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.
University of California San Diego, La Jolla, CA 92093, USA. Electronic address: nbeliako@ucsd.edu.
Nadejda
N
Beliakova-Bethell
University of California San Diego, La Jolla, CA 92093, USA.
Sonia
S
Jain
University of California San Diego, La Jolla, CA 92093, USA; Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA; Faculty of Medicine, University of Southampton, Southampton, Hants SO16 6YD, UK.
Christopher H
CH
Woelk
Los Angeles Biomedical Research Institute at Harbor-UCLA, and Geffen School of Medicine at the University of California, Los Angeles, CA 90502, USA.
Mallory D
MD
Witt
University of California San Diego, La Jolla, CA 92093, USA.
Xiaoying
X
Sun
Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.
Steven M
SM
Lada
University of California San Diego, La Jolla, CA 92093, USA; Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.
Celsa A
CA
Spina
Scripps Clinic Torrey Pines, La Jolla, CA 92037, USA.
Miguel
M
Goicoechea
Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.
Steffney E
SE
Rought
University of California San Diego, La Jolla, CA 92093, USA.
Richard
R
Haubrich
Department of Medicine and Division of Infectious Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA. Electronic address: mdube@usc.edu.
Michael P
MP
Dubé
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D003510:Cyclohexanes / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D006801:Humans; D008297:Male; D000077592:Maraviroc; D046228:Microarray Analysis; D008875:Middle Aged; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014766:Viremia
D019380:Anti-HIV Agents; D003510:Cyclohexanes; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D000077592:Maraviroc
CCR5 inhibitors; CD4+ T cell recovery; Gene expression; HIV; Maraviroc