Identification of rare HIV-1–infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression

Lisco, Andrea; Wong, Chun-Shu; Lage, Silvia Lucena; Levy, Itzchak; Brophy, Jason; Lennox, Jeffrey; Manion, Maura; Anderson, Megan; Mejia, Yolanda; Grivas, Christopher; Mystakelis, Harry; Burbelo, Peter D.; Pérez-Díez, Ainhoa; Rupert, Adam; Martens, Craig; Anzick, Sarah L.; Morse, Caryn G.; Chan, S. L.; Deléage, Claire; Sereti, Irini

doi:10.1172/jci.insight.127113

Cited by 25 publications

(18 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a proof of concept of the application of this method in clinical conditions, we investigated the presence of caspase-1-containing specks in two distinct groups of patients. Because both HIV and Mycobacterium tuberculosis (Mtb) have been shown to activate the NLRP3 inflammasome (41, 42), and it has been reported that polymorphisms or activation of some inflammasome genes can affect Mtb infectious and HIV-related inflammatory conditions, in humans (43–47), we decided to investigate inflammasome activation in four patients presenting active pulmonary tuberculosis and four HIV + individuals with distinct HIV-related complications: one viremic anti-retroviral therapy (ART) naïve patient with lymphoma, and three patients with suppressed HIV viremia on ART but with acute events, one with a Staphylococcal axillary lymphadenitis, the second one with community acquired pneumonia and the last one with immune reconstitution inflammatory syndrome (IRIS) related to Varicella-zoster virus (VZV) co-infection (VZV-IRIS). Applying the same features identified as best discriminators of ASC speck formation found in our nigericin-treated control analysis, we observed that HIV + patients, in general, presented elevated numbers of monocytes with spontaneous FLICA + ASC speck formation compared with healthy volunteers, independently of the viability state (Live/Dead staining low or high fluorescence) of the cells (Figures 6A–D).…”

Section: Resultsmentioning

confidence: 99%

Evaluation of Canonical Inflammasome Activation in Human Monocytes by Imaging Flow Cytometry

et al. 2019

Self Cite

View full text Add to dashboard Cite

Canonical inflammasome activation is a tightly regulated process that has been implicated in a broad spectrum of inflammatory disorders. Inflammasome formation requires assembly of a cytosolic sensor protein with the adapter, ASC (apoptosis-associated speck-like protein containing a caspase activating and recruitment domain). Once formed, this multimeric protein structure allows for the activation of caspase-1, responsible for IL-1ß/IL-18 release. During this process, cytoplasmic dispersed ASC molecules cluster in one condensed micrometric-sized complex named ASC “speck,” which is traditionally assessed by fluorescence microscopy and widely accepted as a readout for canonical inflammasome activation. However, equally reliable but less time-consuming quantitative methods have emerged as a significant need in order to improve clinical assessment of inflammasome-related conditions. Multispectral imaging flow cytometry (MIFC) combines the qualitative power of fluorescence microscopy with high throughput capabilities and multiplexing potential of flow cytometry into one single system. Here we explored the optimal imaging-based tools to measure ASC speck formation via imaging flow cytometry by using peripheral blood mononuclear cells (PBMCs) stimulated with the NLRP3 agonist Nigericin, as a positive control. We demonstrate that this technique is also able to detect the distribution of active caspase-1 within the ASC aggregates by incubating cells with FAM-FLICA TM , a fluorochrome inhibitor of caspase-1. By applying these tools in PBMCs from patients with distinct inflammatory disorders we demonstrate that MIFC is able to assess canonical inflammasome activation in a quantitative and statistically robust manner in clinically relevant samples. Therefore, we propose that accurate assessment of specks by MIFC could help guide preventive or therapeutic strategies in an array of human inflammatory diseases in which inflammasomes play an important role.

show abstract

Section: Resultsmentioning

confidence: 99%

Evaluation of Canonical Inflammasome Activation in Human Monocytes by Imaging Flow Cytometry

