Clinical characteristics of HIV-1-infected patients with high levels of plasma interferon-γ: a multicenter observational study

Watanabe, Dai; Uehira, Tomoko; Suzuki, Sachiko; Matsumoto, Erina; Ueji, Takashi; Hirota, Kaoru; Minami, Ryoji; Takahama, Soichiro; Hayashi, K.; Sawamura, Morio; Yamamoto, Masahiro; Shirasaka, Takuma

doi:10.1186/s12879-018-3643-2

Cited by 23 publications

(14 citation statements)

References 44 publications

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“…Previous reports indicate that interferon gamma (IFN-γ), which is produced in response to HIV infection, is a potent inducer of APOL1 expression in vitro and that IFN-γ treatment can cause collapsing focal segmental glomerulosclerosis (FSGS) in humans with a high-risk APOL1 genotype ( Nichols et al, 2015 ). However, the half-life of interferon is very short in vivo , making it difficult to model the sustained levels observed during human HIV infection or IFN-γ treatment in mice ( Roff et al, 2013 ; Watanabe et al, 2019 ; Markowitz et al, 2010 ). This issue can be circumvented by utilizing an IFN-γ-expressing pCpGfree plasmid that lacks CpG motifs (pCpG-Muγ), expression of which results in sustained serum IFN-γ levels for weeks after tail vein injection ( Mitsui et al, 2009 ).…”

Section: Resultsmentioning

confidence: 99%

Recessive, gain-of-function toxicity in an APOL1 BAC transgenic mouse model mirrors human APOL1 kidney disease

McCarthy

Blasio

Donovan

et al. 2021

Disease Models &Amp; Mechanisms

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People of recent sub-Saharan African ancestry develop kidney failure much more frequently than other groups. A large fraction of this disparity is due to two coding sequence variants in the APOL1 gene. Inheriting two copies of these APOL1 risk variants, known as G1 and G2, causes high rates of focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy and hypertension-associated end-stage kidney disease. Disease risk follows a recessive mode of inheritance, which is puzzling given the considerable data that G1 and G2 are toxic gain-of-function variants. We developed coisogenic bacterial artificial chromosome (BAC) transgenic mice harboring either the wild-type (G0), G1 or G2 forms of human APOL1. Expression of interferon gamma (IFN-γ) via plasmid tail vein injection results in upregulation of APOL1 protein levels together with robust induction of heavy proteinuria and glomerulosclerosis in G1/G1 and G2/G2 but not G0/G0 mice. The disease phenotype was greater in G2/G2 mice. Neither heterozygous (G1/G0 or G2/G0) risk variant mice nor hemizygous (G1/−, G2/−) mice had significant kidney injury in response to IFN-γ, although the heterozygous mice had a greater proteinuric response than the hemizygous mice, suggesting that the lack of significant disease in humans heterozygous for G1 or G2 is not due to G0 rescue of G1 or G2 toxicity. Studies using additional mice (multicopy G2 and a non-isogenic G0 mouse) supported the notion that disease is largely a function of the level of risk variant APOL1 expression. Together, these findings shed light on the recessive nature of APOL1-nephropathy and present an important model for future studies.

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Section: Resultsmentioning

confidence: 99%

Recessive, gain-of-function toxicity in an APOL1 BAC transgenic mouse model mirrors human APOL1 kidney disease

McCarthy

Blasio

Donovan

et al. 2021

Disease Models &Amp; Mechanisms

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“…For instance, plasma IL-6 and IL-10 levels have been reported to be decreased in HAART-experienced while IL-4 remained unchanged [14][15][16] . Additionally, IFN-γ levels have been reported to be elevated in HIV patients on HAART [16][17][18] . Cellular analyses have also revealed increased IL-10 and TGF-β specific natural killer (NK) cells in patients on antiretroviral treatment 19 .…”

Section: Introductionmentioning

confidence: 99%

Cytokine profiles in highly active antiretroviral treatment non-adherent, adherent and naive HIV-1 infected patients in Western Kenya

Musa¹,

Shaviya²,

Mambo³

et al. 2021

Afr H. Sci.

