Diagnosis and antiviral therapy of human herpesvirus 8 infection
- Corey Casper, MD, MPH
Corey Casper, MD, MPH
- Professor of Medicine
- University of Washington and Fred Hutchinson Cancer Research Center
The first disease associated with human herpesvirus 8 (HHV-8) infection was Kaposi sarcoma (KS). Subsequently, several other conditions, such as primary effusion lymphoma (PEL, also known as body cavity based lymphoma) and Castleman's disease (CD), were also linked to this virus. A severe inflammatory syndrome attributed to interleukin-6 production has also been described among HHV-8 infected individuals and is known as the Kaposi sarcoma-associated herpesvirus inflammatory cytokine syndrome (KICKS) . Host factors and other related issues influence disease expression, since HHV-8 infection is relatively common. The onset of disease typically occurs several years after acquisition of infection. HHV-8 can also induce a primary infection characterized by fever and a maculopapular rash in children and more marked manifestations in immunocompromised individuals.
The diagnosis of HHV-8 infection and the possible role of antiviral therapy will be reviewed here. The epidemiology, mode of transmission, and disease associations of HHV-8 infection are discussed separately. (See "Virology, epidemiology, and transmission of human herpesvirus 8 infection" and "Disease associations of human herpesvirus 8 infection".)
The development of diagnostic testing for human herpesvirus 8 (HHV-8) has been hampered by the lack of a cell line that can serve as a culture system for isolating the virus from tissue or mucosal sites. The identification of HHV-8 positive immortalized lymphoma cell lines (eg, BCBL-1, KS-1) has been an important step in maintaining virus for study and in the development of serologic testing. These cell lines contain latent virus in an episomal form that can be stimulated by phorbol esters or butyrate into active replication with production of intact virions .
Polymerase chain reaction — Several different polymerase chain reaction (PCR) assays employing primers unique for HHV-8 have been described. HHV-8 DNA can be identified using PCR in virtually all biopsies of Kaposi sarcoma (KS), including AIDS-associated KS, classic KS, and endemic KS [3-9].
PCR techniques for investigation of disease associations and molecular epidemiology have proven to be of enormous value, but the following caveats must be kept in mind:
- Uldrick TS, Wang V, O'Mahony D, et al. An interleukin-6-related systemic inflammatory syndrome in patients co-infected with Kaposi sarcoma-associated herpesvirus and HIV but without Multicentric Castleman disease. Clin Infect Dis 2010; 51:350.
- Cesarman E, Moore PS, Rao PH, et al. In vitro establishment and characterization of two acquired immunodeficiency syndrome-related lymphoma cell lines (BC-1 and BC-2) containing Kaposi's sarcoma-associated herpesvirus-like (KSHV) DNA sequences. Blood 1995; 86:2708.
- Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 1994; 266:1865.
- Moore PS, Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med 1995; 332:1181.
- Chuck S, Grant RM, Katongole-Mbidde E, et al. Frequent presence of a novel herpesvirus genome in lesions of human immunodeficiency virus-negative Kaposi's sarcoma. J Infect Dis 1996; 173:248.
- Buonaguro FM, Tornesello ML, Beth-Giraldo E, et al. Herpesvirus-like DNA sequences detected in endemic, classic, iatrogenic and epidemic Kaposi's sarcoma (KS) biopsies. Int J Cancer 1996; 65:25.
- Sitas F, Carrara H, Beral V, et al. Antibodies against human herpesvirus 8 in black South African patients with cancer. N Engl J Med 1999; 340:1863.
- Purvis SF, Katongole-Mbidde E, Johnson JL, et al. High incidence of Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus in tumor lesions and peripheral blood mononuclear cells from patients with Kaposi's sarcoma in Uganda. J Infect Dis 1997; 175:947.
- Dupin N, Grandadam M, Calvez V, et al. Herpesvirus-like DNA sequences in patients with Mediterranean Kaposi's sarcoma. Lancet 1995; 345:761.
- Taylor MM, Chohan B, Lavreys L, et al. Shedding of human herpesvirus 8 in oral and genital secretions from HIV-1-seropositive and -seronegative Kenyan women. J Infect Dis 2004; 190:484.
- Engels EA, Biggar RJ, Marshall VA, et al. Detection and quantification of Kaposi's sarcoma-associated herpesvirus to predict AIDS-associated Kaposi's sarcoma. AIDS 2003; 17:1847.
- Campbell TB, Borok M, Gwanzura L, et al. Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi's sarcoma clinical stage. AIDS 2000; 14:2109.
- Johnston C, Orem J, Okuku F, et al. Impact of HIV infection and Kaposi sarcoma on human herpesvirus-8 mucosal replication and dissemination in Uganda. PLoS One 2009; 4:e4222.
- Borok M, Fiorillo S, Gudza I, et al. Evaluation of plasma human herpesvirus 8 DNA as a marker of clinical outcomes during antiretroviral therapy for AIDS-related Kaposi sarcoma in Zimbabwe. Clin Infect Dis 2010; 51:342.
- Oksenhendler E, Carcelain G, Aoki Y, et al. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients. Blood 2000; 96:2069.
- Casper C, Nichols WG, Huang ML, et al. Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. Blood 2004; 103:1632.
- Sayer R, Paul J, Tuke PW, et al. Can plasma HHV8 viral load be used to differentiate multicentric Castleman disease from Kaposi sarcoma? Int J STD AIDS 2011; 22:585.
- Lennette ET, Blackbourn DJ, Levy JA. Antibodies to human herpesvirus type 8 in the general population and in Kaposi's sarcoma patients. Lancet 1996; 348:858.
- Gao SJ, Kingsley L, Hoover DR, et al. Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma. N Engl J Med 1996; 335:233.
