Nonproliferating Bystander CD4+T Cells Lacking Activation Markers Support HIV Replication During Immune Activation

Abstract Resting CD4+ T cells are the best characterized component of the latent reservoir. Activation of these CD4+ T cells is needed to optimize transcription and viral replication, and this strategy has been used to measure the inducible reservoir. There are several methods that can be used to activate CD4+ T cells, and in this study, we compared 3 different strategies: the combination of the lectin phytohaemagglutinin (PHA) and irradiated allogeneic feeders, a combination of PHA and a superagonistic anti-CD28 antibody, and the combination of the protein kinase C agonist phorbol 12-myristate 13-acetate and the calcium ionophore ionomycin. We show that each strategy induces a different pattern of expression of activation markers on CD4+ T cells. However, the different activation strategies induced similar frequencies of latently infected CD4+ T cells from people living with HIV on suppressive antiretroviral therapy regimens to produce replication-competent virus. Furthermore, the frequency of infectious units per million induced by each regimen was positively correlated with the copies of intact proviral DNA per million CD4+ T cells. Our results suggest that no single pattern of activation marker expression is most associated with latency reversal and demonstrate that different immune activation strategies reverse latency in a low frequency of CD4+ T cells that harbor intact proviral DNA.

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Faculty Opinions recommendation of Serum immune activation markers are persistently increased in patients with HIV infection after 6 years of antiretroviral therapy despite suppression of viral replication and reconstitution of CD4+ T cells.

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

10.3410/f.1163907.625742 ◽

2009 ◽

Author(s):

Matthew Dolan

Keyword(s):

T Cells ◽

Antiretroviral Therapy ◽

Hiv Infection ◽

Viral Replication ◽

Immune Activation ◽

Cd4 T Cells ◽

Activation Markers

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Faculty Opinions recommendation of Innate immune activation of CD4 T cells in salmonella-infected mice is dependent on IL-18.

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

10.3410/f.1088901.542031 ◽

2007 ◽

Author(s):

Andreas Baumler

Keyword(s):

T Cells ◽

Immune Activation ◽

Cd4 T Cells ◽

Innate Immune ◽

Innate Immune Activation

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Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells

Viruses ◽

10.3390/v13050753 ◽

2021 ◽

Vol 13 (5) ◽

pp. 753

Author(s):

Mohammad Haque ◽

Fengyang Lei ◽

Xiaofang Xiong ◽

Yijie Ren ◽

Hao-Yun Peng ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Adoptive Transfer ◽

Cd4 T Cells ◽

Viral Antigen ◽

Peritoneal Macrophages ◽

Hiv Replication ◽

Specific Ctls ◽

Immunodeficiency Virus ◽

Hiv 1

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.

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CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Blood ◽

10.1182/blood-2009-01-200923 ◽

2009 ◽

Vol 114 (3) ◽

pp. 580-588 ◽

Cited By ~ 45

Author(s):

Kathrin Gollmer ◽

François Asperti-Boursin ◽

Yoshihiko Tanaka ◽

Klaus Okkenhaug ◽

Bart Vanhaesebroeck ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Early Time ◽

Cell Receptor ◽

Tcr Signaling ◽

Activation Markers

Abstract CD4+ T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)–transgenic (tg) CD4+ T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3KδD910A/D910A or PI3Kγ-deficient TCR-tg CD4+ T cells showed similar responsiveness to CCL21 costimulation as control CD4+ T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4+ T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca2+ signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation.

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Mucosal immune stimulation with HSV-2 and polyICLC boosts control of viremia in SIVΔNef vaccinated rhesus macaques with breakthrough SIV infection

10.1101/2020.06.02.129494 ◽

2020 ◽

Author(s):

Meropi Aravantinou ◽

Olga Mizenina ◽

Thilo Brill ◽

Jessica Kenney ◽

Christine Timmons ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Lymph Nodes ◽

