GB Virus C Viremia Is Associated With Higher Levels of Double-Negative T Cells and Lower T-Cell Activation in HIV-Infected Individuals Receiving Antiretroviral Therapy

ABSTRACTMost 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+CD38+), cycling (Ki-67+), degranulation (CD107a+), and the immune checkpoint protein PD-1 on CD4+and CD8+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+T cell activation and CD107a expression and with increased CD8+T cellular cycling and reduced CD107a expression on CD8+T cells. While some effects disappeared during ART, greater CD4+T cell activation and reduced CD107a expression on CD8+T cells persisted when CMV was present (P < 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.IMPORTANCEChronic 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+T cell activation was higher and CD8+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+T cells are more vulnerable to HIV infection, while the loss of CD8+T cell degranulation may impede the proper killing of infected cells.

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Enhancement of the Tolerogenic Phenotype in the Liver by ImmTOR Nanoparticles

Frontiers in Immunology ◽

10.3389/fimmu.2021.637469 ◽

2021 ◽

Vol 12 ◽

Author(s):

Petr O. Ilyinskii ◽

Christopher J. Roy ◽

Julie LePrevost ◽

Gina L. Rizzo ◽

Takashi Kei Kishimoto

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

Cell Activation ◽

Large Population ◽

Cell Phenotype ◽

Double Negative ◽

Liver Sinusoidal Endothelial Cells ◽

Double Negative T Cells

ImmTOR biodegradable nanoparticles encapsulating rapamycin have been shown to induce a durable tolerogenic immune response to co-administered biologics and gene therapy vectors. Prior mechanism of action studies have demonstrated selective biodistribution of ImmTOR to the spleen and liver following intravenous (IV) administration. In the spleen, ImmTOR has been shown to induce tolerogenic dendritic cells and antigen-specific regulatory T cells and inhibit antigen-specific B cell activation. Splenectomy of mice resulted in partial but incomplete abrogation of the tolerogenic immune response induced by ImmTOR. Here we investigated the ability of ImmTOR to enhance the tolerogenic environment in the liver. All the major resident populations of liver cells, including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), stellate cells (SC), and hepatocytes, actively took up fluorescent-labeled ImmTOR particles, which resulted in downregulation of MHC class II and co-stimulatory molecules and upregulation of the PD-L1 checkpoint molecule. The LSEC, known to play an important role in hepatic tolerance induction, emerged as a key target cell for ImmTOR. LSEC isolated from ImmTOR treated mice inhibited antigen-specific activation of ovalbumin-specific OT-II T cells. The tolerogenic environment led to a multi-pronged modulation of hepatic T cell populations, resulting in an increase in T cells with a regulatory phenotype, upregulation of PD-1 on CD4+ and CD8+ T cells, and the emergence of a large population of CD4–CD8– (double negative) T cells. ImmTOR treatment protected mice in a concanavalin A-induced model of acute hepatitis, as evidenced by reduced production of inflammatory cytokines, infiltrate of activated leukocytes, and tissue necrosis. Modulation of T cell phenotype was seen to a lesser extent after administration by empty nanoparticles, but not free rapamycin. The upregulation of PD-1, but not the appearance of double negative T cells, was inhibited by antibodies against PD-L1 or CTLA-4. These results suggest that the liver may contribute to the tolerogenic properties of ImmTOR treatment.

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Immune Reconstitution During the First Year of Antiretroviral Therapy of HIV-1-Infected Adults in Rural Burkina Faso

The Open AIDS Journal ◽

10.2174/1874613601206010016 ◽

2012 ◽

Vol 6 (1) ◽

pp. 16-25 ◽

Cited By ~ 4

Author(s):

Fabrice Tiba ◽

Frans Nauwelaers ◽

Siaka Traoré ◽

Boubacar Coulibaly ◽

Thierry Ouedraogo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antiretroviral Therapy ◽

Burkina Faso ◽

T Cell Activation ◽

Cell Activation ◽

Naive T Cells ◽

Naïve T Cells ◽

Cell Counts ◽

Hiv 1

There are no data on the outcome of highly active antiretroviral therapy (HAART) in HIV-infected adults in rural Burkina Faso. We therefore assessed CD4+ T-cell counts and HIV-1 plasma viral load (VL), the proportion of naive T-cells (co-expressing CCR7 and CD45RA) and T-cell activation (expression of CD95 or CD38) in 61 previously untreated adult patients from Nouna, Burkina Faso, at baseline and 2 weeks, 1, 3, 6, 9 and 12 months after starting therapy. Median CD4+ T-cell counts increased from 174 (10th-90th percentile: 33-314) cells/µl at baseline to 300 (114- 505) cells/µl after 3 months and 360 (169-562) cells/µl after 12 months of HAART. Median VL decreased from 5.8 (4.6- 6.6) log10 copies/ml at baseline to 1.6 (1.6-2.3) log10 copies/ml after 12 months. Early CD4+ T-cell recovery was accompanied by a reduction of the expression levels of CD95 and CD38 on T-cells. Out of 42 patients with complete virological follow-up under HAART, 19 (45%) achieved concordant good immunological (gain of ≥100 CD4+ T-cells/µl above baseline) and virological (undetectable VL) responses after 12 months of treatment (intention-to-treat analysis). Neither a decreased expression of the T-cell activation markers CD38 and CD95, nor an increase in the percentage of naive T-cells reliably predicted good virological treatment responses in patients with good CD4+ T-cell reconstitution. Repeated measurement of CD4+ T-cell counts during HAART remains the most important parameter for immunologic monitoring. Substitution of repeated VL testing by determination of T-cell activation levels (e.g., CD38 expression on CD8+ T-cells) should be applied with caution.

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Faculty Opinions recommendation of Sub-optimal CD4+ T-cell activation triggers autonomous TGF-β-dependent conversion to Foxp3+ regulatory T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.11127956.12092055 ◽

2011 ◽

Author(s):

Thomas Huenig

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell

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Probiotic supplementation reduces inflammatory profiles but does not prevent oral immune perturbations during SIV infection

Scientific Reports ◽

10.1038/s41598-021-93918-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rhianna Jones ◽

Kyle Kroll ◽

Courtney Broedlow ◽

Luca Schifanella ◽

Scott Smith ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Rhesus Macaques ◽

Oral Microbiome ◽

Probiotic Supplementation ◽

Siv Infection ◽

Anti Inflammatory

AbstractHIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections.

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