Skip to main content
NCBI home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;9(2):199–208. doi: 10.1111/j.1750-3639.1999.tb00218.x

HHV‐8/KSHV is Not Associated with AIDS‐Related Primary Central Nervous System Lymphoma

Andrea Antinori 1,✉, Luigi M Larocca 2, Lucia Fassone 3, Paola Cattani 4, Daniela Capello 3, Antonella Cingolani 1, Giuseppe Saglio 5, Giovanni Fadda 4, Gianluca Gaidano 3, Luigi Ortona 1
PMCID: PMC8098287  PMID: 10219737

Abstract

Primary central nervous system lymphoma (PCNSL) is a major complication of the late stages of human immunodeficiency virus (HIV) disease. Epstein Barr virus (EBV) infection is the only genetic lesion consistently associated with this neoplasia. Recently, it has been proposed that the pathogenesis of AIDS‐related PCNSL (AIDS‐PCNSL) may be associated with infection by human herpesvirus‐8/Kaposi's sarcoma associated herpesvirus (HHV‐8/KSHV), although at present such association remains controversial. In order to conclusively assess the link between HHV‐8/KSHV infection and AIDS‐PCNSL, we performed a comprehensive study based on multiple molecular assays on cerebral tissues and cerebrospinal fluid (CSF) as well as specific immunologic assays on patients’ sera. A well characterized panel of 33 Italian patients with AIDS‐PCNSL and 13 controls with other HIV‐related brain focal diseases from the same geographical area was analyzed. No signs of HHV‐8/KSHV infection were detected in cerebral tissues by single‐step PCR. Cerebral tissues of all AIDS‐PCNSL scored negative for HHV‐8/KSHV DNA sequences also by nested PCR, with the exception of one single patient who was simultaneously affected by Kaposi's sarcoma. All CSF samples analyzed were consistently devoid of HHV‐8/KSHV sequences by molecular assays. By serologic assays, detecting both latent and lytic HHV‐8/KSHV antigens, a specific immunoreactivity was observed in 16/33 (48%) AIDS‐PCNSL and in 6/13 (46%) controls (P=0.88). A significant correlation with HHV‐8/KSHV serum reactivity was seen with a homosexual route of HIV transmission (P=0.018), but not with the presence of AIDS‐PCNSL. The results of our analysis conclusively assess that HHV‐8/KSHV infection is not a feature of AIDS‐PCNSL.

Full Text

The Full Text of this article is available as a PDF (148.4 KB).

References

  • 1. Ahsan H, Neugut AI (1996) High risk of Kaposi's sarcoma and central nervous system lymphoma in the same individual: a finding related to acquired immunodeficiency syndrome. Int J Cancer 66:176–178. [DOI] [PubMed] [Google Scholar]
  • 2. Antinori A, Ammassari A, De Luca A, Cingolani A, Murri R, Scoppettuolo G, Fortini M, Tartaglione T, Larocca LM, Zannoni G, Cattani P, Grillo R, Roselli R, Lacoangeli M, Scerrati M, Ortona L (1997) Diagnosis of AIDS‐related focal brain lesions: a decision‐making analysis based on clinical and neuroradiological characteristics combined with polymerase chain reaction assays in cerebrospinal fluid. Neurology 48:687–694. [DOI] [PubMed] [Google Scholar]
