In Vivo Treatment with Insulin-like Growth Factor 1 Reduces CCR5 Expression on Vaccine-Induced Activated CD4+ T-Cells

Author:

Bissa, Massimiliano [ORCID]

Galli, Veronica

Schifanella, Luca

Vaccari, Monica

Rahman, Mohammad Arif [ORCID]

Gorini, Giacomo

Binello, Nicolò

Sarkis, Sarkis

Gutowska, Anna [ORCID]

Silva de Castro, Isabela

Doster, Melvin N

Moles, Ramona

Ferrari, Guido

Shen, Xiaoying

Tomaras, Georgia D

Montefiori, David C

N'guessan, Kombo F

Paquin-Proulx, Dominic [ORCID]

Kozlowski, Pamela A [ORCID]

Venzon, David J [ORCID]

Choo-Wosoba, Hyoyoung

Breed,Matthew

Kramer,Josh

Franchini, Genoveffa
Author Address

Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, MD 20892, USA., Tulane National Primate Center & School of Medicine, Tulane University, Covington, LA 70118, USA., Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA., US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA., Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA., Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA., Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA., Laboratory Animal Sciences Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, MD 21701, USA.,

Abstract:

At the heart of the DNA/ALVAC/gp120/alum vaccine 39;s efficacy in the absence of neutralizing antibodies is a delicate balance of pro- and anti-inflammatory immune responses that effectively decreases the risk of SIVmac251 acquisition in macaques. Vaccine efficacy is linked to antibodies recognizing the V2 helical conformation, DC-10 tolerogenic dendritic cells eliciting the clearance of apoptotic cells via efferocytosis, and CCR5 downregulation on vaccine-induced gut homing CD4+ cells. RAS activation is also linked to vaccine efficacy, which prompted the testing of IGF-1, a potent inducer of RAS activation with vaccination. We found that IGF-1 changed the hierarchy of V1/V2 epitope recognition and decreased both ADCC specific for helical V2 and efferocytosis. Remarkably, IGF-1 also reduced the expression of CCR5 on vaccine-induced CD4+ gut-homing T-cells, compensating for its negative effect on ADCC and efferocytosis and resulting in equivalent vaccine efficacy (71% with IGF-1 and 69% without).

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Author Address