Herpes viruses and HIV-1 drug resistance mutations influence the virologic and immunologic milieu of the male genital tract

Gianella, Sara; Morris, Sheldon R.; Anderson, Christy M.; Spina, Celsa A.; Vargas, Milenka V.; Young, Jason A.; Richman, Douglas D.; Smith, Davey M.

doi:10.1097/qad.0b013e3283573305

Cited by 44 publications

(48 citation statements)

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“…Specifically, it demonstrates that even during suppressive ART, CMV reactivation in the male genital tract is associated with increased levels of T cell activation and proliferation and higher HIV DNA levels. This mechanism might be important, given that most HIV-infected individuals and almost all MSM are also infected with CMV (35). Future studies are needed to determine if persistent CMV replication could be targeted as a strategy to reduce the size of the latent HIV reservoir and reduce persistent immune activation.…”

Section: Discussionmentioning

confidence: 99%

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

J Virol

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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.

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Section: Discussionmentioning

confidence: 99%

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

J Virol

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“…Additionally, it demonstrated that this effect was not unique to CMV but might be also associated with detection of EBV, although the mechanisms are likely different. Since almost all HIV-infected individuals and especially HIV-infected MSM are infected with multiple HHV (12), future studies are needed to determine if persistent CMV and EBV replication could be targeted as a strategy to reduce the size of the latent HIV reservoir. Further, since our study only evaluated CMV and EBV, future studies should evaluate if other persistent coinfecting viruses might also promote HIV DNA persistence.…”

Section: Discussionmentioning

confidence: 99%

“…This can be important since subclinical bursts of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation are common among HIV-infected individuals, even those with high CD4 ϩ T-cell counts and those receiving effective ART (11). Given that most HIV-infected individuals and almost all HIV-infected men who have sex with men (MSM) are coinfected with multiple HHV (12) and persistent viral replication is a known driver of immune activation, we hypothesized that CMV, and possibly EBV, drives activation and proliferation of latently infected CD4 ϩ T cells and plays a role in the maintenance of the HIV DNA reservoir during ART.…”

mentioning

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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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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“…25 Several studies in HIV-1-infected men have used semen specimens to establish an association between CMV shedding and both HIV-1 shedding and increased levels of HIV-1 proviral DNA. [26][27][28][29][30] Others have reported detectable levels of CMV DNA in CVL, saliva, and peripheral blood mononuclear cells (PBMCs). 25,31,32 However, immunological markers of CMV infection in blood specimens have shown significant associations with biomarkers of inflammation and non-AIDSdefining events.…”

Section: Introductionmentioning

confidence: 99%

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

Lurain

Hanson

Hotton

et al. 2016

AIDS Research and Human Retroviruses

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Three groups of cytomegalovirus (CMV)-seropositive women (total n = 164) were selected from the Chicago Women's Interagency HIV-1 Study to investigate the association between CMV coinfection and immune activation: (1) HIV-1 viremic, (2) HIV-1 aviremic, and (3) HIV-1 uninfected. Quantitative measures of CMV serum IgG, CMV DNA, and serum biomarkers interleukin (IL)-6, soluble CD163 (sCD163), soluble CD14 (sCD14), and interferon gamma-induced protein (IP10) were obtained. Levels of CMV IgG and the serum biomarkers were significantly higher in the HIV-1 viremic group compared to the aviremic and uninfected groups ( p < 0.001). No significant associations with CMV IgG levels were found for HIV-uninfected women. When each of the HIVinfected groups was analyzed, sCD14 levels in the viremic women were significantly associated with CMV IgG levels with p < 0.02 when adjusted for age, CD4 count, and HIV viral load. There was also a modest association ( p = 0.036) with IL-6 from plasma and cervical vaginal lavage specimens both unadjusted and adjusted for CD4 count and HIV viral load. The association of CMV IgG level with sCD14 implicates the monocyte as a potential site for interaction of the two viruses, which eventually may lead to non-AIDS-defining pathological conditions.

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Herpes viruses and HIV-1 drug resistance mutations influence the virologic and immunologic milieu of the male genital tract

Cited by 44 publications

References 48 publications

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

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

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

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

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Herpes viruses and HIV-1 drug resistance mutations influence the virologic and immunologic milieu of the male genital tract

Cited by 44 publications

References 48 publications

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

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

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

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

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Product

Resources

About

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

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