nucleus. HT withdrawal leads to gradual slowing and cessation of growth of the LCLs. When seeded at a low density, HT withdrawal led to an immediate cessation of LCL growth, implying that EBNA3A is required for ongoing cell proliferation of LCLs. EBNA3A did not regulate the expression of other EBV genes (eg, LMP-1, EBNA-1, EBNA-2 and EBNA-3B) under normal growth conditions. Finally, withdrawal of EBNA3A in LCLs had a small effect on CD21 expression but no effect on CD23 and c-Myc expression. Thus, EBNA3A appears to be critical for the maintenance of LCL growth (Figure 2).
Figure 2. EBV EBNA-3A is necessary for the maintenance of LCL growth.
Harrelson and Raab-Traub[7] from the University of North Carolina at Chapel Hill showed that the LMP2A protein of EBV was capable of activating the PI3-Kinase/AKT pathway in human keratinocytes (Figure 3). They also demonstrated that the Akt kinase is activated in several different EBV-associated malignancies such as EBV-associated Hodgkin's disease and EBV-positive nasopharyngeal carcinomas. They suggested that the expression of EBV LMP2A in these malignancies contributes to the activation of the Akt signaling pathway and that this LMP2A-mediated activation of Akt may promote cell cycle progression in EBV-associated Hodgkin's disease and nasopharyngeal carcinomas.
Figure 3. EBV LMP2A can activate the PI3-Kinase/Akt pathway.
Many of the presentations focused on HHV-8-induced malignancies, including primary effusion lymphomas (PEL), multicentric Castleman's disease (MCD), and Kaposi's sarcoma (KS).
Patrick S. Moore, MD,[8] from the University of Pittsburgh, Pittsburgh, Pennsylvania, presented data demonstrating that the expression pattern of HHV-8 viral genes is dependent on the virus' environment and is not intrinsic to the virus itself. He showed that there are tumor-specific expression patterns and presented in situ hybridization data suggesting that there is a restricted gene expression pattern in different tumor types: MCD > KS > PEL. Thus, the determination of the expression patterns of viral genes in situ has critical importance for discovering the key players in HHV-8-induced tumorigenesis. He also discussed the roles of several HHV-8-encoded gene products -- LANA1, vCYC, vFLIP, vIL-6, vGCR, and LANA2 -- and suggested that some of these may enhance HHV-8-associated tumorigenesis through a paracrine mechanism.[9]
Watanabe and colleagues[10] at the National Cancer Institute in Bethesda, Maryland, presented evidence to show that the HHV-8 latency-associated nuclear antigen (LANA/LANA1) can immortalize primary human umbilical vein endothelial cells (HUVEC). LANA-transduced NIH3T3 cells and HUVEC cells assumed a spindle morphology and their rate of cellular proliferation increased 4- to 10-fold compared with the vector control. Of importance, transduction of HUVEC with HHV-8 LANA greatly extended the cellular lifespan of these cells, similar to SV40 large T-antigen-expressing cells but unlike the v-Cyclin expressing cells or the pLXRN vector control cells (Figure 4). However, the LANA-transduced HUVEC could not form foci in soft agar or induce tumors in nude mice, suggesting that HHV-8 LANA induces cellular immortalization but not cellular transformation.
Figure 4. Increased proliferation in LANA-transduced HUVEC.
In a similar vein, Moses and colleagues[11] at Oregon Health & Science University, Portland, and R.W. Johnson Pharmaceutical Research Institute demonstrated that HHV-8 infection of dermal microvascular endothelial cells (DMVEC) resulted in an upregulation of the c-Kit proto-oncogene, as identified by gene expression profiling experiments. As a result of the increased c-Kit expression, HHV-8-infected DMVECs displayed an enhanced proliferation in response to stem cell factor (SCF), which is the ligand for c-Kit. Inhibition of c-Kit activity resulted in a reversal of HHV-8-induced morphologic transformation of DMVEC. Thus, c-Kit may play a role in KS tumorigenesis (Figure 5), and agents known to target c-Kit may be useful for treatment of KS.
Figure 5. Role of c-Kit in KSHV-induced DMVEC transformation.
