Attenuation of HIV-Specific T Cell Responses Among People with HIV on art Following Dipyridamole Treatment
Benjamin C MorrisEmily A HixsonCynthia Klamar-BlainDelbert G. GillespieKaleab Z. AbebeCharles R. RinaldoJohn W. MellorsEdwin K. JacksonSharon A. RiddlerBernard Macatangay
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Twelve weeks of dipyridamole increased extracellular adenosine levels and decreased T cell activation in people with human immunodeficiency virus (HIV). In this analysis, we investigated the effect of dipyridamole on HIV-specific T cell responses. We compared changes in Gag- and Env-specific T cell responses using intracellular cytokine staining, following 12 wk of dipyridamole treatment vs placebo. We evaluated whether frequencies of polyfunctional HIV-specific T cells were associated with purines in the adenosine pathway and with measures of HIV persistence and chronic inflammation. There was a significant decrease in CD4+ polyfunctional T cell responses to Gag (-62.6% vs -23.0%; P < 0.001) and Env (-56.1% vs -6.0%; P < 0.001) in the dipyridamole arm. In the dipyridamole group, lower frequencies of polyfunctional Env-specific CD4+ T cells were associated with higher plasma levels of adenosine (r = -0.85, P < 0.01) and inosine (r = -0.70, P = 0.04). Higher adenosine levels induced by dipyridamole treatment is associated with decreased HIV-specific CD4+ T cell polyfunctional responses in people with HIV on antiretroviral therapy.Keywords:
Dipyridamole
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Abstract The effects of HIV infection upon the thymus and peripheral T cell turnover have been implicated in the pathogenesis of AIDS. In this study, we investigated whether decreased thymic output, increased T cell proliferation, or both can occur in HIV infection. We measured peripheral blood levels of TCR rearrangement excision circles (TREC) and parameters of cell proliferation, including Ki67 expression and ex vivo bromodeoxyuridine incorporation in 22 individuals with early untreated HIV disease and in 15 HIV-infected individuals undergoing temporary interruption of therapy. We found an inverse association between increased T cell proliferation with rapid viral recrudescence and a decrease in TREC levels. However, during early HIV infection, we found that CD45RO−CD27high (naive) CD4+ T cell proliferation did not increase, despite a loss of TREC within naive CD4+ T cells. A possible explanation for this is that decreased thymic output occurs in HIV-infected humans. This suggests that the loss of TREC during HIV infection can arise from a combination of increased T cell proliferation and decreased thymic output, and that both mechanisms can contribute to the perturbations in T cell homeostasis that underlie the pathogenesis of AIDS.
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Alteration of γδ T-cell distribution and function in peripheral blood is among the earliest defects during HIV-infection. We asked whether the polyfunctional response could also be affected, and how this impairment could be associated to CD4 T-cell count. To this aim, we performed a cross-sectional study on HIV-infected individuals. In order to evaluate the polyfunctional-Vγ9Vδ2 T-cell response after phosphoantigen-stimulation, we assessed the cytokine/chemokine production and cytotoxicity by flow-cytometry in HAART-treated-HIV+ persons and healthy-donors. During HIV-infection Vγ9Vδ2-polyfunctional response quality is affected, since several Vγ9Vδ2 T-cell subsets resulted significantly lower in HIV+ patients in respect to healthy donors. Interestingly, we found a weak positive correlation between Vγ9Vδ2 T-cell-response and CD4 T-cell counts. By dividing the HIV+ patients according to CD4 T-cell count, we found that Low-CD4 patients expressed a lower number of two Vγ9Vδ2 T-cell subsets expressing MIP-1β in different combinations with other molecules (CD107a/IFNγ) in respect to High-CD4 individuals. Our results show that the Vγ9Vδ2 T-cell-response quality in Low-CD4 patients is specifically affected, suggesting a direct link between innate Vγ9Vδ2 T-cells and CD4 T-cell count. These findings suggest that Vγ9Vδ2 T-cell quality may be indirectly influenced by HAART therapy and could be included in a new therapeutical strategy which would perform an important role in fighting HIV infection.