  • 3. Antinori A, Cingolani A, De Luca A, Gaidano G, Ammassari A, Larocca LM, Ortona L. (1999) Epstein‐Barr virus in monitoring the response to therapy of AIDS‐related primary central nervous system lymphoma. Ann Neurol 45: 259–261. [PubMed] [Google Scholar]
  • 4. Antinori A, De Rossi G, Ammassari A, Cingolani A, Murri R, Di Giuda D, De Luca A, Pierconti F, Tartaglione T, Scerrati M, Larocca LM, Ortona L. (1999) Value of combined approach with 201TI‐single photon emission computed tomography (SPECT) and Epstein‐Barr virus DNA polymerase chain reaction in cerebrospinal fluid for the diagnosis of AIDS‐related primary central nervous system lymphoma. J Clin Oncol 17: 554–560. [DOI] [PubMed] [Google Scholar]
  • 5. Bishop YMM, Fienberg SE, Holland PW (1975) Discrete multivariate analysis. MIT Press. Cambridge , MA . [Google Scholar]
  • 6. Cattani P, Capuano M, Lesnoni La Parola I, Guido R, Santangelo R, Cerimele F, Masini C, Nanni G, Fadda G, Cerimele D (1998) Human herpesvirus 8 in Italian HIV‐seronegative patients with Kaposi sarcoma. Arch Dermatol 134:695–699. [DOI] [PubMed] [Google Scholar]
  • 7. Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM (1995) Kaposi's sarcoma‐associated herpesvirus‐like DNA sequences in AIDS‐related body‐cavity‐based lymphoma. N Engl J Med 332:1186–1191. [DOI] [PubMed] [Google Scholar]
  • 8. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper Y, Knowles DM, Moore PS (1994) A identification of herpesvirus‐like DNA sequences in AIDS‐associated Kaposi's sarcoma. Science 266:1965–1969. [DOI] [PubMed] [Google Scholar]
  • 9. Cingolani A, De Luca A, Larocca LM, Ammassari A, Scerrati M, Antinori A, Ortona L (1998) Minimally invasive diagnosis of acquired immunodeficiency syndrome‐related primary central nervous system lymphoma. J Natl Cancer Inst 90:364–369. [DOI] [PubMed] [Google Scholar]
  • 10. Cinque P, Vago L, Dahl H, Brytting M, Terrani MR, Fornara C, Racca S, Castagna A, D'Arminio Monforte A, Wahren B, Lazzarin A, Linde A (1996) Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus‐associated opportunistic diseases of the central nervous system in HIV‐infected patients. AIDS 10:951–958. [DOI] [PubMed] [Google Scholar]
  • 11. Corboy JR, Garl PJ, Kleinschmidt‐DeMasters (1998) Human herpesvirus 8 DNA in CNS lymphomas from patients with and without AIDS. Neurology 50:335–340. [DOI] [PubMed] [Google Scholar]
  • 12. Coté TR, Manns A, Hardy CR, Yellin FJ, Hartge P, and the AIDS/Cancer Study Group (1996) Epidemiology of brain lymphoma among people with or without acquired immunodeficiency syndrome. J Natl Cancer Inst 88:675–679. [DOI] [PubMed] [Google Scholar]
  • 13. Epstein LG (1998) Does human herpesvirus 8 have a pathogenetic role in primary CNS lymphoma Neurology 50:322–323. [DOI] [PubMed] [Google Scholar]
  • 14. Feichtinger H, Putkonen P, Parravicini C, Li S‐L, Kaaya EE, Bottiger D, Biberfeld G, Biberfeld P (1990) Malignant lymphomas in cynomolgus monkeys infected with simian immunodeficiency virus. Am J Pathol 137:1311–1315. [PMC free article] [PubMed] [Google Scholar]
  • 15. Gaidano G, Capello D, Pastore C, Antinori A, Gloghini A, Carbone A, Larocca LM, Saglio G (1997) Analysis of human herpesvirus type 8 infection in AIDS‐related and AIDS‐unrelated primary central nervous system lymphoma. J Infect Dis 175:1193–1197. [DOI] [PubMed] [Google Scholar]