Immune Activation ◽

Vaccine Efficacy ◽

Cd4 T Cells ◽

Hiv Vaccine ◽

Live Attenuated Vaccine ◽

Siv Infection ◽

The Impact

ABSTRACTDevelopment of an effective human immunodeficiency virus (HIV) vaccine is among the highest priorities in the biomedical research agenda. Adjuvants enhance vaccine efficacy, but in the case of HIV, strong or inappropriate immune activation may undermine protection by increasing HIV susceptibility. Co-infection with immunomodulatory pathogens may also impact vaccine efficacy. In the rhesus macaque rectal SIVΔNef live attenuated vaccine model, we utilized a low virulence HSV-2 infection and the double-stranded RNA viral mimic polyICLC as tools to probe the effects of distinct types of immune activation on HIV vaccine efficacy and explore novel correlates of protection from wild type SIV. Rectally administered HSV-2 and polyICLC impacted the protection conferred by mucosal SIVΔNef vaccination by favoring partial protection in animals with breakthrough infection following virulent SIV challenge (“Controllers”). However, SIVΔNef persistence in blood and tissues did not predict protection in this rectal immunization and challenge model. Non-controllers had similar SIVΔNef viremia as completely protected macaques, and while they tended to have less replication competent SIVΔNef in lymph nodes, controllers had no recoverable virus in the lymph nodes. Non-controllers differed from protected macaques immunologically by having a greater frequency of pro-inflammatory CXCR3+CCR6+ CD4 T cells in blood and a monofunctional IFNγ-dominant CD8 T cell response in lymph nodes. Controller phenotype was associated with heightened IFNα production during acute SIV infection and a greater frequency of CXCR5+ CD4 T cells in blood pre-challenge despite a lower frequency of cells with the T follicular helper (Tfh) cell phenotype in blood and lymph nodes. Our results establish novel correlates of immunological control of SIV infection while reinforcing the potential importance of T cell functionality and location in SIVΔNef efficacy. Moreover, this work highlights that triggering of mucosal immunity can aid mucosal vaccine strategies rather than undermine protection.AUTHOR SUMMARYAn efficacious HIV vaccine is essential to contain the HIV pandemic. Vaccine-mediated protection from HIV may be either enhanced or obstructed by mucosal immune activation; thus, the impact of adjuvants and underlying co-infections that lead to immune activation needs to be evaluated. Using the SIV macaque model, we set out to study the impact of underlying infection with HSV-2 or treatment with the adjuvant polyICLC on rectal immunization with the live attenuated vaccine SIVΔNef. We found that neither stimulus impacted complete protection from SIV; however, the combination of HSV-2 and polyICLC improved control of infection in animals that were not completely protected. Compared with non-controller macaques, controllers had less inflammatory T cells before SIV challenge as well as greater gene expression of IFNα and more functional SIV-specific T cells after infection. The results add to our understanding of the mechanisms of SIVΔNef protection and demonstrate that mucosal immune activation does not necessarily undermine protection in mucosal vaccination against HIV.

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HLA-E Up-Regulation Induced by HIV Infection May Directly Contribute to CD94-Mediated Impairment of NK Cells

International Journal of Immunopathology and Pharmacology ◽

10.1177/039463200501800209 ◽

2005 ◽

Vol 18 (2) ◽

pp. 269-276 ◽

Cited By ~ 26

Author(s):

F. Martini ◽

C. Agrati ◽

G. D'Offizi ◽

F. Poccia

Keyword(s):

T Cells ◽

Hiv Infection ◽

Nk Cells ◽

Cd4 T Cells ◽

Nk Cell ◽

Treatment Interruption ◽

Cell Number ◽

Hiv Replication

Alterations in NK cell numbers and function have been repeatedly shown during HIV infection. In this study, NK cell number and MHC class I expression on CD4+ T cells were studied in HIV patients at different stages of disease progression. An increased expression of HLA-E was seen on CD4+ T cells. In parallel, a reduced number of CD94+ NK cells was observed in advanced disease stages. Moreover, a decline in CD94 expression on NK cells was observed at the HIV replication peak in patients undergoing antiretroviral treatment interruption, suggesting a role of viral replication on NK cells alterations. In vitro HIV infection induced a rapid down-regulation of HLA-A,B,C expression, paralleled by an increased expression of HLA-E surface molecules, the formal ligands of CD94 NK receptors. HIV-infected HLA-E expressing cells were able to inhibit NK cell cytotoxicity through HLA-E expression, since cytotoxicity was restored by antibody masking experiments. These data indicate that the CD94/HLA-E interaction may contribute to NK cell dysfunction in HIV infection, suggesting a role of HIV replication in this process.

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Betamethasone induces potent immunosuppression and reduces HIV infection in a PBMC in vitro model

Journal of Investigative Medicine ◽

10.1136/jim-2020-001424 ◽

2020 ◽

Vol 69 (1) ◽

pp. 28-40 ◽

Cited By ~ 1

Author(s):

Ross Cromarty ◽

Alexander Sigal ◽

Lenine Julie Liebenberg ◽

Lyle Robert Mckinnon ◽

Salim Safurdeen Abdool Karim ◽

...

Keyword(s):

T Cells ◽

Hiv Infection ◽

Immune Activation ◽

Cd4 T Cells ◽

Drug Targets ◽

Complex Nature ◽

Peripheral Blood Mononuclear ◽

Established Risk Factor ◽

Anti Inflammatory

Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.

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