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition, Lisco et al. demonstrated that anti‐CD4 antibody‐mediated ADCC and aberrant inflammasome/caspase‐1 activation may be an important cause of extreme CD4 + T‐cell count decline in HIV‐1‐infected individuals with ART‐mediated viral suppression . A study by Tincati et al.…”

Section: Potential Mechanisms Of Incomplete Immune Reconstitutionmentioning

confidence: 99%

“…Total CD4 + T-cell count > 270 cells/µl at 2 years after ART initiation, with an undetectable plasma VL. 176 a Viral load.…”

Section: Definition Of "Immunological Nonresponder" Definition Of "Immentioning

confidence: 99%

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Yang

Zhang

et al. 2020

Journal of Leukocyte Biology

219

214

View full text Add to dashboard Cite

The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4+ T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4+ T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

show abstract

“…Author details 1 Division of HIV/AIDS, The second a liated hospital, also The a liated infectious disease hospital, of Soochow university, China…”

Section: Declarationsmentioning

confidence: 99%

“…Immune non-responder (INR) state usually occurs in patients who start treatment late, and whose CD4 + T cell numbers still stay at a lower level, i.e. [1]. The de nition of INR is that the virus replication is controlled by cART for 1 year, but the CD4 + T cell count is still less than 200/ul by at least two years after the treatment [2].…”

Section: Introductionmentioning

confidence: 99%

Multiple factors involved in T cell depletion in AIDS patients with immune non-responder to cART

Qian¹,

Hu²,

Zhu³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: The replication of HIV-1 can be effectively controlled by combination antiretroviral therapy (cART) at present. However, in approximately 20% of AIDS patients with undetectable viral load under effective cART, the amount of CD4+ T cells continues to be lower than normal, showing poor immune reconstitution, which is called immune non-responder (INR). The mechanism of immune reconstitution in AIDS patients is still unclear, and thus far there is no effective improvement strategy. Aim: To investigate what factors involved in T lymphocyte depletion in INR patients.Methods: A retrospective analysis of a cohort from Suzhou Infectious Disease Hospital was performed. From October 2015 to April 2019, 29 AIDS patients, whose CD4+ T cells were less than 100/ul before treatment, were included in this study. Laboratory results were obtained from the medical records, including basic clinical information, and the results of Flow cytometer detection for CD4 T cells and ELISA for T cell-related cytokines.Results: According to the number of CD4+ T cells after 24 months of treatment, the 29 patients were divided into two groups: 15 patients with CD4+ T cells <200/ul were INR, and 14 patients with CD4+ T cells >200/ul were immune responder (IR). When Compared with IR patients, the total number of red blood cells and white blood cells, especially T lymphocytes in INR patients, was significantly lower, while programmed cell death protein 1（PD-1）on CD4+T and CD8+ T lymphocyte surface were significantly higher in INR group, which implies that the probability of T cell apoptosis was greatly increased (p<0.05). ELISA results showed that the overall production of T cell-related cytokines were lower in INR group, but the amount of cytokine secreted from each T cell was higher in INR group than that in IR group due to the significant decrease of T cell in this group. Furthermore, the proportion and the killing efficiency of CD56dim subgroup of NK cells were significantly higher in INR group. Conclusion: Multiple factors are involved in the immune reconstitution in AIDS patients, including myelosuppression, T cell destruction enhanced through PD-1 pathway, over-activation of T lymphocyte, and higher killing efficiency of CD56dim subgroup of NK cells.

show abstract

Identification of rare HIV-1–infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression

Cited by 25 publications

References 37 publications

Evaluation of Canonical Inflammasome Activation in Human Monocytes by Imaging Flow Cytometry

Evaluation of Canonical Inflammasome Activation in Human Monocytes by Imaging Flow Cytometry

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Multiple factors involved in T cell depletion in AIDS patients with immune non-responder to cART

Contact Info

Product

Resources

About