The Role of Human Herpesvirus 8 Molecular Characterization in the Management of HIV Infected Patients Diagnosed with Malignancies Associated with Its Infection

Martínez Pedro Ariel, Kourí Vivian, Blanco Orestes, Capó Virginia, Abad Yoandra, Alemán Yoan, Verdasquera Denis, Jiménez Narciso, Caballero Iraida, Fleites Gilberto, Ugarte Yaumara, Calderón Odalys, Álvarez Alina, Ulrich Hengge

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Institute of Tropical Medicine “Pedro Kourí” (IPK), Autopista Novia del Mediodía, Habana, Cuba.

DOI: 10.4236/wja.2013.33030                

Abstract

Despite the progress has been reached with Human herpesvirus 8 (HHV-8) research, there are gaps in the knowledge of viral induced oncogenesis. The aim of the present study was to identify possible associations between HHV-8 subtypes, HHV-8 loads and clinical manifestations of HIV infected patients diagnosed with different malignancies associated with HHV-8 infection. Forty six HIV-1 infected individuals diagnosed with different HHV-8 associated diseases were studied [37 epidemic Kaposi’s sarcoma (KS), 3 pleural effusion lymphoma (PEL); 5 peripheral lymphadenopathies (PL); 1 Hodgkin’s lymphoma (HL); 1 non Hodgkin’s lymphoma (NHL)]. HHV-8 loads were determined by quantitative real time PCR (qRT-PCR) whilst HHV-8 subtypes were determined by open-reading frame (ORF)-K1 gen genotyping. HHV-8 subtypes B, A, C, A5 and E were exhibited by 31.8%, 23.4%, 19.1%, 17% and 8.5% of the studied patients, respectively. The median HHV-8 viral load did not differ between subtypes (p > 0.05) but HHV-8 viral loads were significantly higher in PEL than in epidemic KS lesion or lymph nodes (p = 0.04). Subtype B was detected in 60% of patients with B cell lymphoma (NHL, PEL and HL) whereas subtype E was only detected in patients with epidemic KS diagnosis. Our data suggest that HHV-8 DNA quantification instead of subtype identification could be used as a surrogate marker for monitoring its infection, not only in epidemic KS patients but also in HIV infected individuals with lymphoproliferative disorders.

Keywords

Human Herpesvirus 8 or Kaposi’s Sarcoma-Associated Herpesvirus; Real Time PCR; Subtypes; Lymphoproliferative Disorders; Cuban; HIV/AIDS