  • 16. Gaidano G, Pastore C, Gloghini A, Cusini M, Nomodedeu J, Volpe G, Capello D, Vaccher E, Bordes R, Tirelli U, Saglio G, Carbone A (1996) Distribution of human herpesvirus‐8 sequences throughout the spectrum of AIDS‐related neoplasia. AIDS 10:941–949. [DOI] [PubMed] [Google Scholar]
  • 17. Gao SJ, Kingsley L, Hoover DR, Spira TJ, Rinaldo CR, Saah A, Phair J, Detels R, Parry P, Chang Y, Moore PS (1996) Seroconversion to antibodies against Kaposi's sarcoma‐associated herpesvirus‐related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med 335:233–241. [DOI] [PubMed] [Google Scholar]
  • 18. Gao SJ, Kingsley L, Li M, Zheng W, Parravicini C, Zieglesr J, Newton R, Rinaldo CR, Saah A, Phair J, Detels R, Chang Y, Moore PS (1996) KSHV antibodies among Americans, Italians and Ugandans with and without Kaposi's sarcoma. Nat Med 2:925–928. [DOI] [PubMed] [Google Scholar]
  • 19. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JKC, Cleary ML, Delsos G, De Wolf‐Peeters, Falini B, Gatter KC, Grogan TM, Isaacson PG, Knowles DM, Mason DY, Muller‐Hermelink HK, Pileri SA, Piris MA, Ralfkiaer E, Warnke RA (1994) A revised european‐american classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84:1361–1392. [PubMed] [Google Scholar]
  • 20. Jellinger KA, Paulus W (1995) Primary central nervous system lymphomas ‐ new pathological developments. J Neurooncol 24:33–36. [DOI] [PubMed] [Google Scholar]
  • 21. Jones JL, Hanson DL, Ward JW (1998) Effect of antiretroviral therapy on recent trends in cancers among HIV‐infected persons. The Second National AIDS Malignancy Conference. Bethesda, MD, April 6–8, [Abst S4]. J Acquir Immune Defic Syndr Hum Retrovirol 17:A39. [Google Scholar]
  • 22. Kwok S, Higuchi R (1989) Avoiding false positives with PCR. Nature 339:237–238. [DOI] [PubMed] [Google Scholar]
  • 23. Larocca LM, Capello D, Rinelli A, Nori S, Antinori S, Gloghini A, Cingolani A, Migliazza A, Saglio G, Cammilleri‐Broet S, Raphael M, Carbone A, Gaidano G (1998) The molecular and phenotypic profile of primary central nervous system lymphoma identifies distinct categories of the diseases and is consistent with histogenetic derivation from germinal center‐related B‐cells. Blood 92:1011–1019. [PubMed] [Google Scholar]
  • 24. Lennette ET, Blackbourne DJ, Levy JA (1996) Antibodies to human herpesvirus type 8 in the general population and in Kaposi's sarcoma patients. Lancet 348:858–861. [DOI] [PubMed] [Google Scholar]
  • 25. Levine AM (1993) AIDS‐related malignancies: the emerging epidemic. J Natl Cancer Inst 85:1382–1397. [DOI] [PubMed] [Google Scholar]
  • 26. Liedtke W, Trubner K, Schwechheimer K (1995) On the role of human herpesvirus 6 in viral latency in nervous tissue and in cerebral lymphoma. J Neurol Sci 134:184–188. [DOI] [PubMed] [Google Scholar]
  • 27. Lin JC, Lin SC, Mar EC, Pellett PE, Stamey FR, Stuart JA, Spira TJ (1995) Is Kaposi's sarcoma‐associated herpesvirus detectable in semen of HIV‐infected homosexual men. Lancet 346:1601–1602. [DOI] [PubMed] [Google Scholar]
