Herpes simplex virus lymphadenitis is associated with tumor reduction in a patient with chronic lymphocytic leukemia
Andres Chang, … , Christopher R. Flowers, Rafi Ahmed
Andres Chang, … , Christopher R. Flowers, Rafi Ahmed
Published July 21, 2022
Citation Information: J Clin Invest. 2022;132(18):e161109. https://doi.org/10.1172/JCI161109.
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Clinical Research and Public Health Hematology Immunology Article has an altmetric score of 7

Herpes simplex virus lymphadenitis is associated with tumor reduction in a patient with chronic lymphocytic leukemia

Abstract

Background Herpes simplex virus lymphadenitis (HSVL) is an unusual presentation of HSV reactivation in patients with chronic lymphocytic leukemia (CLL) and is characterized by systemic symptoms and no herpetic lesions. The immune responses during HSVL have not, to our knowledge, been studied.Methods Peripheral blood and lymph node (LN) samples were obtained from a patient with HSVL. HSV-2 viral load, antibody levels, B and T cell responses, cytokine levels, and tumor burden were measured.Results The patient showed HSV-2 viremia for at least 6 weeks. During this period, she had a robust HSV-specific antibody response with neutralizing and antibody-dependent cellular phagocytotic activity. Activated (HLA-DR+, CD38+) CD4+ and CD8+ T cells increased 18-fold, and HSV-specific CD8+ T cells in the blood were detected at higher numbers. HSV-specific B and T cell responses were also detected in the LN. Markedly elevated levels of proinflammatory cytokines in the blood were also observed. Surprisingly, a sustained decrease in CLL tumor burden without CLL-directed therapy was observed with this and also a prior episode of HSVL.Conclusion HSVL should be considered part of the differential diagnosis in patients with CLL who present with signs and symptoms of aggressive lymphoma transformation. An interesting finding was the sustained tumor control after 2 episodes of HSVL in this patient. A possible explanation for the reduction in tumor burden may be that the HSV-specific response served as an adjuvant for the activation of tumor-specific or bystander T cells. Studies in additional patients with CLL are needed to confirm and extend these findings.Funding NIH grants 4T32CA160040, UL1TR002378, and 5U19AI057266 and NIH contracts 75N93019C00063 and HHSN261200800001E. Neil W. and William S. Elkin Fellowship (Winship Cancer Institute).

Authors

Andres Chang, Anton M. Sholukh, Andreas Wieland, David L. Jaye, Mary Carrington, Meei-Li Huang, Hong Xie, Keith R. Jerome, Pavitra Roychoudhury, Alexander L. Greninger, Jean L. Koff, Jonathon B. Cohen, David M. Koelle, Lawrence Corey, Christopher R. Flowers, Rafi Ahmed

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Figure 2

Vigorous HSV-specific B cell responses were observed in the blood and LN.

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Vigorous HSV-specific B cell responses were observed in the blood and LN...
(A) Quantification of plasmablasts per million live PBMCs in the blood over time. Red indicates the viral titer depicted in Figure 1C. (B) Flow cytometric analysis shows plasmablasts in the LN (left). ELISPOT assay (right) shows that LN plasmablasts secreted HSV-2–specific IgG antibodies. (C) Persistent hypogammaglobulinemia was observed in this patient. Shaded area indicates the expected normal range. (D) Relative IgG-binding titers against HSV-2 lysates by ELISA (blue) and neutralizing antibody titers leading to a 50% reduction in virus infectivity (black). Error bars indicate the SEM. Positive control neutralizing antibody titer = 1:256. (E) IgG, IgA, and IgM antibody binding to different HSV-2 surface proteins at each time point versus pooled plasma from HSV-2+ and HSV-1/-2– controls. White denotes the sample not analyzed. (F) HSV-2 ADCP score (in thousands) of gD2-covered microspheres incubated with plasma from each time point. ADCP score for pooled healthy HSV-2+ control = 111,320. Error bars indicate the SD. (G) IgG subclass analysis of antibodies that bound to HSV-2 surface proteins at each time point versus pooled plasma from HSV-2+ and HSV-1/-2– controls. For E and G, antibody binding to influenza HA (FluHA) was included as a control. Heatmap scale reflects the endpoint titer in log2. All measurements were performed in duplicate. For all applicable graphs, the vertical dotted line indicates the time of presentation. Day, days since symptom onset.