- Rabkin CS, Schulz TF, Whitby D, et al. Interassay correlation of human herpesvirus 8 serologic tests. HHV-8 Interlaboratory Collaborative Group. J Infect Dis 1998; 178:304.
- Enbom M, Sheldon J, Lennette E, et al. Antibodies to human herpesvirus 8 latent and lytic antigens in blood donors and potential high-risk groups in Sweden: variable frequencies found in a multicenter serological study. J Med Virol 2000; 62:498.
- Topino S, Vincenzi L, Mezzaroma I, et al. Correlation between enzyme-linked immunosorbent assay and immunofluorescence assay with lytic antigens for detection of antibodies to human herpesvirus 8. Clin Diagn Lab Immunol 2001; 8:203.
- Kedes DH, Lagunoff M, Renne R, Ganem D. Identification of the gene encoding the major latency-associated nuclear antigen of the Kaposi's sarcoma-associated herpesvirus. J Clin Invest 1997; 100:2606.
- Olsen SJ, Sarid R, Chang Y, Moore PS. Evaluation of the latency-associated nuclear antigen (ORF73) of Kaposi's sarcoma-associated herpesvirus by peptide mapping and bacterially expressed recombinant western blot assay. J Infect Dis 2000; 182:306.
- Simpson GR, Schulz TF, Whitby D, et al. Prevalence of Kaposi's sarcoma associated herpesvirus infection measured by antibodies to recombinant capsid protein and latent immunofluorescence antigen. Lancet 1996; 348:1133.
- Davis DA, Humphrey RW, Newcomb FM, et al. Detection of serum antibodies to a Kaposi's sarcoma-associated herpesvirus-specific peptide. J Infect Dis 1997; 175:1071.
- Chandran B, Bloomer C, Chan SR, et al. Human herpesvirus-8 ORF K8.1 gene encodes immunogenic glycoproteins generated by spliced transcripts. Virology 1998; 249:140.
- Chatlynne LG, Lapps W, Handy M, et al. Detection and titration of human herpesvirus-8-specific antibodies in sera from blood donors, acquired immunodeficiency syndrome patients, and Kaposi's sarcoma patients using a whole virus enzyme-linked immunosorbent assay. Blood 1998; 92:53.
- André S, Schatz O, Bogner JR, et al. Detection of antibodies against viral capsid proteins of human herpesvirus 8 in AIDS-associated Kaposi's sarcoma. J Mol Med (Berl) 1997; 75:145.
- Casper C, Krantz E, Taylor H, et al. Assessment of a combined testing strategy for detection of antibodies to human herpesvirus 8 (HHV-8) in persons with Kaposi's sarcoma, persons with asymptomatic HHV-8 infection, and persons at low risk for HHV-8 infection. J Clin Microbiol 2002; 40:3822.
- Spira TJ, Lam L, Dollard SC, et al. Comparison of serologic assays and PCR for diagnosis of human herpesvirus 8 infection. J Clin Microbiol 2000; 38:2174.
- Engels EA, Whitby D, Goebel PB, et al. Identifying human herpesvirus 8 infection: performance characteristics of serologic assays. J Acquir Immune Defic Syndr 2000; 23:346.
- Burbelo PD, Issa AT, Ching KH, et al. Distinct profiles of antibodies to Kaposi sarcoma-associated herpesvirus antigens in patients with Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma. J Infect Dis 2010; 201:1919.
- Kedes DH, Ganem D. Sensitivity of Kaposi's sarcoma-associated herpesvirus replication to antiviral drugs. Implications for potential therapy. J Clin Invest 1997; 99:2082.
- Medveczky MM, Horvath E, Lund T, Medveczky PG. In vitro antiviral drug sensitivity of the Kaposi's sarcoma-associated herpesvirus. AIDS 1997; 11:1327.
- Neyts J, De Clercq E. Antiviral drug susceptibility of human herpesvirus 8. Antimicrob Agents Chemother 1997; 41:2754.
- Flore O, Gao SJ. Effect of DNA synthesis inhibitors on Kaposi's sarcoma-associated herpesvirus cyclin and major capsid protein gene expression. AIDS Res Hum Retroviruses 1997; 13:1229.
- Cannon JS, Hamzeh F, Moore S, et al. Human herpesvirus 8-encoded thymidine kinase and phosphotransferase homologues confer sensitivity to ganciclovir. J Virol 1999; 73:4786.
- Casper C, Wald A. The use of antiviral drugs in the prevention and treatment of Kaposi sarcoma, multicentric Castleman disease and primary effusion lymphoma. Curr Top Microbiol Immunol 2007; 312:289.
- Gantt S, Carlsson J, Ikoma M, et al. The HIV protease inhibitor nelfinavir inhibits Kaposi's sarcoma-associated herpesvirus replication in vitro. Antimicrob Agents Chemother 2011; 55:2696.
- Sgadari C, Monini P, Barillari G, Ensoli B. Use of HIV protease inhibitors to block Kaposi's sarcoma and tumour growth. Lancet Oncol 2003; 4:537.
- Casper C, Krantz EM, Corey L, et al. Valganciclovir for suppression of human herpesvirus-8 replication: a randomized, double-blind, placebo-controlled, crossover trial. J Infect Dis 2008; 198:23.
- Boivin G, Gaudreau A, Toma E, et al. Human herpesvirus 8 DNA load in leukocytes of human immunodeficiency virus-infected subjects: correlation with the presence of Kaposi's sarcoma and response to anticytomegalovirus therapy. Antimicrob Agents Chemother 1999; 43:377.
- Cattamanchi A, Saracino M, Selke S, et al. Treatment with valacyclovir, famciclovir, or antiretrovirals reduces human herpesvirus-8 replication in HIV-1 seropositive men. J Med Virol 2011; 83:1696.