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Background: Cytokines play an important role in signaling the immune system to build an adequate immune responseagainst HIV. HIV distorts the balance between pro and anti-inflammatory cytokines causing viral replication. Highly active antiretroviral treatment (HAART) acts by trying to restore pro and anti-inflammatory cytokine balance. It is not clear how HAART non-adherence influences circulating cytokine levels. This study therefore determined cytokine levels in HAART non-adherent individuals. Methods: This cross-sectional study recruited 163 participants (51 controls, 23 HIV-1+ HAART naive, 28 HAART-adherent6 months, 19 HAART-adherent 12 months and 42 HAART non-adherent). Cytokines were analyzed by ELISA while CD4 T cells determined in 3.0 μl of whole blood using BD FACSCaliburTM and viral load in 0.2ml plasma sample using Abbott Molecular m2000sp sample preparation and m2000rt real-time amplification and detection systems (Abbott MolecularInc., Illinois, USA) according to the manufacturer’s methods. Results: IL-4, IL-6, IL-10, TNF-α and TGF-β were significantly elevated in HIV-1 HAART non-adherent compared withHIV-1 HAART adherent and healthy controls P<0.01. IFN- γ was significantly decreased in HIV-1 HAART non-adherentcompared with HIV-1 HAART adherent and healthy controls P<0.01. TNF-α and TGF-β were significantly reduced in HIV-1 HAART adherent patients at 12 months compared to those at 6 months P<0.01. IL-4 and IL-10 correlated positively withviral load. IL-4, IL-6, IL-10, TNF-α and TGF- β associated inversely with CD4 T cell counts and body mass index (BMI). Conclusion: This study established that HAART adherence is immunologically beneficial to the pro and anti-inflammatory cytokine balance milieu while non-adherence appears to cause alterations in pro and anti-inflammatory cytokines warping the balance in this dichotomy. Keywords: Cytokines; non-adherence; HAART.

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“…Another concordance result was found in Watanabe and college study, which also addressed the negative correlation between IFN-γ and the number of CD4 count in patients with ART treatment. 19 These results suggested the possible use of IFN-γ as a monitoring tool for the immunological suppression in patients with HIV infection during antiretroviral treatment, so as to avoid drug suppress of immune activity. However, this strategy has some limitations.…”

Section: Discussionmentioning

confidence: 86%

Interferon Gamma and Soluble MICA as A New Biomarker for Immunological Severity Detection in HIV Infected Patients Undergoing Retroviral Therapy

Rareongjai

Pongtassanaham²,

Bhuddhisa

et al. 2021

J Health Sci Med Res

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Objective: Variations in immune responses to viral particles and antiretroviral drugs show interference of the cluster of differentiation number 4 T cell monitoring methods, leading to an inaccurate evaluation for human immunodeficiency virus infected patients receiving antiretroviral therapy. Other biological markers; such as cytokine; especially interferon gamma (IFN-γ) and soluble molecules of major histocompatibility complex class I chain related molecule A (sMICA), were designed as a novel severity marker.Material and Methods: Levels of IFN-γ and sMICA were evaluated for 69 patients, who presented with HIV infection; with no other diseases or inflammation. The candidates were classified into four groups, depending on their CD4 T cell count. The IFN-γ and sMICA serum content of the patients was detected in triplicate, using enzyme-linked immunosorbent assay.Results: Mean value of IFN-γ in each severity group was 49.1±9.7, 69.1±21.8, 63.0±12.8, and 69.4±18.4 picograms/ milliliter for none, mild, advanced, and severe cases, respectively. sMICA was detected at 36.8±19.6, 134.7±122.5, 33.6±12.4, and 83.9±40.0 international unit/milliliter, respectively. A significant association between IFN-γ and CD4 cells of normal anti-retroviral treatment response, defined by CD4 cells and viral loads, was observed using Spearman correlation, with p-values 0.033, r -0.434, 0.026 and -0.321, respectively. Conclusion: IFN-γ and sMICA were found to be associated with the CD4 count in the normal responses to antiretroviral treatment. This suggested that IFN-γ could be used as a biological marker for monitoring of immunological severity during anti-retroviral responses.

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Clinical characteristics of HIV-1-infected patients with high levels of plasma interferon-γ: a multicenter observational study

Cited by 23 publications

References 44 publications

Recessive, gain-of-function toxicity in an APOL1 BAC transgenic mouse model mirrors human APOL1 kidney disease

Recessive, gain-of-function toxicity in an APOL1 BAC transgenic mouse model mirrors human APOL1 kidney disease

Cytokine profiles in highly active antiretroviral treatment non-adherent, adherent and naive HIV-1 infected patients in Western Kenya

Interferon Gamma and Soluble MICA as A New Biomarker for Immunological Severity Detection in HIV Infected Patients Undergoing Retroviral Therapy

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