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Maraviroc intensification in patients with suppressed HIV viremia has limited effects on CD4+ T cell recovery and gene expression

Maraviroc intensification in patients with suppressed HIV viremia has limited effects on CD4+ T cell recovery and gene expression
Maraviroc intensification in patients with suppressed HIV viremia has limited effects on CD4+ T cell recovery and gene expression
Addition of the CCR5 inhibitor Maraviroc (MVC) to ongoing antiretroviral therapy increases CD4+ T cell counts in some virologically suppressed patients with suboptimal CD4+ T cell recovery. To understand the mechanisms by which MVC elicits increases in CD4+ T cell counts, the present study was undertaken to identify host factors (i.e. genes) that are modulated and are correlated with CD4+ T cell recovery during the 24weeks of MVC intensification in 32 subjects. Median changes of CD4+ T cell counts over 24weeks of MVC compared to baseline were 38cells/mm(3) (p<0.001). The median slope of CD4+ T cell recovery was 39cells/mm(3) per year before initiation of MVC and 76cells/mm(3) per year during MVC intensification, however, this increase was not statistically significant (p=0.33). Microarray analysis (N=31,426 genes) identified a single differentially expressed gene, tumor necrosis factor alpha (TNF), which was modestly (1.44-fold, p<0.001) downregulated by MVC at week 24 compared to baseline. TNF differential expression was evaluated using an independent method of droplet digital PCR, but the difference was not significant (p=0.6). Changes in gene expression did not correlate with CD4+ T cell recovery or any changes in the CD4+ T cell maturation, proliferation and activation phenotypes. In summary, our data suggest that modest improvements of CD4+ T cell counts during MVC intensification cannot be explained by changes in gene expression elicited by MVC. However, the modest changes in T cell composition, including reduction of the percentages of Tregs, proliferating CD4+ T cells and senescent CD8+ T cells, suggest immunologically favorable effects of MVC.
HIV, CCR5 inhibitors, maraviroc, gene expression, CD4+ T cell recovery
0166-3542
42-49
Beliakova-Bethell, N.
5919f4d5-b2a8-4d9a-a3be-d0a78d8485b1
Jain, S.
b8b00f1d-ed07-4964-a168-f90eda714b5e
Woelk, C.H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Witt, M.D.
2a09d847-f90a-47cb-9083-e4ef82abc7ae
Sun, X.
0b3cfc8d-1504-42e4-86d7-220353552eba
Lada, S.M.
f8e82dc7-a801-4986-809d-ec3bba647280
Spina, C.A.
644b537b-d0f2-4c09-a43e-8b54f74c68a9
Goicoechea, M.
eedc2dba-3d4f-442d-b514-0505d93d8034
Rought, S.E.
e0f29ac0-6446-43c9-89db-293ee2e21c76
Haubrich, R.
c63c8edf-d642-4e0a-8294-0ea35842e780
Dube, M.P.
acae875f-95cf-455b-bec0-f0e6acd27779
Beliakova-Bethell, N.
5919f4d5-b2a8-4d9a-a3be-d0a78d8485b1
Jain, S.
b8b00f1d-ed07-4964-a168-f90eda714b5e
Woelk, C.H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
Witt, M.D.
2a09d847-f90a-47cb-9083-e4ef82abc7ae
Sun, X.
0b3cfc8d-1504-42e4-86d7-220353552eba
Lada, S.M.
f8e82dc7-a801-4986-809d-ec3bba647280
Spina, C.A.
644b537b-d0f2-4c09-a43e-8b54f74c68a9
Goicoechea, M.
eedc2dba-3d4f-442d-b514-0505d93d8034
Rought, S.E.
e0f29ac0-6446-43c9-89db-293ee2e21c76
Haubrich, R.
c63c8edf-d642-4e0a-8294-0ea35842e780
Dube, M.P.
acae875f-95cf-455b-bec0-f0e6acd27779

Beliakova-Bethell, N., Jain, S., Woelk, C.H., Witt, M.D., Sun, X., Lada, S.M., Spina, C.A., Goicoechea, M., Rought, S.E., Haubrich, R. and Dube, M.P. (2014) Maraviroc intensification in patients with suppressed HIV viremia has limited effects on CD4+ T cell recovery and gene expression. Antiviral Research, 107, 42-49. (doi:10.1016/j.antiviral.2014.04.005).

Record type: Article

Abstract

Addition of the CCR5 inhibitor Maraviroc (MVC) to ongoing antiretroviral therapy increases CD4+ T cell counts in some virologically suppressed patients with suboptimal CD4+ T cell recovery. To understand the mechanisms by which MVC elicits increases in CD4+ T cell counts, the present study was undertaken to identify host factors (i.e. genes) that are modulated and are correlated with CD4+ T cell recovery during the 24weeks of MVC intensification in 32 subjects. Median changes of CD4+ T cell counts over 24weeks of MVC compared to baseline were 38cells/mm(3) (p<0.001). The median slope of CD4+ T cell recovery was 39cells/mm(3) per year before initiation of MVC and 76cells/mm(3) per year during MVC intensification, however, this increase was not statistically significant (p=0.33). Microarray analysis (N=31,426 genes) identified a single differentially expressed gene, tumor necrosis factor alpha (TNF), which was modestly (1.44-fold, p<0.001) downregulated by MVC at week 24 compared to baseline. TNF differential expression was evaluated using an independent method of droplet digital PCR, but the difference was not significant (p=0.6). Changes in gene expression did not correlate with CD4+ T cell recovery or any changes in the CD4+ T cell maturation, proliferation and activation phenotypes. In summary, our data suggest that modest improvements of CD4+ T cell counts during MVC intensification cannot be explained by changes in gene expression elicited by MVC. However, the modest changes in T cell composition, including reduction of the percentages of Tregs, proliferating CD4+ T cells and senescent CD8+ T cells, suggest immunologically favorable effects of MVC.

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More information

Accepted/In Press date: 14 April 2014
e-pub ahead of print date: 24 April 2014
Published date: July 2014
Keywords: HIV, CCR5 inhibitors, maraviroc, gene expression, CD4+ T cell recovery
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 379203
URI: https://eprints.soton.ac.uk/id/eprint/379203
ISSN: 0166-3542
PURE UUID: 4551edaf-c9f7-49d0-a10b-47182e82c5eb

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Date deposited: 18 Jul 2015 14:21
Last modified: 15 Jul 2019 21:12

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Contributors

Author: N. Beliakova-Bethell
Author: S. Jain
Author: C.H. Woelk
Author: M.D. Witt
Author: X. Sun
Author: S.M. Lada
Author: C.A. Spina
Author: M. Goicoechea
Author: S.E. Rought
Author: R. Haubrich
Author: M.P. Dube

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