Modified interferon-α subtypes production and chemokine networks in the thymus during acute simian immunodeficiency virus infection, impact on thymopoiesis

Dutrieux, Jacques; Fabre-Mersseman, Véronique; Muylder, Bénédicte Charmeteau-De; Rancez, Magali; Ponte, Rosalie; Rozlan, Sandra; Figueiredo-Morgado, Suzanne; Bernard, Amandine; Beq, Stéphanie; Couëdel-Courteille, Anne; Cheynier, Rémi

doi:10.1097/qad.0000000000000249

Cited by 30 publications

(32 citation statements)

References 46 publications

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“…In keeping with recent observations in acutely HIV-infected humans (34, 47), absolute CD4 + T-cell counts remained stable in the gut mucosa during the first 2 weeks of SIV infection. By contrast, we showed that circulating CD4 + and CD8 + T-cell counts decreased rapidly in SIV-infected Chinese rhesus macaques, consistent with our previous observations (48). These results suggest that CD4 + and CD8 + T-cells homed into tissues.…”

Section: Discussionsupporting

confidence: 93%

Acute Simian Immunodeficiency Virus Infection Triggers Early and Transient Interleukin-7 Production in the Gut, Leading to Enhanced Local Chemokine Expression and Intestinal Immune Cell Homing

et al. 2017

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The intestinal barrier, one of the first targets of HIV/simian immunodeficiency virus (SIV) is subjected to major physiological changes during acute infection. Having previously shown that pharmaceutical injection of interleukin-7 (IL-7) triggers chemokine expression in many organs leading to massive T-cell homing, in particular to the intestine, we here explored mucosal IL-7 expression as part of the cytokine storm occurring during the acute phase of SIV infection in rhesus macaques. Quantifying both mRNA and protein in tissues, we demonstrated a transient increase of IL-7 expression in the small intestine of SIV-infected rhesus macaques, starting with local detection of the virus by day 3 of infection. We also observed increased transcription levels of several chemokines in the small intestine. In infected macaques, ileal IL-7 expression correlated with the transcription of four of these chemokines. Among these chemokines, the macrophage and/or T-cell attractant chemokines CCL4, CCL25, and CCL28 also demonstrated increased transcription in uninfected IL-7-treated monkeys. Through immunohistofluorescence staining and image analysis, we observed increased CD8+ T-cell numbers and stable CD4+ T-cell counts in the infected lamina propria (LP) during hyperacute infection. Concomitantly, circulating CCR9+beta7+ CD4+ and CD8+ T-cells dropped during acute infection, suggesting augmented intestinal homing of gut-imprinted T-cells. Finally, CD4+ macrophages transiently decreased in the submucosa and concentrated in the LP during the first days of infection. Overall, our study identifies IL-7 as a danger signal in the small intestine of Chinese rhesus macaques in response to acute SIV infection. Through stimulation of local chemokine expressions, this overexpression of IL-7 triggers immune cell recruitment to the gut. These findings suggest a role for IL-7 in the initiation of early mucosal immune responses to SIV and HIV infections. However, IL-7 triggered CD4+ T-cells and macrophages localization at viral replication sites could also participate to viral spread and establishment of viral reservoirs.

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Section: Discussionsupporting

confidence: 93%

Acute Simian Immunodeficiency Virus Infection Triggers Early and Transient Interleukin-7 Production in the Gut, Leading to Enhanced Local Chemokine Expression and Intestinal Immune Cell Homing

et al. 2017

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“…Furthermore, viral entry, viral replication kinetics, and the cytopathicity of HIV-1 in human thymocytes have been shown to be highly dependent on viral tropism, due to the predominance of CXCR4 (X4) versus CCR5 (R5) expression in the human thymus (9,12,13). Thymic disruption has also been described in nonhuman primate models of simian immunodeficiency virus infection (14).…”

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confidence: 99%

Thymic HIV-2 Infection Uncovers Posttranscriptional Control of Viral Replication in Human Thymocytes