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Abstract HIV infection has been identified as one of the major risk factors for severe COVID-19 disease, but the mechanisms underpinning this susceptability are still unclear. Here, we assessed the impact of HIV infection on the quality and epitope specificity of SARS-CoV-2 T cell responses in the first wave and second wave of the COVID-19 epidemic in South Africa. Flow cytometry was used to measure T cell responses following PBMC stimulation with SARS-CoV-2 peptide pools. Culture expansion was used to determine T cell immunodominance hierarchies and to assess potential SARS-CoV-2 escape from T cell recognition. HIV-seronegative individuals had significantly greater CD4 + and CD8 + T cell responses against the Spike protein compared to the viremic PLWH. Absolute CD4 count correlated positively with SARS-CoV-2 specific CD4 + and CD8 + T cell responses (CD4 r= 0.5, p=0.03; CD8 r=0.5, p=0.001), whereas T cell activation was negatively correlated with CD4 + T cell responses (CD4 r= −0.7, p=0.04). There was diminished T cell cross-recognition between the two waves, which was more pronounced in individuals with unsuppressed HIV infection. Importantly, we identify four mutations in the Beta variant that resulted in abrogation of T cell recognition. Together, we show that unsuppressed HIV infection markedly impairs T cell responses to SARS-Cov-2 infection and diminishes T cell cross-recognition. These findings may partly explain the increased susceptibility of PLWH to severe COVID-19 and also highlights their vulnerability to emerging SARS-CoV-2 variants of concern. One sentence summary Unsuppressed HIV infection is associated with muted SARS-CoV-2 T cell responses and poorer recognition of the Beta variant.
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Background HIV-specific T cell dysfunction is a prominent feature of HIV infection. We have reported that the PD-1 and IL-10 pathways mediate a reversible impairment of HIV-specific proliferative T cell responses. However, the responses are frequently modest and not all infected subjects respond to blockade of either pathway. It is therefore crucial to determine whether combined PD-L1 and IL-10Rα blockade can overcome these limitations and synergistically revive HIV-specific T cell responses.
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The progressive loss of CD4+ T cell population and thymic dysfunction is the hallmark of HIV-1 (human immunodeficiency virus-1) infection but the mechanism underlying the slow T cell decline and thymic involution remains elusive. Although the chemokine receptor CCR5 (cysteine-cysteine chemokine receptor 5) is the predominant co-receptor exploited for transmission and replication of HIV in vivo but the previous mechanism described via CCR5, based on single-receptor tropism, was insufficient to elucidate the thymic dysfunction and progressive loss of CD4+ T cells caused by HIV infection. It has been demonstrated that acute HIV infection causes retinoic acid (RA) levels to drop quickly and immune cell populations, whose identities and functions are largely regulated by RA. Through this study, we predicted and discovered human STRA6 as a novel binding receptor of HIV that may play a critical role in the pathogenicity of HIV and its immune suppression. Binding between human STRA6 (signaling receptor and transporter of retinol 6) receptor and HIV glycoprotein 120 (GP120) was studied through molecular docking and molecular dynamics simulation analysis. The results showed that the HIV surface glycoprotein (GP120) binds strongly and efficiently to the chain B of the STRA6 receptor at proximity to the RBP (retinol binding protein)- binding motif located in the receptor (ZDOCK score: 1924). From the MD simulation analysis, the binding energies were determined using MM/GBSA (Molecular mechanics with generalised Born and surface area solvation) and was found to be -841.2 kcal/mol signifying a high stability of the complex. It might be possible that HIV infects the thymus gland by binding of the surface glycoprotein (GP120) to the chain B of the membrane STRA6 receptor- a receptor of retinol /Vitamin A (VitA)- which is highly expressed on thymic gland and T cells, leading to retinol signaling disorder or retinol insufficiency which may lead to thymus gland damage and thymic dysfunction resulting in low CD4+ T cells in HIV patients. This study paves the way towards understanding the complex mechanism of HIV infection and its immune dysregulation and may lead to the discovery of new drug