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Effect of CMV and HIV replication on T cell exhaustion and senescence during ART
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Reported by Jules Levin
CROI 2015
Jennifer M. Dan1, Marta Massanella1, Davey M. Smith1,2, Celsa A. Spina1,2, Eric S. Daar3, Michael P. Dube4, Richard Haubrich1, Sheldon R. Morris1, Sara Gianella Weibel1 and the CCTG 592 team
1 Division of Infectious Disease, University of California, San Diego, La Jolla, CA, USA, 2Veterans Affairs San Diego Healthcare System, San Diego, CA, 3Los Angeles Biomedical Research Institute at Harbor- UCLA Medical Center, Torrance, CA, USA, 4University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
Program abstract
Background: HIV-infected men who have sex with men (MSM) are nearly universally infected with CMV, and both viruses are associated with T-cell dysfunction and inflammation-related morbidities. The effect of asymptomatic CMV replication and persistent HIV transcription during suppressive ART on markers of T cell exhaustion and senescence is poorly defined.
Methods: Paired seminal and blood samples from 45 asymptomatic chronically HIV-infected CMV-seropositive MSM on long term ART and with HIV RNA levels in blood plasma <50 copies/ml were studied. Levels of CMV DNA in semen and blood were measured by RT-PCR, and cell-associated HIV DNA and RNA transcripts (unspliced) were measured in PBMC by droplet digital PCR. Markers of T cell exhaustion (PD-1) and senescence (CD57) were measured in PBMC by flow cytometry for CD4 and CD8 T cells and subsets (naïve [CD45RA+CD27+CD28+], central memory [CD45RA-CD27+CD28+], effectors [CD4+CD45RA-/+CD27-CD28+ or CD8+CD45RA-/+CD27+CD28-] and terminally differentiated [CD45RA+/-CD27-CD28-]).
Associations between immunological markers and asymptomatic CMV and HIV replication, HIV DNA, CMV IgG, age, current and nadir CD4 and time on ART were determined using univariate and multivariate analysis.
Results: CMV DNA was detected in 42% of seminal samples and 20% of PBMC. Detectable CMV DNA in semen but not blood was associated with increased PD-1 expression on circulating CD4 T cells compared to no CMV (P=0.01), particularly in the effector and terminally differentiated subsets (P<0.05). Similarly, higher levels of cellular HIV RNA (but not HIV DNA) were positively associated with greater PD-1 expression on total CD4 and central memory blood subset (P<0.01). There was no association between CMV DNA (blood and semen) or cellular HIV RNA with CD8 exhaustion or senescence or with markers of CD4 senescence. In multivariate analysis, detection of seminal CMV and higher cellular HIV RNA remained associated with increased PD-1 expression on total CD4 T cells (P<0.05). No other variable contributed significantly to the model.
Conclusions: Our data suggest that detection of CMV in the genital tract may contribute to the activation of the PD-1 axis on circulating T cells during suppressive ART. Because increased PD-1 on T cells has been implicated in the maintenance of the HIV reservoir, HIV disease progression and the inability of the immune system to adequately control HIV infection, future studies should examine whether CMV-dependent mechanisms play a role in T cell exhaustion.
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