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	D. Ganem, “Kaposi’s Sarcoma-Associated Herpesvirus,” In: D. M. Knipe and P. M. Howley, Eds., Fields Virology, 5th Edition, Lippincott Williams & Wilkins, 2007, p. 2847-2888.
[2]	J. C. Zong, D. M. Ciufo, D. J. Alcendor, X. Wan, J. Nicholas, P. J. Browning, et al., “High-Level Variability in the ORF-K1 Membrane Protein Gene at the Left End of the Kaposi’s Sarcoma-Associated Herpesvirus Genome Defines Four Major Virus Subtypes and Multiple Variants or Clades in Different Human Populations,” Journal of Virology, Vol. 73, No. 5, 1999, pp. 4156-4170.
[3]	S. Franceschi, L. D. Maso, M. Rickenbach, J. Polesel, B. Hirschel, M. Cavassini, et al., “Kaposi Sarcoma Incidence in the Swiss HIV Cohort Study before and after Highly Active Antiretroviral Therapy,” British Journal of Cancer, Vol. 99, No. 5, 2008, pp. 800-804. doi:10.1038/sj.bjc.6604520
[4]	T. Maurer, M. Ponte and K. Leslie, “HIV-Associated Kaposi’s Sarcoma with a High CD4 Count and a Low Viral Load,” New England Journal of Medicine, Vol. 357, No. 13, 2007, pp. 1352-1353. doi:10.1056/NEJMc070508
[5]	V. Kouri, A. Marini, R. Doroudi, S. Nambiar, M. E. Rodriguez, V. Capo, et al., “Molecular Epidemiology of Kaposi’s Sarcoma Herpesvirus (KSHV) in Cuban and German Patients with Kaposi’s Sarcoma (KS) and Asymptomatic Sexual Contacts,” Virology, Vol. 337, No. 2, 2005, pp. 297-303. doi:10.1016/j.virol.2005.04.033
[6]	V. Kouri, X. Liang, M. E. Rodriguez, V. Capo, S. Resik, J. Barrios, et al., “Molecular Epidemiology and KSHV K1 Subtypes in a Cuban AIDS-Kaposi’s Sarcoma Population,” Aids, Vol. 19, No. 9, 2005, pp. 984-987. doi:10.1097/01.aids.0000171416.07034.d6
[7]	V. Kouri, P. A. Martinez, V. Capo, O. Blanco, M. E. Rodriguez, N. Jimenez, et al., “Kaposi’s Sarcoma and Human Herpesvirus 8 in Cuba: Evidence of Subtype B Expansion,” Virology, Vol. 432, No. 2, 2012, pp. 361-369. doi:10.1016/j.virol.2012.06.014
[8]	R. Kumar, A. Abbas, A. DeLancey and E. Malone, “Diseases of the Immune System,” In: R. Kumar, A. Abbas, A. DeLancey and E. Malone, Eds., Robbins and Cotran Pathologic Basis of Disease, 8 Edition, Elsevier Inc., 2010, pp. 183-257.
[9]	F. Watzinger, M. Suda, S. Preuner, R. Baumgartinger, K. Ebner, L. Baskova, et al., “Real-Time Quantitative PCR Assays for Detection and Monitoring of Pathogenic Human Viruses in Immunosuppressed Pediatric Patients,” Journal of Clinical Microbiology, Vol. 42, No. 11, 2004, pp. 5189-5198. doi:10.1128/JCM.42.11.5189-5198.2004
[10]	V. Kouri, P. A. Martinez, O. Blanco, V. Capo, M. E. Rodriguez, C. Dovigny Mdel, et al., “Simultaneous Quantification of Human Herpesvirus 8 DNA by Real Time PCR in Different Tissues of HIV Infected Cuban Patients with Kaposi’s Sarcoma,” Herpesviridae, Vol. 1, No. 1, 2010, p. 3. doi:10.1186/2042-4280-1-3
[11]	M. Schmitz, C. Scheungraber, J. Herrmann, K. Teller, M. Gajda, I. B. Runnebaum, et al., “Quantitative Multiplex PCR Assay for the Detection of the Seven Clinically Most Relevant High-Risk HPV Types,” Journal of Clinical Virology, Vol. 44, No. 4, 2009, pp. 302-307. doi:10.1016/j.jcv.2009.01.006
