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

Smith, Davey M.; Nakazawa, Masato; Freeman, Michael L.; Anderson, Christy M.; Oliveira, Michelli F.; Little, Susan J.; Gianella, Sara

doi:10.1093/cid/ciw612

Cited by 42 publications

(34 citation statements)

References 34 publications

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“…A recent paper reported that even among individuals who started ART early (with high CD cell count), asymptomatic CMV reactivation was associated with slower CD4/CD8 recovery. [20] Although CMV has not been reported as a significant cause of death in previous studies, we agree that CMV viremia could be associated with direct CMV pathogenic effects underestimated in their contribution to death. CMV viremia could be a cause, or a consequence, of poor immune function.…”

Section: Discussionsupporting

confidence: 63%

The Outcome of HIV-Positive Late Presenters According to Detectable CMV DNA and Anti-CMV Treatment

et al. 2017

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Section: Discussionsupporting

confidence: 63%

The Outcome of HIV-Positive Late Presenters According to Detectable CMV DNA and Anti-CMV Treatment

et al. 2017

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“…Several studies demonstrate links between reservoir size, chronic inflammation, and earlier onset of age-related diseases, despite long-term, successful viral suppression (reviewed in reference 23). Similarly, persistent replication by the chronic viral infection CMV, a herpesvirus, is associated with inflammation, age-related disease, and, in PLWH, larger HIV reservoirs (7,22,24,25,28).…”

Section: Discussionmentioning

confidence: 99%

Subclinical Cytomegalovirus DNA Is Associated with CD4 T Cell Activation and Impaired CD8 T Cell CD107a Expression in People Living with HIV despite Early Antiretroviral Therapy

Christensen-Quick

Massanella

Frick

et al. 2019

J Virol

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Most people living with HIV (PLWH) are coinfected with cytomegalovirus (CMV). Subclinical CMV replication is associated with immune dysfunction and with increased HIV DNA in antiretroviral therapy (ART)-naive and -suppressed PLWH. To identify immunological mechanisms by which CMV could favor HIV persistence, we analyzed 181 peripheral blood mononuclear cell (PBMC) samples from 64 PLWH starting ART during early HIV infection with subsequent virologic suppression up to 58 months. In each sample, we measured levels of CMV and Epstein-Barr virus (EBV) DNA by droplet digital PCR (ddPCR). We also measured expression of immunological markers for activation (HLA-DR ϩ CD38 ϩ ), cycling (Ki-67 ϩ ), degranulation (CD107a ϩ ), and the immune checkpoint protein PD-1 on CD4 ϩ and CD8 ϩ T cell memory subsets. Significant differences in percentages of lymphocyte markers by CMV/EBV shedding were identified using generalized linear mixed-effects models. Overall, CMV DNA was detected at 60/181 time points. At the time of ART initiation, the presence of detectable CMV DNA was associated with increased CD4 ϩ T cell activation and CD107a expression and with increased CD8 ϩ T cellular cycling and reduced CD107a expression on CD8 ϩ T cells. While some effects disappeared during ART, greater CD4 ϩ T cell activation and reduced CD107a expression on CD8 ϩ T cells persisted when CMV was present (P Ͻ 0.01). In contrast, EBV was not associated with any immunological differences. Among the covariates, peak HIV RNA and CD4/CD8 ratio had the most significant effect on the immune system. In conclusion, our study identified immune differences in PLWH with detectable CMV starting early ART, which may represent an additional hurdle for HIV cure efforts.IMPORTANCE Chronic viral infections such as with HIV and CMV last a lifetime and can continually antagonize the immune system. Both viruses are associated with higher expression of inflammation markers, and recent evidence suggests that CMV may complicate efforts to deplete HIV reservoirs. Our group and others have shown that CMV shedding is associated with a larger HIV reservoir. Subclinical CMV replication could favor HIV persistence via bystander effects on our immune system. In this study, we collected longitudinal PBMC samples from people starting ART and measured immune changes associated with detectable CMV. We found that when CMV was detectable, CD4 ϩ T cell activation was higher and CD8 ϩ T cell degranulation was lower. Both results may contribute to the slower decay of the size of the reservoir during CMV replication, since activated CD4 ϩ T cells are more vulnerable to HIV infection, while the loss of CD8 ϩ T cell degranulation may impede the proper killing of infected cells.

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“…Associations with CD4/CD8 ratios remained at V1 and V3, but not thereafter. This disconnect may reflect clearance of CMV DNA from some patients in our study, as CMV DNA detected in PBMC and the patient's age associated with CD4/CD8 ratios over 3 years when ART was initiated in early HIV disease (24). Here levels of CMV lysate antibody at V6 and V12 correlated inversely with CD4/CD8 ratios, directly with proportions of CD8 T-cells and inversely with proportions of CD4 T-cells.…”

Section: Discussionmentioning

confidence: 72%

Active and Persistent Cytomegalovirus Infections Affect T Cells in Young Adult HIV Patients Commencing Antiretroviral Therapy

et al. 2018

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Altered T cell profiles have been linked with metrics of persistent cytomegalovirus (CMV) infections in healthy aging and older HIV patients stable on antiretroviral therapy (ART). In this study, we use CMV DNA to identify active infections, and levels of CMV-reactive antibody to assess the persistent burden of CMV in a longitudinal study of 78 young adult patients beginning ART in Jakarta, Indonesia, with <200 CD4 T cells/μL. CMV antibodies, inflammatory markers (C-reactive protein [CRP], soluble interferon-α/β receptor) and T cell phenotypes were assessed before ART (V0) and after 1, 3, 6, and 12 months (V1-V12). CMV DNA was detected in 41 patients (52%) at V0, irrespective of CD4 T cell counts, gender, age, or plasma HIV RNA. CMV DNA+ patients had higher levels of antibody reactive with CMV Immediate Early 1 (IE-1) at V0 and V12 (p = 0.04), and with CMV lysate at V12 (p = 0.01). Detectable CMV DNA did not align with inflammatory markers, but associated with lower CD4/CD8 ratios until V3. CMV antibody levels correlated inversely with proportions of naive CD4 and CD8 T cells, and directly with proportions of CD57 and activated memory T cells (CD3 CD45RA) after 3-12 months on ART. Overall, active CMV replication is common in HIV patients beginning ART in Indonesia and associates with low CD4/CD8 ratios. Elevated levels of CMV-reactive antibody measured on ART also mark a depletion of naive T cells, accumulation of memory T cells, and may be a stable metric of the burden of CMV.

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

Cited by 42 publications

References 34 publications

The Outcome of HIV-Positive Late Presenters According to Detectable CMV DNA and Anti-CMV Treatment

The Outcome of HIV-Positive Late Presenters According to Detectable CMV DNA and Anti-CMV Treatment

Subclinical Cytomegalovirus DNA Is Associated with CD4 T Cell Activation and Impaired CD8 T Cell CD107a Expression in People Living with HIV despite Early Antiretroviral Therapy

Active and Persistent Cytomegalovirus Infections Affect T Cells in Young Adult HIV Patients Commencing Antiretroviral Therapy

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