Therapeutic immunisation plus cytokine and hormone therapy improves CD4 T-cell counts, restores anti-HIV-1 responses and reduces immune activation in treated chronic HIV-1 infection
File(s)
Author(s)
Type
Journal Article
Abstract
Background
This randomised, open label, phase I, immunotherapeutic study investigated the effects of interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), recombinant human growth hormone (rhGH), and therapeutic immunisation (a Clade B DNA vaccine) on combination antiretroviral therapy (cART)-treated HIV-1-infected individuals, with the objective to reverse residual T-cell dysfunction.
Methods
Twelve HIV-1+ patients on suppressive cART with baseline CD4 T-cell counts >400 cells/mm3 blood were randomised into one of three groups: (1) vaccine, IL-2, GM-CSF and rhGH (n = 3); (2) vaccine alone (n = 4); or (3) IL-2, GM-CSF and rhGH (n = 5). Samples were collected at weeks 0, 1, 2, 4, 6, 8, 12, 16, 24 and 48. Interferon (IFN)-γ, IL-2, IL-4 and perforin ELISpot assays performed at each time point quantified functional responses to Gag p17/p24, Nef, Rev, and Tat peptides; and detailed T-cell immunophenotyping was undertaken by flow cytometry. Proviral DNA was also measured.
Results
Median baseline CD4 T-cell count was 757 cells/mm3 (interquartile range [IQR] 567–886 cells/mm3), median age 48 years (IQR 42–51 years), and plasma HIV-1-RNA <50 copies/ml for all subjects. Patients who received vaccine plus IL-2, GM-CSF and rhGH (group 1) showed the most marked changes. Assessing mean changes from baseline to week 48 revealed significantly elevated numbers of CD4 T cells (p = 0.0083) and improved CD4/CD8 T-cell ratios (p = 0.0033). This was accompanied by a significant reduction in expression of CD38 on CD4 T cells (p = 0.0194), significantly increased IFN-γ and IL-2 production in response to Gag (p = 0.0122) and elevated IFN-γ production in response to Tat (p = 0.041) at week 48 compared to baseline. Subjects in all treatment groups showed significantly reduced PD-1 expression at week 48 compared to baseline, with some reductions in proviral DNA.
Conclusions
Multifarious immunotherapeutic approaches in the context of fully suppressive cART further reduce immune activation, and improve both CD4 T-lymphocyte counts and HIV-1-specific T-cell responses (NCT01130376).
This randomised, open label, phase I, immunotherapeutic study investigated the effects of interleukin (IL)-2, granulocyte-macrophage colony-stimulating factor (GM-CSF), recombinant human growth hormone (rhGH), and therapeutic immunisation (a Clade B DNA vaccine) on combination antiretroviral therapy (cART)-treated HIV-1-infected individuals, with the objective to reverse residual T-cell dysfunction.
Methods
Twelve HIV-1+ patients on suppressive cART with baseline CD4 T-cell counts >400 cells/mm3 blood were randomised into one of three groups: (1) vaccine, IL-2, GM-CSF and rhGH (n = 3); (2) vaccine alone (n = 4); or (3) IL-2, GM-CSF and rhGH (n = 5). Samples were collected at weeks 0, 1, 2, 4, 6, 8, 12, 16, 24 and 48. Interferon (IFN)-γ, IL-2, IL-4 and perforin ELISpot assays performed at each time point quantified functional responses to Gag p17/p24, Nef, Rev, and Tat peptides; and detailed T-cell immunophenotyping was undertaken by flow cytometry. Proviral DNA was also measured.
Results
Median baseline CD4 T-cell count was 757 cells/mm3 (interquartile range [IQR] 567–886 cells/mm3), median age 48 years (IQR 42–51 years), and plasma HIV-1-RNA <50 copies/ml for all subjects. Patients who received vaccine plus IL-2, GM-CSF and rhGH (group 1) showed the most marked changes. Assessing mean changes from baseline to week 48 revealed significantly elevated numbers of CD4 T cells (p = 0.0083) and improved CD4/CD8 T-cell ratios (p = 0.0033). This was accompanied by a significant reduction in expression of CD38 on CD4 T cells (p = 0.0194), significantly increased IFN-γ and IL-2 production in response to Gag (p = 0.0122) and elevated IFN-γ production in response to Tat (p = 0.041) at week 48 compared to baseline. Subjects in all treatment groups showed significantly reduced PD-1 expression at week 48 compared to baseline, with some reductions in proviral DNA.
Conclusions
Multifarious immunotherapeutic approaches in the context of fully suppressive cART further reduce immune activation, and improve both CD4 T-lymphocyte counts and HIV-1-specific T-cell responses (NCT01130376).
Date Issued
2014-12-05
Date Acceptance
2014-09-08
Citation
VACCINE, 2014, 32 (51), pp.7005-7013
ISSN
0264-410X
Publisher
ELSEVIER SCI LTD
Start Page
7005
End Page
7013
Journal / Book Title
VACCINE
Volume
32
Issue
51
Copyright Statement
© 2014 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Medical Research Council (MRC)
Medical Research Council
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000346222000019&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
G0501957
G0501957
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
Medicine, Research & Experimental
Research & Experimental Medicine
HIV-1
DNA vaccine
Immune-based therapy
ACTIVE ANTIRETROVIRAL THERAPY
DOSE GROWTH-HORMONE
HIV-1-INFECTED INDIVIDUALS
INTERLEUKIN-2 THERAPY
DNA VACCINE
IN-VIVO
IL-2
INTERRUPTION
TRIAL
COMBINATION
Publication Status
Published
Date Publish Online
2014-10-22