Gender differences in innate responses and gene expression profiles in memory CD4 T cells are apparent very early during acute simian immunodeficiency virus infection

George, Jeffy; Johnson, Ryan C.; Mattapallil, Mary J.; Renn, Lynnsey; Rabin, Ronald L.; Merrell, D. Scott; Mattapallil, Joseph J.

doi:10.1371/journal.pone.0221159

Cited by 6 publications

(5 citation statements)

References 83 publications

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“…Sex differences in MCP-1/CCL2 have been found in macaques, with females having significantly higher levels of MCP-1/CCL2 in their plasma compared to their male counterparts during HIV infection. The elevated levels of MCP-1 in female macaques were surprising given the lower viral loads in HIV infected women reported in earlier studies [ 27 ]. One possibility is that difference observed between males and females in serum MCP-1 production following infection is due to sex-dependent differences in monocyte trafficking.…”

Section: Discussionmentioning

confidence: 87%

An Exaggerated Immune Response in Female BALB/c Mice Controls Initial Toxoplasma gondii Multiplication but Increases Mortality and Morbidity Relative to Male Mice

et al. 2021

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Studies indicate that female mice are more susceptible to T. gondii infection, as defined by higher mortality rates in comparison to male mice. However, whether this is due to an inability to control initial parasite multiplication or due to detrimental effects of the immune system has not been determined. Therefore, the following studies were undertaken to determine the influence of sex on early parasite multiplication and the immune response during T. gondii infection and to correlate this with disease outcome. Early parasite replication was studied through applying an in vivo imaging system (IVIS) with luciferase expressing T. gondii. In parallel immunological events were studied by cytometric bead array to quantify key immunological mediators. The results confirmed the previous findings that female mice are more susceptible to acute infection, as determined by higher mortality rates and weight loss compared with males. However, conflicting with expectations, female mice had lower parasite burdens during the acute infection than male mice. Female mice also exhibited significantly increased production of Monocyte Chemoattractant Protein-1 (MCP-1), Interferon (IFN)-γ, and Tumour Necrosis Factor (TNF)-α than male mice. MCP-1 was found to be induced by T. gondii in a dose dependent manner suggesting that the observed increased levels detected in female mice was due to a host-mediated sex difference rather than due to parasite load. However, MCP-1 was not affected by physiological concentration of estrogen or testosterone, indicating that MCP-1 differences observed between the sexes in vivo are due to an as yet unidentified intermediary factor that in turn influences MCP-1 levels. These results suggest that a stronger immune response in female mice compared with male mice enhances their ability to control parasite replication but increases their morbidity and mortality.

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Section: Discussionmentioning

confidence: 87%

An Exaggerated Immune Response in Female BALB/c Mice Controls Initial Toxoplasma gondii Multiplication but Increases Mortality and Morbidity Relative to Male Mice

et al. 2021

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“…The sex-based difference in inflammation seems to be also set very early in the course of infection. In a nonhuman primate model, George et al [32] in 2019 not only showed that pathogenic sequelae seen during chronic infection was shaped early during the course of HIV infection but that female macaques already had significantly higher levels of pro-inflammatory cytokines as compared with their male counterparts day 4 postinoculation. Ultimately these female animals progressed faster to SHIV than their male counterparts [33].…”

Section: Discussionmentioning

confidence: 99%

Sex differences in cytokine profiles during suppressive antiretroviral therapy

Vanpouille

Wilkin

Mathad

et al. 2022

Aids

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Objective: Despite lower plasma HIV RNA levels, women progress faster to AIDS than men. The reasons for these differences are not clear but might be a consequence of an elevated inflammatory response in women. Methods: We investigated sex differences in cytokine profiles by measuring the concentrations of 36 cytokines/chemokines by Luminex in blood of women and men (sex at birth) with chronic HIV infection under suppressive therapy. We initially performed a principal component analysis to see if participants clustered by sex, and then fit a partial least squares discriminant analysis (PLS-DA) model where we used cytokines to predict sex at birth. The significance of the difference in nine cytokines with VIP greater than 1 was tested using Wilcoxon test-rank. Further, potential confounding factors were tested by multivariate linear regression models. Results: Overall, we predicted sex at birth in the PLS-DA model with an error rate of approximately 13%. We identified five cytokines, which were significantly higher in women compared with men, namely the pro-inflammatory chemokines CXCL1 (Gro-α), CCL5 (RANTES), CCL3 (MIP-1α), CCL4 (MIP-1β), as well as the T-cell homeostatic factor IL-7. The effect of sex remained significant after adjusting for CD4+, age, ethnicity, and race for all cytokines, except for CCL3 and race. Conclusion: The observed sex-based differences in cytokines might contribute to higher immune activation in women compared with men despite suppressive therapy. Increased levels of IL-7 in women suggest that homeostatic proliferation may have a differential contribution to HIV reservoir maintenance in female and male individuals. Our study emphasizes the importance of sex-specific studies of viral pathogenesis.

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“…— sex differences in SIV and HIV disease progression and morbidities between species, including altered expression levels of interferons and other immune response genes, 220 and differences in vaccine-induced antibody species and their functions in SIV-infected rhesus macaques; 221…”

Section: The Continued Need For Hiv/aids Vaccinesmentioning

confidence: 99%

“…significantly different transcriptome profiles in CD4 and CD8 cells between cynomolgus macaques and humans; 219 sex differences in SIV and HIV disease progression and morbidities between species, including altered expression levels of interferons and other immune response genes, 220 and differences in vaccineinduced antibody species and their functions in SIV-infected rhesus macaques; 221 differential expression of the α4β7 integrin in CD4 T-cells of different NHPs used in HIV/AIDS research, which are one of the major targets of infection and which affect the course and rate of progress of the disease; 222 differences in several interferon-induced transmembrane protein (IFITM) genes between different NHPs used in HIV/AIDS research and humans, which can restrict SIV/HIV infection and replication; 223 and species specificity of Nef and Vpu genes/proteins in overcoming restriction of SIV/HIV, mapped to just a small number of amino acids. 224 There have been a number of notable issues recently reported that could affect the translation of data from NHPs to humans, 225 namely that:…”

Section: The Continued Need For Hiv/aids Vaccinesmentioning

confidence: 99%

Poor Translatability of Biomedical Research Using Animals — A Narrative Review

Marshall

Bailey

Cassotta³

et al. 2023

Altern Lab Anim

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The failure rate for the translation of drugs from animal testing to human treatments remains at over 92%, where it has been for the past few decades. The majority of these failures are due to unexpected toxicity — that is, safety issues revealed in human trials that were not apparent in animal tests — or lack of efficacy. However, the use of more innovative tools, such as organs-on-chips, in the preclinical pipeline for drug testing, has revealed that these tools are more able to predict unexpected safety events prior to clinical trials and so can be used for this, as well as for efficacy testing. Here, we review several disease areas, and consider how the use of animal models has failed to offer effective new treatments. We also make some suggestions as to how the more human-relevant new approach methodologies might be applied to address this.

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Gender differences in innate responses and gene expression profiles in memory CD4 T cells are apparent very early during acute simian immunodeficiency virus infection

Cited by 6 publications

References 83 publications

An Exaggerated Immune Response in Female BALB/c Mice Controls Initial Toxoplasma gondii Multiplication but Increases Mortality and Morbidity Relative to Male Mice

An Exaggerated Immune Response in Female BALB/c Mice Controls Initial Toxoplasma gondii Multiplication but Increases Mortality and Morbidity Relative to Male Mice

Sex differences in cytokine profiles during suppressive antiretroviral therapy

Poor Translatability of Biomedical Research Using Animals — A Narrative Review

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