Associations between Virologic and Immunologic Dynamics in Blood and in the Male Genital Tract

Natural hosts of simian immunodeficiency virus (SIV), IMPORTANCEThe effects of HIV/SIV infections on the capacity of plasmacytoid dendritic cells (pDCs) to produce IFN-I in vivo are still incompletely defined. As IFN-I can restrict viral replication, contribute to inflammation, and influence immune responses, alteration of this capacity could impact the viral reservoir size. We observed that even in nonpathogenic SIV infection, the frequency of pDCs capable of efficiently sensing SIV and producing IFN-I was reduced during acute infection. We discovered that, concomitantly, cells other than pDCs had increased abilities for viral sensing. Our results suggest that pDC-produced IFN-I upregulates viral sensors in bystander cells, the latter gaining the capacity to produce IFN-I. These results indicate that in certain settings, cells other than pDCs can drive IFN-I-associated inflammation in SIV infection. This has important implications for the understanding of persistent inflammation and the establishment of viral reservoirs.

Section: Discussionmentioning

confidence: 99%

Modulation of Type I Interferon-Associated Viral Sensing during Acute Simian Immunodeficiency Virus Infection in African Green Monkeys

Jochems

Petitjean

Kunkel

et al. 2015

“…All included participants were CMV seropositive (26). Semen was collected and processed as previously described (27,28). Blood CD4 ϩ T lymphocyte absolute counts were measured by flow cytometry, and HIV RNA levels in blood plasma were quantified by the Amplicor HIV Monitor Test (Roche Molecular Systems Inc.).…”

Section: Methodsmentioning

confidence: 99%

“…Copy numbers were calculated as the mean of replicate PCR measurements and normalized to 1 million CD4 ϩ T cells as determined by RPP30 (total cell count) and flow cytometry (percentage of CD4 T cells). The levels of 7 herpesviruses (CMV; EBV; herpes simplex virus 1 [HSV-1] and HSV-2; and human herpesvirus 6 [HHV-6], HHV-7, and HHV-8) were also measured by real-time PCR in the DNA extracted from seminal plasma, as described previously (21).…”

Section: Methodsmentioning

confidence: 99%

“…Cytomegalovirus (CMV) infection is highly prevalent among HIV-infected individuals and is associated with increased levels of T cell activation and HIV disease progression (21,22). We have demonstrated that asymptomatic CMV replication in the male genital tract is associated with higher levels of total HIV DNA in the blood of untreated HIV-infected individuals (23).…”

mentioning

confidence: 98%

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Cytomegalovirus Replication in Semen Is Associated with Higher Levels of Proviral HIV DNA and CD4 ⁺ T Cell Activation during Antiretroviral Treatment

Gianella

Massanella

Richman

et al. 2014

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Asymptomatic cytomegalovirus (CMV) replication occurs frequently in the genital tract in untreated HIV-infected men and is associated with increased immune activation and HIV disease progression. To determine the connections between CMV-associated immune activation and the size of the viral reservoir, we evaluated the interactions between (i) asymptomatic seminal CMV replication, (ii) levels of T cell activation and proliferation in blood, and (iii) the size and transcriptional activity of the HIV DNA reservoir in blood from 53 HIV-infected men on long-term antiretroviral therapy (ART) with suppressed HIV RNA in blood plasma. We found that asymptomatic CMV shedding in semen was associated with significantly higher levels of proliferating and activated CD4 ؉ T cells in blood (P < 0.01). Subjects with detectable CMV in semen had approximately five times higher average levels of HIV DNA in blood CD4؉ T cells than subjects with no CMV. There was also a trend for CMV shedders to have increased cellular (multiply spliced) HIV RNA transcription (P ‫؍‬ 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 (P ‫؍‬ 0.04), detectable 2-long terminal repeat (2-LTR), and lower nadir CD4 ؉ (P < 0.01) were independent predictors of higher levels of proviral HIV DNA in blood. Interventions aimed 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 described associations. IMPORTANCEAlmost all individuals infected with HIV are also infected with cytomegalovirus (CMV), and the replication dynamics 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 primary hypothesis, shedding 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.

“…ϩ T cells (10,14). This cross-sectional study had a number of limitations which may have confounded the analysis, including the lack of longitudinal data and missing information about timing of HIV infection, ART history, and dynamics of viral suppression.…”

Section: Cd4mentioning

confidence: 99%

Replication of Human Herpesviruses Is Associated with Higher HIV DNA Levels during Antiretroviral Therapy Started at Early Phases of HIV Infection

Gianella

Anderson

Var

et al. 2016

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Asymptomatic replication of human herpesviruses (HHV) is frequent in HIV-infected men and is associated with increased Tcell activation and HIV disease progression. We hypothesized that the presence of replication of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) (the most frequently detected HHV) might influence HIV DNA decay during antiretroviral therapy (ART). We investigated 607 peripheral blood mononuclear cell (PBMC) samples from 107 CMV-seropositive, HIV-infected men who have sex with men, who started ART within a median of 3 months from their estimated date of infection (EDI) and were monitored for a median of 19 months thereafter. Levels of HIV, CMV, and EBV DNA and cellular HIV RNA were measured by droplet digital PCR (ddPCR) for each time point. Using a general linear mixed-effect regression model, we evaluated associations between the presence of detectable CMV DNA and EBV DNA levels and HIV DNA decay and cellular HIV RNA levels, while adjusting for peak HIV RNA, nadir CD4؉ count, CD4/CD8 ratio, CMV IgG levels, time from EDI to ART initiation, time from ART initiation to virologic suppression, detectable CMV DNA pre-ART, and age. The presence of intermittent CMV DNA in PBMC during ART was significantly associated with slower decay of HIV DNA (P ‫؍‬ 0.011) but not with increased cellular HIV RNA transcription or more detectable 2-long terminal repeat circles. Higher levels of EBV DNA were also associated with higher levels of HIV DNA (P < 0.001) and increased unspliced cellular HIV RNA transcription (P ‫؍‬ 0.010). These observations suggest that replication of HHV may help maintain a larger HIV DNA reservoir, but the underlying mechanisms remain unclear. IMPORTANCEOver three-fourths of HIV-infected men have at least one actively replicating human herpesvirus (HHV) in their mucosal secretions at any one time. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are the most common, and although it is often asymptomatic, such CMV and EBV replication is associated with higher levels of immune activation and HIV disease progression. We hypothesized that HHV-associated activation of HIV-infected CD4 ؉ T cells might lead to increased HIV DNA. This study found that detectable CMV in blood cells of HIV-infected men was associated with slower decay of HIV DNA even during antiretroviral therapy (ART) that was started during early HIV infection. Similarly, levels of EBV DNA were associated with higher levels of HIV DNA during ART. If this observation points to a causal pathway, interventions that control CMV and EBV replication may be able to reduce the HIV reservoir, which might be relevant to current HIV cure efforts.