Asymptomatic cytomegalovirus (CMV) replication occurs frequently in the genital tract in untreated HIV-infected men and is usually associated with increased immune activation and HIV disease progression. in blood CD4+ T cells than subjects with no CMV. There was also a pattern for CMV shedders to have increased cellular (multiply spliced) HIV Myh11 RNA transcription (= 0.068) compared to participants without CMV, but it is unclear if this transcription pattern is associated with residual HIV replication. In multivariate analysis, the presence of seminal plasma CMV (= 0.04), detectable 2-long airport terminal repeat (2-LTR), and lower nadir CD4+ (< 0.01) were indie predictors of higher levels of proviral HIV DNA in blood. Interventions targeted at reducing seminal CMV and associated immune activation may be important for HIV curative strategies. Future studies of anti-CMV therapeutics will help to establish causality and determine the mechanisms underlying these explained associations. IMPORTANCE Almost all individuals infected with HIV are also infected with cytomegalovirus (CMV), and the replication mechanics of the two viruses likely influence each other. This study investigated interactions between asymptomatic CMV replication within the male genital tract, levels of inflammation in blood, and the size of the HIV DNA reservoir in 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. In support of our main hypothesis, dropping of CMV DNA in semen was associated with increased activation and proliferation of T cells in blood and also significantly higher levels of HIV DNA in blood cells. These results suggest that CMV reactivation might play a role in the maintenance of the HIV DNA reservoir during suppressive ART and that it could be a target of pharmacologic intervention in future studies. INTRODUCTION Although antiretroviral therapy (ART) can suppress HIV RNA levels to below the limit of detection in the blood of HIV-infected individuals (1, 2), the computer virus persists despite long term Brivanib alaninate continuous treatment, and the viral weight rebounds when therapy is usually interrupted (3). The reason for this quick rebound is usually the presence of a long-lived reservoir of latent HIV proviruses, which is usually established early in the course of contamination (4, 5). Several Brivanib alaninate non-mutually unique mechanisms underlie HIV perseverance in a very small proportion of memory CD4+ T cells during suppressive ART (6,C9). First, the presence of residual HIV replication could lead to contamination of memory CD4+ T cells (10, 11). Second, the HIV latent reservoir could be managed by proliferation of latently infected CD4+ T cells, driven by antigenic activation (12) or cytokines (homeostatic proliferation) (13, 14). The comparative efforts of antigen-driven and homeostatic proliferation to the size and maintenance of the HIV reservoir are ambiguous, but both mechanisms likely play a role in HIV perseverance (13, 15). Both mechanisms of HIV perseverance (i.at the., residual replication and cell proliferation) are modulated by inflammation and immune activation, widely explained in patients receiving ART (16). Similarly, inflammatory cytokines and general CD4+ T cell activation can modulate HIV Brivanib alaninate manifestation in latently infected cells, sensitize target cells for new cycles of contamination (17, 18), lead to dysfunctional HIV-specific T cell responses (19, 20), and impair the clearance of HIV-infected cells (13). It is usually therefore crucial to understand which factors contribute to prolonged immune activation and if the same factors also modulate and maintain the HIV reservoir. Cytomegalovirus (CMV) contamination is usually highly prevalent among Brivanib alaninate HIV-infected individuals and is usually associated with increased levels of T cell activation and HIV disease progression (21, 22). We have exhibited that asymptomatic CMV replication in the male genital tract is usually associated with higher levels of total HIV DNA in the blood of untreated HIV-infected individuals (23). Since our previous study investigated participants not receiving ART, the assessed HIV DNA levels included both integrated and unintegrated viral forms and did not represent solely the latent HIV reservoir (24). It is usually ambiguous if these observed associations still persist during suppressive ART, which is usually relevant to inform future eradication strategies. In this study, we evaluated the associations between (i) asymptomatic CMV replication within the male genital tract, (ii) levels of T cell activation and proliferation in blood, and (iii) the size and transcriptional activity of the HIV DNA reservoir in paired semen and blood samples from 53 HIV-infected CMV-seropositive men on long-term ART and with suppressed.