[12]	K. Tamura, J. Dudley, M. Nei and S. Kumar, “MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) Software Version 4.0,” Molecular Biology and Evolution, Vol. 24, 2007, pp. 1596-1599. doi:10.1093/molbev/msm092
[13]	M. Clamp, J. Cuff, S. M. Searle and G. J. Barton, “The Jalview Java Alignment Editor,” Bioinformatics, Vol. 20, 2004, pp. 426-427. doi:10.1093/bioinformatics/btg430
[14]	D. Posada and K. A. Crandall, “MODELTEST: Testing the Model of DNA Substitution,” Bioinformatics, Vol. 14, 1998, pp. 817-818. doi:10.1093/bioinformatics/14.9.817
[15]	N. H. Dukers and G. Rezza, “Human Herpesvirus 8 Epidemiology: What We Do and Do Not Know,” Aids, Vol. 17, No. 12, 2003, pp. 1717-1730. doi:10.1097/00002030-200308150-00001
[16]	A. G. Marcelin, J. Motol, A. Guihot, E. Caumes, J. P. Viard, E. Dussaix, et al., “Relationship between the Quantity of Kaposi Sarcoma-Associated Herpesvirus (KSHV) in Peripheral Blood and Effusion Fluid Samples and KSHV-Associated Disease,” Journal of Infectious Disease, Vol. 196, No. 8, 2007, pp. 1163-1166. doi:10.1086/521625
[17]	Y. Asahi-Ozaki, Y. Sato, T. Kanno, T. Sata and H. Katano, “Quantitative Analysis of Kaposi Sarcoma-Associated Herpesvirus (KSHV) in KSHV-Associated Diseases,” Journal of Infectious Disease, Vol. 193, No. 6, 2006, pp. 773-782. doi:10.1086/500560
[18]	C. Casper, “Defining a Role for Antiviral Drugs in the Treatment of Persons with HHV-8 Infection,” Herpes, Vol. 13, No. 2, 2006, pp. 42-47.
[19]	E. Kadyrova, V. Lacoste, R. Duprez, K. Pozharissky, V. Molochkov, M. Huerre, et al., “Molecular Epidemiology of Kaposi’s Sarcoma-Associated Herpesvirus/Human Herpesvirus 8 Strains from Russian Patients with Classic, Posttransplant, and AIDS-Associated Kaposi’s Sarcoma,” Journal of Medical Virology, Vol. 71, No. 4, 2003, pp. 548-556. doi:10.1002/jmv.10530
[20]	O. Cassar, M. L. Blondot, S. Mohanna, G. Jouvion, F. Bravo, V. Maco, et al., “Human Herpesvirus 8 Genotype E in Patients with Kaposi Sarcoma, Peru,” Emerging Infectious Diseases, Vol. 16, No. 9, 2010, pp. 1459-1462. doi:10.3201/eid1609.100381
[21]	R. J. Biggar, D. Whitby, V. Marshall, A. C. Linhares and F. Black, “Human Herpesvirus 8 in Brazilian Amerindians: A Hyper-Endemic Population with a New Subtype,” Journal of Infectious Diseases, Vol. 181, No. 5, 2000, pp. 1562-1568. doi:10.1086/315456
[22]	R. Alegre, J. Moscoso, J. Martinez-Laso, M. Martin-Villa, J. Suarez, A. Moreno, et al., “HLA Genes in Cubans and the Detection of Amerindian Alleles,” Molecular Immunology, Vol. 44, No. 9, 2007, pp. 2426-2435. doi:10.1016/j.molimm.2006.10.017
[23]	V. Kouri, P. A. Martinez, B. Acosta, M. E. Rodriguez, O. Blanco, V. Capo, et al., “First report of Kaposi’s Sarcoma-Associated Herpesvirus DNA Sequences from Cuban Kaposi’s Sarcoma Patients without HIV Infection,” Aids, Vol. 21, No. 15, 2007, pp. 2113-2115. doi:10.1097/QAD.0b013e3282f01cc6
[24]	E. Cesarman, “Gammaherpesvirus and Lymphoproliferative Disorders in Immunocompromised Patients,” Cancer Letters, Vol. 305, No. 2, 2011, pp. 163-174. doi:10.1016/j.canlet.2011.03.003
[25]	A. D’Antonio, M. Addesso, D. Memoli, P. Liguori, R. Cuomo, A. Boscaino, et al., “Lymph Node-Based Disease and HHV-8/KSHV Infection in HIV Seronegative Patients: Report of Three New Cases of a Heterogeneous Group of Diseases,” International Journal of Hematology, Vol. 93, No. 6, 2011, pp. 795-801. doi:10.1007/s12185-011-0849-0