  • 28. Luppi M, Barozzi P, Maiorana A, Artusi T, Trovato R, Marasca R, Savarino M, Ceccherini‐Nelli L, Torelli G (1996) Human herpesvirus‐8 DNA sequences in human immunodeficiency virus‐negative angioimmunoblastic lymphadenopathy and benign lymphadenopathy with giant germinal center hyperplasia and increased vascularity. Blood 87:3903–3909. [PubMed] [Google Scholar]
  • 29. MacKenzie J, Sheldon J, Morgan G, Cook G, Schultz TF, Jarret RF (1997) HHV‐8/KSHV and multiple myeloma in the UK. Lancet 350:1144–1145. [DOI] [PubMed] [Google Scholar]
  • 30. MacMahon EME, Glass JD, Hayward SD, Mann RB, Scott BP, Charache P, McArthur JC, Ambinder RF (1991) Epstein‐Barr virus in AIDS‐related primary central nervous system lymphoma. Lancet 338:969–973. [DOI] [PubMed] [Google Scholar]
  • 31. Maggiorella MT, Monardo F, Koanga‐Motomo ML, Cioe L, Sernicola L, Corrias F, Baroni CD, Verani P, Titti F (1998) Detection of infectious simian immunodeficiency virus in B‐ and T‐cell lymphomas of experimentally infected macaques. Blood 91:3103–3111. [PubMed] [Google Scholar]
  • 32. Marcelin AG, Dupin N, Bouscary D, Bossi P, Cacoub P, Ravaud P, Calvez V (1997) HHV‐8/KSHV and multiple myeloma in France. Lancet 350:1144. [DOI] [PubMed] [Google Scholar]
  • 33. Mikol J, Deplanche M, Moulinier A, Dupont B, Morinet F (1996) Herpesvirus‐like DNA sequences in primary non‐Hodgkin lymphomas of the central nervous system. J Neuropathol Exp Neurol 55:623. [Google Scholar]
  • 34. Miller G, Rigsby MO, Heston L, Grogan E, Sun R, Metroka C, Levy JA, Gao SJ, Chang Y, Moore PS (1996) Antibodies to butyrate‐inducible antigens of Kaposi's sarcoma‐associated herpesvirus in patients with HIV‐1 infection. N Engl J Med 334:1292–1297. [DOI] [PubMed] [Google Scholar]
  • 35. Monini P, De Lellis L, Fabris M, Rigolin F, Cassai E (1996) Kaposi's sarcoma‐associated herpesvirus DNA sequences in prostate tissue and human semen. N Engl J Med 334:1168–1172. [DOI] [PubMed] [Google Scholar]
  • 36. Moore PS (1998) Human herpesvirus 8 variant. Lancet 351:679–680. [DOI] [PubMed] [Google Scholar]
  • 37. Moore PS, Chang Y (1995) Detection of herpesvirus‐like DNA sequences in Kaposi's sarcoma lesions from persons with and without HIV infection. N Engl J Med 332:1181–1185. [DOI] [PubMed] [Google Scholar]
  • 38. Moore PS, Kingsley L, Holmberg SD, Spira T, Gupta P, Hoover DR, Parry JP, Conley LJ, Jaffe HW, Chang Y (1996) Kaposi's sarcoma‐associated herpesvirus infection prior to onset of Kaposi's sarcoma. AIDS 10:175–180. [DOI] [PubMed] [Google Scholar]
  • 39. Morgello S, Tagliati M, Ewart MR (1997) HHV‐8/KSHV and AIDS‐related CNS lymphoma. Neurology 48:1333–1335. [DOI] [PubMed] [Google Scholar]
  • 40. National Cancer Institute sponsored study of classifications of non‐Hodgkin's lymphomas (1982). Summary and description of a Working Formulation for clinical usage. Cancer 49:2112–2135. [DOI] [PubMed] [Google Scholar]
  • 41. Paulus W, Jellinger K, Hallas C, Ott G, Muller‐Hermelink HK (1993) Human herpesvirus‐6 and Epstein‐Barr virus genome in primary cerebral lymphoma. Neurology 43:1591–1993. [DOI] [PubMed] [Google Scholar]