targets for management of HIV. More research is needed to fully understand the link between STRA6 receptor and HIV, and it is possible that future studies using animal models, including genetically modified animals, will provide further insights into the mechanisms by which STRA6 receptor play a role in HIV pathogenesis and progression.Funding: No FundedDeclaration of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Abstract Unlike HIV-1-infected people, most HIV-2-infected subjects maintain a healthy CD4+ T cell count and a strong HIV-specific CD4+ T cell response. To define the cellular immunological correlates of good prognosis in HIV-2 infection, we conducted a cross-sectional study of HIV Gag-specific T cell function in HIV-1- and HIV-2-infected Gambians. Using cytokine flow cytometry and lymphoproliferation assays, we show that HIV-specific CD4+ T cells from HIV-2-infected individuals maintained proliferative capacity, were not terminally differentiated (CD57−), and more frequently produced IFN-γ or IL-2 than CD4+ T cells from HIV-1-infected donors. Polyfunctional (IFN-γ+/IL-2+) HIV-specific CD4+ T cells were found exclusively in HIV-2+ donors. The disparity in CD4+ T cell responses between asymptomatic HIV-1- and HIV-2-infected subjects was not associated with differences in the proliferative capacity of HIV-specific CD8+ T cells. This study demonstrates that HIV-2-infected donors have a well-preserved and functionally heterogeneous HIV-specific memory CD4+ T cell response that is associated with delayed disease progression in the majority of infected people.
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Human immunodeficiency virus (HIV) immunopathogenesis in children remains poorly understood. We assessed T cell immune activation in antiretroviral therapy—naive children in Uganda (n= 154). Increased CD4+ and CD8+ T cell activation strongly correlated with decreased CD4+ T cell percentage. Interestingly, no correlation between plasma HIV RNA level and T cell activation was observed after controlling for CD4+ T cell count. In addition, the presence of Gag-specific CD4+ T helper responses was associated with increased HIV-specific CD8+ T cells. Understanding the balance between immune activation and T cell immunity in HIV-infected children may provide further insights into the mechanisms leading to effective immune control.
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It is well-known that CD4+T cell is now divided into four subsets,including Th1,Th2,Th17 and Treg cell.The discovery of Th17 cell rises a new hot spot of the research on CD4+T cell subsets.Different CD4+T cell subsets can mediate the autoimmune reaction and inflammation by the interaction of cytokine network.CD4+ T cell subsets themselves and their effects in non-infectious uveitis are concerned now.The current research progression in the relationship of CD4+T cell subsets and non-infectious uveitis as well as the interaction among the CD4+T cell subsets in uveitis are reviewed.
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Abstract Objectives Conventional glucocorticoid (GC) treatment poses significant risks for opportunistic infections due to its suppressive impact on CD4 + T cells. This study aimed to explore the mechanisms by which GCs modulate the functionality of CD4 + T cells during infection. Methods We consistently measured FOXP3, inflammatory cytokines and phospho‐S6 ribosomal protein levels in CD4 + T cells from patients undergoing conventional GC treatment. Using Foxp3 EGFP animals, we investigated the dynamic activation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and its correlation with the immunoregulatory function of CD4 + T cells under the influence of GCs. Results GCs dynamically altered the expression pattern of FOXP3 in CD4 + T cells, promoting their acquisition of an active T regulatory (Treg) cell phenotype upon stimulation. Mechanistically, GCs undermined the kinetics of the mTORC1 pathway, which was closely correlated with phenotype conversion and functional properties of CD4 + T cells. Dynamic activation of the mTORC1 signaling modified the GC‐dampened immunoregulatory capacity of CD4 + T cells by phenotypically and functionally bolstering the FOXP3 + Treg cells. Interventions targeting the mTORC1 pathway effectively modulated the GC‐dampened immunoregulatory capacity of CD4 + T cells. Conclusion These findings highlight a novel mTORC1‐mediated mechanism underlying CD4 + T cell immunity in the context of conventional GC treatment.
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