Rapid Emergence of T Follicular Helper and Germinal Center B Cells Following Antiretroviral Therapy in Advanced HIV Disease

Front Immunol. 2021 Dec 1:12:752782. doi: 10.3389/fimmu.2021.752782. eCollection 2021.


Low nadir CD4 T-cell counts in HIV+ patients are associated with high morbidity and mortality and lasting immune dysfunction, even after antiretroviral therapy (ART). The early events of immune recovery of T cells and B cells in severely lymphopenic HIV+ patients have not been fully characterized. In a cohort of lymphopenic (CD4 T-cell count < 100/µL) HIV+ patients, we studied mononuclear cells isolated from peripheral blood (PB) and lymph nodes (LN) pre-ART (n = 40) and 6-8 weeks post-ART (n = 30) with evaluation of cellular immunophenotypes; histology on LN sections; functionality of circulating T follicular helper (cTfh) cells; transcriptional and B-cell receptor profile on unfractionated LN and PB samples; and plasma biomarker measurements. A group of 19 healthy controls (HC, n = 19) was used as a comparator. T-cell and B-cell lymphopenia was present in PB pre-ART in HIV+ patients. CD4:CD8 and CD4 T- and B-cell PB subsets partly normalized compared to HC post-ART as viral load decreased. Strikingly in LN, ART led to a rapid decrease in interferon signaling pathways and an increase in Tfh, germinal center and IgD-CD27- B cells, consistent with histological findings of post-ART follicular hyperplasia. However, there was evidence of cTfh cells with decreased helper capacity and of limited B-cell receptor diversification post-ART. In conclusion, we found early signs of immune reconstitution, evidenced by a surge in LN germinal center cells, albeit limited in functionality, in HIV+ patients who initiate ART late in disease.

Keywords: HIV; T follicular helper cells; germinal centers; interferon; reconstitution.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Acquired Immunodeficiency Syndrome / blood
  • Acquired Immunodeficiency Syndrome / drug therapy*
  • Acquired Immunodeficiency Syndrome / immunology
  • Adult
  • Anti-HIV Agents / pharmacology
  • Anti-HIV Agents / therapeutic use*
  • Antibodies, Viral / blood
  • B-Lymphocytes / immunology*
  • Coculture Techniques
  • Female
  • Germinal Center / immunology*
  • Germinal Center / pathology
  • Hemoglobins / analysis
  • Humans
  • Hyperplasia
  • Lymph Nodes / immunology
  • Lymphocyte Count
  • Lymphocyte Subsets / immunology*
  • Male
  • Middle Aged
  • Receptors, Antigen, B-Cell / genetics
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Transcription, Genetic
  • Viral Load
  • Viremia / drug therapy*
  • Viremia / immunology
  • Young Adult


  • Anti-HIV Agents
  • Antibodies, Viral
  • Hemoglobins
  • Receptors, Antigen, B-Cell