Relationship of HIV reservoir characteristics with immune status and viral rebound kinetics in an HIV therapeutic vaccine study

Li, Jonathan Z.a; Heisey, Andreaa; Ahmed, Hayata; Wang, Hongyingb; Zheng, Lub; Carrington, Maryc,d; Wrin, Terrie; Schooley, Robert T.f; Lederman, Michael M.g; Kuritzkes, Daniel R.a; the ACTG A5197 Study Team

doi: 10.1097/QAD.0000000000000478
Basic Science

Objectives: The objective of this study is to evaluate the impact of therapeutic HIV vaccination on the HIV reservoir and assess the relationship of the viral reservoir with HIV-specific immune status and viral rebound kinetics.

Design: A retrospective analysis of ACTG A5197, a randomized, placebo-controlled trial of a therapeutic rAd5 HIV-1 gag vaccine.

Methods: Participants received vaccine/placebo at weeks 0, 4 and 26 prior to a 16-week analytic treatment interruption (ATI) at week 38. Cell-associated HIV-1 RNA and DNA (CA-RNA and CA-DNA) and HIV-1 residual viremia were quantified at weeks 0, 8 and 38. HIV-specific CD4+/CD8+ activity was assessed by an intracellular cytokine staining assay.

Results: At study entry, CA-RNA and CA-DNA levels were correlated inversely with the numbers of HIV-specific CD4+ interferon-γ producing cells (CA-RNA: r = −0.23, P = 0.03 and CA-DNA: r = −0.28, P < 0.01, N = 93). Therapeutic HIV vaccination induced HIV-specific CD4+ activity, but did not significantly affect levels of CA-RNA or CA-DNA. Vaccine recipients with undetectable residual viremia at week 8 had higher frequencies of HIV-specific CD4+ and CD8+ interferon-γ producing cells (undetectable versus detectable residual viremia: 277 versus 161 CD4+ cells/106 lymphocytes, P = 0.03 and 1326 versus 669 CD8+ cells/106 lymphocytes, P = 0.04). Pre-ATI CA-RNA and CA-DNA were associated with post-ATI plasma HIV set point (CA-RNA: r = 0.51, P < 0.01 and CA-DNA: r = 0.47, P < 0.01).

Conclusion: Vaccine-induced T-cell responses were associated with a modest transient effect on residual viremia, but more potent immune responses and/or combination treatment with latency-reversing agents are needed to reduce the HIV reservoir. HIV reservoir measures may act as biomarkers of post-ATI viral rebound kinetics.

Clinical Trials Registration: NCT00080106.

aBrigham and Women's Hospital, Harvard Med School

bHarvard School of Public Health, Boston, Massachusetts

cCancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Institute, Frederick National Laboratory for Cancer Research, Frederick, Maryland

dRagon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts

eMonogram Biosciences

fUniversity of California, San Diego, La Jolla, California

gCase Western Reserve University, Cleveland, Ohio, USA.

Correspondence to Jonathan Z. Li, MD, Division of Infectious Diseases, Brigham and Women's Hospital, 65 Landsdowne Street, Rm 421, Cambridge, MA 02139, USA. E-mail: Jli22@partners.org

Received 30 May, 2014

Revised 29 August, 2014

Accepted 29 August, 2014

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© 2014 Lippincott Williams & Wilkins, Inc.