[26]	A. Chadburn, E. Hyjek, S. Mathew, E. Cesarman, J. Said and D. M. Knowles, “KSHV-Positive Solid Lymphomas Represent an Extra-Cavitary Variant of Primary Effusion Lymphoma,” The American Journal of Surgical Pathology, Vol. 28, No. 11, 2004, pp. 1401-1416. doi:10.1097/01.pas.0000138177.10829.5c
[27]	E. A. Engels, S. M. Mbulaiteye, E. Othieno, M. Gomez, S. Mathew, E. Cesarman, et al., “Kaposi Sarcoma-Associated Herpesvirus in Non-Hodgkin Lymphoma and Reactive Lymphadenopathy in Uganda,” Human Pathology, Vol. 38, No. 2, 2007, pp. 308-314. doi:10.1016/j.humpath.2006.08.009
[28]	V. Lacoste, E. Kadyrova, I. Chistiakova, V. Gurtsevitch, J. G. Judde and A. Gessain, “Molecular Characterization of Kaposi’s Sarcoma-Associated Herpesvirus/Human Herpesvirus-8 Strains from Russia,” Journal of General Virology, Vol. 81, No. P5, 2000, pp. 1217-1222.
[29]	J. Zong, D. M. Ciufo, R. Viscidi, L. Alagiozoglou, S. Tyring, P. Rady, et al., “Genotypic Analysis at Multiple Loci across Kaposi’s Sarcoma Herpesvirus (KSHV) DNA Molecules: Clustering Patterns, Novel Variants and Chimerism,” Journal of Clinical Virology, Vol. 23, No. 3, 2002, pp. 119-148. doi:10.1016/S1386-6532(01)00205-0
[30]	L. A. Dourmishev, A. L. Dourmishev, D. Palmeri, R. A. Schwartz and D. M. Lukac, “Molecular Genetics of Kaposi’s Sarcoma-Associated Herpesvirus (Human Herpesvirus-8) Epidemiology and Pathogenesis,” Microbiology and Molecular Biology Reviews, Vol. 67, No. 2, 2003, pp. 175-212. doi:10.1128/MMBR.67.2.175-212.2003
[31]	E. Oksenhendler, D. Cazals-Hatem, T. F. Schulz, V. Barateau, L. Grollet, J. Sheldon, et al., “Transient Angiolymphoid Hyperplasia and Kaposi’s Sarcoma after Primary Infection with Human Herpesvirus 8 in a Patient with Human Immunodeficiency Virus Infection,” New England Journal of Medicine, Vol. 338, No. 22, 1998, pp. 1585-1590. doi:10.1056/NEJM199805283382204
[32]	M. Luppi, P. Barozzi, V. Rasini, G. Riva, A. Re, G. Rossi, et al., “Severe Pancytopenia and Hemophagocytosis after HHV-8 Primary Infection in a Renal Transplant Patient Successfully Treated with Foscarnet,” Transplantation, Vol. 74, No. 1, 2002, pp. 131-132. doi:10.1097/00007890-200207150-00023
[33]	O. Thaunat, M. F. Mamzer-Bruneel, F. Agbalika, F. Valensi, M. Venditto, C. Lebbe, et al., “Severe Human Herpesvirus-8 Primary Infection in a Renal Transplant Patient Successfully Treated with Anti-CD20 Monoclonal Antibody,” Blood, Vol. 107, No. 7, 2006, pp. 3009-3010. doi:10.1182/blood-2005-08-3213
[34]	M. Andreoni, L. Sarmati, E. Nicastri, G. El Sawaf, M. El Zalabani, I. Uccella, et al., “Primary Human Herpesvirus 8 Infection in Immunocompetent Children,” Jama, Vol. 287, No. 10, 2002, pp. 1295-300. doi:10.1001/jama.287.10.1295
[35]	F. C. Kasolo, J. Spinks, H. Bima, M. Bates and U. A. Gompels, “Diverse Genotypes of Kaposi’s Sarcoma Associated Herpesvirus (KSHV) Identified in Infant Blood Infections in African Childhood-KS and HIV/AIDS Endemic Region,” Journal of Medical Virology, Vol. 79, No. 10, 2007, pp. 1555-1556. doi:10.1002/jmv.20952