Nunes‐Cabaço

Matoso

Foxall

et al. 2015

J Virol

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A unique HIV-host equilibrium exists in untreated HIV-2-infected individuals. This equilibrium is characterized by low to undetectable levels of viremia throughout the disease course, despite the establishment of disseminated HIV-2 reservoirs at levels comparable to those observed in untreated HIV-1 infection. Although the clinical spectrum is similar in the two infections, HIV-2 infection is associated with a much lower rate of CD4 T-cell decline and has a limited impact on the mortality of infected adults. Here we investigated HIV-2 infection of the human thymus, the primary organ for T-cell production. Human thymic tissue and suspensions of total or purified CD4 single-positive thymocytes were infected with HIV-2 or HIV-1 primary isolates using either CCR5 or CXCR4 coreceptors. We found that HIV-2 infected both thymic organ cultures and thymocyte suspensions, as attested to by the total HIV DNA and cell-associated viral mRNA levels. Nevertheless, thymocytes featured reduced levels of intracellular Gag viral protein, irrespective of HIV-2 coreceptor tropism and cell differentiation stage, in agreement with the low viral load in culture supernatants. Our data show that HIV-2 is able to infect the human thymus, but the HIV-2 replication cycle in thymocytes is impaired, providing a new model to identify therapeutic targets for viral replication control. IMPORTANCE HIV-1 infects the thymus, leading to a decrease in CD4 T-cell production that contributes to the characteristic CD4 T-cell loss.HIV-2 infection is associated with a very low rate of progression to AIDS and is therefore considered a unique naturally occurring model of attenuated HIV disease. HIV-2-infected individuals feature low to undetectable plasma viral loads, in spite of the numbers of circulating infected T cells being similar to those found in patients infected with HIV-1. We assessed, for the first time, the direct impact of HIV-2 infection on the human thymus. We show that HIV-2 is able to infect the thymus but that the HIV-2 replication cycle in thymocytes is impaired. We propose that this system will be important to devise immunotherapies that target viral production, aiding the design of future therapeutic strategies for HIV control.

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“…Thymus dysfunction is known to characterize HIV-1/SIV infections and contributes to their pathophysiology. In human thymus, thymocytes and medullary pDCs constitutively express IFNα and type I IFNs can suppress thymic output, further limiting CD4T cell recovery [82]. A strong alteration of both chemokines and IFNα subtype transcriptional patterns in SIV-infected thymuses was also recorded, and the IFNα subtypes produced in the infected thymuses inhibited thymocyte proliferation [82].…”

Section: Detrimental Effectsmentioning

confidence: 99%

Type I interferon and HIV: Subtle balance between antiviral activity, immunopathogenesis and the microbiome

Scagnolari

Antonelli

2018

Cytokine & Growth Factor Reviews

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Type I interferon (IFN) response initially limits HIV-1 spread and may delay disease progression by stimulating several immune system components. Nonetheless, persistent exposure to type I IFN in the chronic phase of HIV-1 infection is associated with desensitization and/or detrimental immune activation, thereby hindering immune recovery and fostering viral persistence. This review provides a basis for understanding the complexity and function of IFN pleiotropic activity in HIV-1 infection. In particular, the dichotomous role of the IFN response in HIV-1 immunopathogenesis will be discussed, highlighting recent advances in the dynamic modulation of IFN production in acute versus chronic infection, expression signatures of IFN subtypes, and viral and host factors affecting the magnitude of IFN response during HIV-1 infection. Lastly, the review gives a forward-looking perspective on the interplay between microbiome compositions and IFN response.

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Modified interferon-α subtypes production and chemokine networks in the thymus during acute simian immunodeficiency virus infection, impact on thymopoiesis

Cited by 30 publications

References 46 publications

Acute Simian Immunodeficiency Virus Infection Triggers Early and Transient Interleukin-7 Production in the Gut, Leading to Enhanced Local Chemokine Expression and Intestinal Immune Cell Homing

Acute Simian Immunodeficiency Virus Infection Triggers Early and Transient Interleukin-7 Production in the Gut, Leading to Enhanced Local Chemokine Expression and Intestinal Immune Cell Homing

Thymic HIV-2 Infection Uncovers Posttranscriptional Control of Viral Replication in Human Thymocytes

Type I interferon and HIV: Subtle balance between antiviral activity, immunopathogenesis and the microbiome

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