Strong TH1-biased CD4 T cell responses are associated with diminished SIV vaccine efficacy

Sci Transl Med. 2019 Nov 20;11(519):eaav1800. doi: 10.1126/scitranslmed.aav1800.


Activated CD4 T cells are a major target of HIV infection. Results from the STEP HIV vaccine trial highlighted a potential role for total activated CD4 T cells in promoting HIV acquisition. However, the influence of vaccine insert-specific CD4 T cell responses on HIV acquisition is not known. Here, using the data obtained from four macaque studies, we show that the DNA prime/modified vaccinia Ankara boost vaccine induced interferon γ (IFNγ+) CD4 T cells [T helper 1 (TH1) cells] rapidly migrate to multiple tissues including colon, cervix, and vaginal mucosa. These mucosal TH1 cells persisted at higher frequencies and expressed higher density of CCR5, a viral coreceptor, compared to cells in blood. After intravaginal or intrarectal simian immunodeficiency virus (SIV)/simian-human immunodeficiency virus (SHIV) challenges, strong vaccine protection was evident only in animals that had lower frequencies of vaccine-specific TH1 cells but not in animals that had higher frequencies of TH1 cells, despite comparable vaccine-induced humoral and CD8 T cell immunity in both groups. An RNA transcriptome signature in blood at 7 days after priming immunization from one study was associated with induction of fewer TH1-type CD4 cells and enhanced protection. These results demonstrate that high and persisting frequencies of HIV vaccine-induced TH1-biased CD4 T cells in the intestinal and genital mucosa can mitigate beneficial effects of protective antibodies and CD8 T cells, highlighting a critical role of priming immunization and vaccine adjuvants in modulating HIV vaccine efficacy.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Viral / immunology
  • Antibody Formation / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Colon / pathology
  • Female
  • Gene Expression Profiling
  • Interferon-gamma / metabolism
  • Lymphocyte Count
  • Macaca mulatta
  • Male
  • Mucous Membrane / pathology
  • Receptors, CCR5 / metabolism
  • SAIDS Vaccines / immunology*
  • Simian Acquired Immunodeficiency Syndrome / blood
  • Simian Acquired Immunodeficiency Syndrome / drug therapy*
  • Simian Acquired Immunodeficiency Syndrome / genetics
  • Simian Acquired Immunodeficiency Syndrome / immunology*
  • Simian Immunodeficiency Virus / immunology*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Treatment Outcome
  • Vaccination
  • Vagina / immunology
  • Vagina / virology


  • Antibodies, Viral
  • Receptors, CCR5
  • SAIDS Vaccines
  • Interferon-gamma