HIV-1 sequence evolution after dendritic cell-based immune therapy

Anna De Goede, Brenda De Keersmaecker, M Schutten, Sabine Allard, Jeanette Koetsveld, Jurgen Corthals, Ab Osterhaus, Carlo Heirman, Carel A. Van Baalen, Patrick Lacor, M.e. Van Der Ende, Kris Thielemans, Rob A. Gruters, Joeri Aerts

Research output: Chapter in Book/Report/Conference proceedingMeeting abstract (Book)

Abstract

Background: Therapeutic vaccination of HIV infected patients is explored as an alternative to antiretroviral therapy (HAART). In a phase I/II clinical trial HIV infected participants were treated with autologous dendritic cells (DC) expressing the early HIV proteins Tat, Rev and Nef. We evaluated the effect of immune therapy on the cellular immune response and the impact on the viral genome by analysis of HIV genotype evolution.
Methods: Seventeen asymptomatic HIV-1 infected patients on HAART therapy were treated with a DC-based vaccine. The vaccine consisted of autologous mature DC electroporated separately with mRNA expressing Tat, Rev and Nef and each formulation was administered at a distinct anatomical site. After four monthly vaccinations HAART treatment was interrupted. PBMC taken at 4 time points were used for stimulation with pools of overlapping Tat, Rev, Nef and Gag peptides and the number of IFN-g producing cells was analyzed using Elispot (peptide Elispot). Elispot was also performed using electroporated DC (DC Elispot) for in vitro re-stimulation.
For sequence analysis, HIV RNA was extracted and partly amplified by RT-PCR. The open reading frames of the genes present in the vaccine (tat, rev and nef) and the control genes (vif, vpr and vpu) were analyzed. Variation in DNA and protein sequences from pre-HAART and (early) post vaccination was analyzed. HIV sequences spanning known and predicted epitopes of the relevant HLA alleles from each participant were analyzed in detail.
Results:
In 12 out of 16 patients screened with both peptide and DC Elispot, increased post-vaccination responses to vaccine-antigens were found. For 12/17 patients a complete set of both pre-HAART and post-vaccination sequences for the vaccine and control genes could be obtained. With one exception, variation in pre-HAART and post vaccination HIV sequences was limited, in all genes examined. Viral sequences spanning specific epitopes for the individual participants were examined in further detail. Although we could find evidence for viral evolution in these epitopes, this was not a common phenomenon.
Conclusions:
Immune therapy with autologous DC expressing Tat Rev and Nef was well-tolerated and did not have adverse effects. Increased cellular immunity against the immunogens was found with both assays. There was no significant correlation between the breadth and/or extent of the immune response after vaccination and the rate of virus evolution.

Keywords: HIV-1, immune therapy, immune assays, sequence analysis, virus evolution

Corresponding author: r.gruters@erasmusmc.nl
Original languageEnglish
Title of host publicationNVZA congress 2009, The Netherlands
Publication statusPublished - 2009

Keywords

  • HIV-1
  • immune therapy
  • immune assays
  • sequence analysis
  • virus evolution

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