The EBV-HIV interrelationship and the value of EBV-DNA analysis

Epstein-Barr virus (EBV) infects the vast majority of humans and resides latently in B-cells. This virus carries genes that can induce and sustain mature B cell growth. EBV is associated with a wide range of B-cell lymphomas including Burkitt lymphoma and non Hodgkin lymphoma (NHL) in human immunodeficiency virus 1 (HIV-1) infected patients. Latent EBV infection in B lymphocytes is a risk factor for B-cell lymphomas in conditions of combined antigen stimulation and immunosuppression as with Burkitts lymphoma in malaria endemic African regions and non Hodgkin lymphoma in HIV-1 infected patients. In the era of modern combination antiretroviral therapy (cART) there has been an impressive reduction of Acquired Immunodeficiency syndrome (AIDS)-related opportunistic infections and lymphomas, although patients still suffer an increased risk for NHL. This work is based on EBV-DNA load measurement in blood as a tool to analyse EBV-host relationship in HIV-1 infection.

In general HIV-1 infected individuals have a higher EBV-DNA load and symptomatic HIV-1 infected even higher. Individual variables, immunological factors and treatments as cART affect this pattern. In one of our studies we identified one group and one risk factor that influenced EBV-DNA load. HIV-1 infected individuals with a history of a symptomatic primary infection in combination with induced immune stimulation by therapeutic vaccination/adjuvant showed an increased load. Without the vaccination/adjuvant stimuli this group did not show the same increase. HIV-1 infected patients with a history of a symptomatic primary infection might therefore be at risk for developing NHL. Therapeutic vaccination/adjuvant increases the EBV- DNA load and we regard this immunomodulation as a risk factor. Different pattern of EBV- host restoration by cART was seen in a long term follow of patients with increased EBV-DNA load after vaccination. The EBV-host relation seems to be reconditioned by successful cART treatment, measured by the CD4+ cell count returning to normal levels, with some reservation for the functional restoration, together with remaining undetectable HIV-1 RNA. For individuals with unsuccessful cART treatment the distinct decrease of EBV-DNA could not be seen. In a patient treated for EBV positive plasmablastic lymphoma we observed a sharp increase of EBV-DNA load before clinical signs of recurrence.

Measurement of EBV-DNA load is valuable in monitoring disease progression in HIV-1 infected patients. After cART treatment the dynamics of EBV-DNA load reveal if the antiviral treatment is suboptimal, even if breakthroughs detected as HIV RNA peaks are missed. When an EBV positive tumour is treated successfully EBV-DNA monitoring can be of importance to observe early signs of relapse. Monitoring EBV-DNA load during therapeutic vaccination studies seems highly motivated. In conclusion EBV-DNA load analysis is a useful additional instrument to monitor different groups of HIV-1 patients with increased risk for lymphoma development.

List of scientific papers

I. Anna M.C. Friis, Katarina Gyllensten, Anna Aleman, Ingemar Ernberg, and Börje Åkerlund. The Effect of Antiretroviral Combination Treatment on Epstein-Barr Virus (EBV) Genome Load in HIV-Infected Patients. Viruses. 2010; 2: 867–879.
https://doi.org/10.3390/v2040867

II. Anna M.C. Friis, Börje Åkerlund, Katarina Gyllensten, Anna Aleman, Ingemar Ernberg. Host-Epstein-Barr virus relationship affected by immunostimulation in HIV-infected patients representing distinct progressor profile groups. Scand J Infect Dis. 2012 May; 44(5):388-92.
https://doi.org/10.3109/00365548.2011.645503

III. Anna M.C. Friis, Börje Åkerlund, Katarina Gyllensten, Anna Aleman, Eric Sandström, Göran Bratt, Ingemar Ernberg. Epstein-Barr virus genome load is increased by therapeutic vaccination in HIV-l carriers, and further enhanced after a history of symptomatic primary infection. [Submitted]

IV. Anna M.C. Friis, Birger Christensson, Katarina Gyllensten, Anna Aleman, Jie-Zhi Zou, Börje Åkerlund, Ingemar Ernberg. EBV-DNA analysis in blood predicts disease progression in a rare case of plasmablastic lymphoma with effusion. [Manuscript]