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HIV-1 evolution in patients undergoing immunotherapy with Tat, Rev, and Nef expressing dendritic cells followed by treatment interruption

de Goede, Anna L.a,b; van Deutekom, Hanneke W.M.c; Vrancken, Bramd; Schutten, Martina; Allard, Sabine D.f; van Baalen, Carel A.a; Osterhaus, Albert D.M.E.a; Thielemans, Krise; Aerts, Joeri L.e; Keşmir, Canc; Lemey, Philipped; Gruters, Rob A.a

doi: 10.1097/01.aids.0000433813.67662.92
Basic Science

Objectives: This study aimed to evaluate HIV sequence evolution in whole genes and in CD8+ T-cell epitope regions following immunotherapy and subsequent analytical treatment interruption (ATI). A second objective of this study was to analyze associations between vaccine-specific immune responses and epitope mutation rates.

Design: HIV-1-infected patients on combined antiretroviral therapy (cART) were subjected to immunotherapy by the administration of an autologous dendritic cell-based therapeutic vaccine expressing Tat, Rev, and Nef and subsequent ATI.

Methods: HIV-1 genes were amplified and sequenced from plasma RNA obtained before initiation of cART as well as during ATI. Control sequences for virus evolution in untreated HIV-1-infected individuals were obtained from the HIV Sequence Database (Los Alamos). CD8+ T-cell epitope regions were defined based on literature data and prediction models. HIV-1-specific immune responses were evaluated to analyze their impact on sequence evolution.

Results: Viral sequence evolution in the tat, rev, and nef genes of vaccinated patients was similar to that of controls. The number of mutations observed inside and outside CD8+ T-cell epitopes was comparable for vaccine-targeted and nontargeted proteins. We found no evidence for an impact of vaccine-induced or enhanced immune responses on the number of mutations inside or outside epitopes.

Conclusion: Therapeutic vaccination of HIV-1-infected patients with a dendritic cell-based vaccine targeting Tat, Rev, and Nef did not affect virus evolution at the whole gene level nor at the CD8+ T-cell epitope level.

aDepartment of Viroscience

bDepartment of Hospital Pharmacy, Erasmus MC, Rotterdam

cTheoretical Biology and Bioinformatics, Utrecht University, Utrecht, the Netherlands

dDepartment of Microbiology and Immunology, Rega Institute, KU Leuven, Leuven

eLaboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Medical School of the Vrije Universiteit Brussel

fDepartment of Internal Medicine and Infectious Diseases, Universitair Ziekenhuis Brussel, Brussels, Belgium.

Correspondence to Rob A. Gruters, Erasmus MC, Rotterdam, 's-Gravendijkwal 230, PO Box 2040, 3000 CA Rotterdam, the Netherlands. Tel: +31 10 7044063; fax: +31 10 7044760; e-mail: r.gruters@erasmusmc.nl

Received 15 July, 2013

Accepted 18 July, 2013

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© 2013 Lippincott Williams & Wilkins, Inc.