  • 42. Rettig MB, Ma M, Pold M, Schiller G, Belson D, Savage A, Nishikubo C, Fraser J, Said JW, Barenson JR (1997) KSHV infection of multiple myeloma bone marrow stroma. Science 276:1851–1854. [DOI] [PubMed] [Google Scholar]
  • 43. Rezza G, Lennette ET, Giuliani M, Pezzotti P, Caprilli F, Monini P, Buttò S, Lodi G, Di Carlo A, Levy JA, Ensoli B (1998) Prevalence and determinants of anti‐lytic and anti‐latent antibodies to human herpesvirus‐8 among italian individuals at risk of sexually and parenterally transmitted infections. Int J Cancer 77:361–365. [DOI] [PubMed] [Google Scholar]
  • 44. Said JW, Rettig MB, Heppner K, Vescio RA, Schiller G, Ma HJ, Belson D, Savage A, Shintaku IP, Koeffler HP, Asou H, Pinkus G, Pinkus J, Schrage M, Green E, Berenson JR (1997) Localization of Kaposi's sarcoma‐associated herpesvirus in bone marrow biopsy samples from patients with multiple myeloma. Blood 90:4278–4282. [PubMed] [Google Scholar]
  • 45. Simpson GR, Schultz TF, Whitby D, Cook PM, Boshoff C, Rainbow L, Howard MR, Gao SJ, Bohenzky RA, Simmonds P, Lee C, De Ruiter A, Hatzakis A, Tedder RS, Weller IVD, Weiss R, Moore PS (1996) Prevalence of Kaposi's sarcoma associated herpesvirus infection mesured by antibodies to recombinant capsid protein and latent immunofluorescent antigens. Lancet 348:1133–1138. [DOI] [PubMed] [Google Scholar]
  • 46. Smith MS, Bloomer C, Horvat R, Goldstein E, Casparian JM, Chandran B (1997) Detection of human herpesvirus 8 DNA in Kaposi's sarcoma lesions and peripheral blood of human immunodeficiency virus‐positive patients and correlation with serologic measurements. J Infect Dis 176:84–93. [DOI] [PubMed] [Google Scholar]
  • 47. Soulier J, Grollet L, Oksenhendler E, Cacoub P, CazalsHatem D, Babinet P, D'Agai MF, Clauvel JP, Raphael M, Degos L, Sigaux F (1995) Kaposi's sarcoma‐associated herpesvirus‐like DNA sequences in multicentric Castelman's disease. Blood 86:1276–1280. [PubMed] [Google Scholar]
  • 48. Tarte K, Holsen SJ, Lu ZY, Legouffe E, Rossi JF, Chang Y, Klein B (1998) Clinical‐grade functional dentritic cells from patients with multiple myeloma are not infected with Kaposi's sarcoma‐associated herpesvirus. Blood 91:1852–1857. [PubMed] [Google Scholar]
  • 49. Whitby D, Howard MR, Tenant‐Flowers M, Brink NS, Copas A, Boshoff C, Hatzioannou T, Suggett FEA, Aldam DM, Denton AS, Miller RF, Weller IVD, Weiss RA, Tedder RS, Schulz TF (1995) Detection of Kaposi sarcoma associated herpesvirus in peripheral blood of HIV‐infected individuals and progression to Kaposi's sarcoma. Lancet 346:799–802. [DOI] [PubMed] [Google Scholar]
  • 50. Whitby D, Luppi M, Barozzi P, Boshoff C. Weiss RA, Torelli G (1998) Human herpesvirus 8 seroprevalence in blood donors and lymphoma patientsfrom different regions of Italy. J Natl Cancer Inst 90:395–397. [DOI] [PubMed] [Google Scholar]
  • 51. Yi Q, Ekman M, Anton D, Bergenbrant S, Österborg A, Georgii‐Hemming P, Holm G, Nilsson K, Biberfeld P (1998) Blood dendritic cells from myeloma patients are not infected with Kaposi's sarcoma‐associated Herpesvirus (KSHV/HHV‐8). Blood 92:402–404. [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES