Partners in Crime: The Role of CMV in Immune Dysregulation and Clinical Outcome During HIV Infection

Freeman, Michael L.; Lederman, Michael M.; Gianella, Sara

doi:10.1007/s11904-016-0297-9

Cited by 91 publications

(88 citation statements)

References 131 publications

(120 reference statements)

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“…The immunologic and virologic connections between HIV and HHV are intertwined and complicated, especially with the very prevalent HHV CMV and EBV (9,24). To better understand how asymptomatic CMV and EBV replication in blood cells is associated with HIV DNA levels over time, we investigated a large, uniquely well-characterized cohort of HIV-infected MSM who started ART during the early phases of HIV infection and sustained stable HIV RNA suppression.…”

Section: Discussionmentioning

confidence: 99%

“…The observed association between higher HIV DNA levels and presence of detectable EBV DNA could suggest that coinfection with HHV in general might contribute to HIV persistence. Through millions of years of coexistence, HHV have developed numerous strategies to modulate the human immune response, including impeding antigen-reactive immune cells from eradicating virus-infected cells (24). It is reasonable to hypothesize that other coinfecting pathogens, like HIV, could exploit this particular immune environment to promote HIV pathogen persistence and replication, for example, through upregulation of immune-inhibitory molecules like interleukin 10 (IL-10) and programmed cell death protein 1 (PD-1), which are also involved in HIV persistence (25,26).…”

Section: Discussionmentioning

confidence: 99%

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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

J Virol

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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

J Virol

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“…About 70% of adults under good socioeconomic conditions and 90% under poor conditions become infected with CMV [13]. Following primary infection, the virus persists in a true latent form or in a state of low-level replication made possible by multiple immune evasion mechanisms [18,19]. Latent CMV can reactivate in response to inflammatory stimuli and other physiologic stressors, releasing intact virions that can infect new cells, including cells in the central nervous system (CNS) [20][21][22][23] and the vascular endothelium [24,25].…”

Section: Epidemiology and Pathogenesis Of CMVmentioning

confidence: 99%

“…Subclinical shedding of CMV has been described in genital secretions, saliva, urine, blood, stool, and breast milk [13]. The frequency of CMV shedding at mucosal sites varies and is dependent on the geographical location, cohort characteristics, and detection methods [19].…”

Section: Epidemiology and Pathogenesis Of CMVmentioning

confidence: 99%

Cytomegalovirus and HIV: A Dangerous Pas de Deux

2016

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Human immunodeficiency virus (HIV)-infected adults who take stable antiretroviral therapy (ART) are at risk for early onset of agerelated diseases. This is likely due to a complex interaction between traditional risk factors, HIV infection itself, and other factors, such as underlying immune dysfunction and persistent inflammation. HIV disrupts the balance between the host and coinfecting microbes, worsening control of these potential pathogens. For example, HIV-infected adults are more likely than the general population to have subclinical bursts of cytomegalovirus (CMV) replication at mucosal sites. Production of antigens can activate the immune system and stimulate HIV replication, and it could contribute to the pathogenesis of adverse outcomes of aging, like cardiovascular disease and neurocognitive impairment. Further investigation of the relationships between CMV, immune dysfunction, and unsuccessful aging during chronic HIV infection is warranted.

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“…Similar to HIV, human cytomegalovirus (CMV) is a persistent pathogen associated with inflammation and increased morbidity [11,12]. HIV-infected individuals are almost all coinfected with CMV, and in the setting of HIV, most individuals experience intermittent bursts of CMV replication during ART [11].…”

mentioning

confidence: 99%

Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment

et al. 2016

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Background. A low CD4/CD8 ratio in human immunodeficiency virus (HIV)-infected individuals is associated with inflammation and higher risk of non-AIDS morbidity and mortality. In this study, we investigated the effect of subclinical cytomegalovirus (CMV) and Epstein-Barr virus (EBV) replication on CD4 + and CD8 + T-cell dynamics when antiretroviral therapy (ART) is started during early infection.Methods. We investigated 604 peripheral blood mononuclear cell samples from 108 CMV-and EBV-seropositive HIV-infected men who have sex with men, who started ART within a median of 4 months from their estimated date of infection and were followed for a median of 29.1 months thereafter. Levels of CMV and EBV DNA were measured at each timepoint. Mixed-effects asymptotic regression models were applied to characterize CD4 + and CD8 + T-cell dynamics, and Bayesian hierarchical models were used to quantify individual differences in CMV and EBV DNA replication.Results. Higher levels of subclinical CMV replication were associated with lower predicted maximum levels of CD4/CD8 ratio (P < .05), which was driven by higher levels of CD8 + T-cell counts (P < .05), without affecting CD4 + T-cell counts (P > .1). Age was negatively associated with CD4/CD8 levels (P < .05), and this effect was independent of the CMV association (P < .05 for both CMV and age in a multivariate model).Conclusions. Subclinical CMV replication in blood cells during early HIV infection and younger age were associated with lower CD4/CD8 ratios during suppressive ART. These findings suggest that active CMV infection in the setting of treated HIV may represent an attractive potential target for therapeutic intervention.

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Partners in Crime: The Role of CMV in Immune Dysregulation and Clinical Outcome During HIV Infection

Cited by 91 publications

References 131 publications

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

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

Cytomegalovirus and HIV: A Dangerous Pas de Deux

Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment

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