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Asymptomatic genital CMV replication in MSM linked to T-cell exhaustion
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CROI 2015, February 23-26, 2015, Seattle, Washington
Mark Mascolini
Asymptomatic cytomegalovirus (CMV) replication in semen of HIV-positive men who have sex with men (MSM) was linked to higher levels of PD-1, a marker of T-cell exhaustion, in a cross-sectional study in California [1]. Study participants were taking suppressive antiretroviral therapy.
Jennifer Dan of the University of California, San Diego (UCSD) and colleagues at other centers noted that almost all HIV-positive men also carry CMV. Both viruses, they observed, lead to T-cell dysfunction and inflammation-related morbidities. The researchers hypothesized that asymptomatic CMV replication may be linked to T-cell exhaustion and senescence in men with antiretroviral-suppressed HIV replication.
To test that hypothesis they measured expression of PD-1, a T-cell exhaustion marker, and CD57, a senescence marker, in semen and peripheral blood mononuclear cells (PBMCs). They collected paired seminal and blood samples from 45 CMV-positive MSM with chronic HIV infection and a plasma HIV load below 50 copies. Median CD4 count stood at 644 and ranged from 83 to 1149.
The UCSD team measured PD-1 and CD57 expression on four CD4 and CD8-cell subsets: naive, central memory, effector memory, and terminally differentiated T cells. They also measured CMV DNA in PBMCs and seminal plasma and cellular HIV DNA and unspliced RNA. They used multivariate analysis to explore associations between immunologic markers and asymptomatic CMV and HIV replication, HIV DNA, age, current and nadir CD4 count, and time on antiretroviral therapy.
CMV DNA could be detected in 42% of seminal samples and 20% of PBMC samples. Detection of CMV in PBMCs did not correlate with detection of CMV DNA in semen. Detection of CMV DNA in semen but not blood was associated with higher PD-1 expression in circulating CD4 cells (P = 0.017), especially effector memory CD4 cells (P = 0.03) and terminally differentiated CD4 cells (P = 0.04).
Detectable CMV DNA in semen was not associated with PD-1 expression on circulating CD8 cells or CD57 expression on circulating CD4 or CD8 cells. Nor were higher levels of cellular HIV RNA transcripts linked to PD-1 expression on CD8 cells or CD57 expression on CD4 or CD8 cells. But higher cellular HIV RNA transcripts were associated with increased PD-1 expression on total circulating CD4 cells (r = 0.41, P = 0.007), particularly central memory CD4 cells (r = 0.48, P = 0.002).
In multivariate analysis only detection of CMV DNA in semen and higher cellular HIV RNA were independently associated with increased PD-1 expression on total CD4 cells (P < 0.05). The analysis identified no associations between HIV DNA and PD-1 or CD57 expression on CD4 cells or CD8 cells.
Dan and colleagues proposed that asymptomatic CMV replication and ongoing HIV RNA transcription may contribute to T-cell exhaustion in people taking suppressive antiretroviral therapy. They suggested that future studies explore the possible role of CMV-dependent mechanisms in T-cell exhaustion.
Reference
1. Dan J, Massanella M, Smith D, et al. Effect of CMV and HIV replication on T-cell exhaustion and senescence during ART. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 300. For the e-poster: www.croiconference.org/sites/default/files/posters-2015/300.pdf
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Reported by Jules Levin
"We hypothesize that asymptomatic CMV replication might be associated with T cell exhaustion (PD-1) ......HIV-infected men who have sex with men (MSM) are nearly universally co-infected with CMV. .......HIV and CMV infections are both associated with T cell dysfunction and inflammation-related morbidities ......Paired seminal and blood samples from 45 CMV seropositive, chronically HIV-infected MSM on ART with suppressed HIV RNA levels in blood (<50 copies/ml, median CD4+ T cell count 644 cells/μL [range: 83-1149]). .....CMV DNA was detected in 42% of seminal samples and 20% of PBMCs .....Detectable CMV DNA in semen (but not blood) was associated with increased PD-1 expression on total circulating CD4+ T cells compared to those with no detectable CMV (p=0.01)......
....Increased PD-1 on T cells has been associated with a larger HIV DNA reservoir, HIV disease progression and the inability of the immune system to adequately control HIV infection......Asymptomatic seminal CMV replication and ongoing cellular HIV RNA transcription may contribute to an exhaustive phenotype in circulating CD4+ T cells during effective ART. .......Future studies should examine whether CMV-dependent mechanisms play a role in T cell exhaustion."
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