Research Article: HIV-1 gp120 envelope glycoprotein determinants for cytokine burst in human monocytes

Date Published: March 27, 2017

Publisher: Public Library of Science

Author(s): Benoît Levast, Lucie Barblu, Mathieu Coutu, Jérémie Prévost, Nathalie Brassard, Adam Peres, Camille Stegen, Joaquín Madrenas, Daniel E. Kaufmann, Andrés Finzi, Stefan Pöhlmann.

http://doi.org/10.1371/journal.pone.0174550

Abstract

The first step of HIV infection involves the interaction of the gp120 envelope glycoprotein to its receptor CD4, mainly expressed on CD4+ T cells. Besides its role on HIV-1 entry, the gp120 has been shown to be involved in the production of IL-1, IL-6, CCL20 and other innate response cytokines by bystander, uninfected CD4+ T cells and monocytes. However, the gp120 determinants involved in these functions are not completely understood. Whether signalling leading to cytokine production is due to CD4 or other receptors is still unclear. Enhanced chemokine receptor binding and subsequent clustering receptors may lead to cytokine production. By using a comprehensive panel of gp120 mutants, here we show that CD4 binding is mandatory for cytokine outburst in monocytes. Our data suggest that targeting monocytes in HIV-infected patients might decrease systemic inflammation and the potential tissue injury associated with the production of inflammatory cytokines. Understanding how gp120 mediates a cytokine burst in monocytes might help develop new approaches to improve the chronic inflammation that persists in these patients despite effective suppression of viremia by antiretroviral therapy.

Partial Text

After more than 30 years, the HIV pandemia is still a major health problem with near 37 million people infected and 2 million new infections each year [1]. Despite major efforts by scientists around the globe, there is still no effective vaccine to prevent HIV-1 acquisition. Current anti-retroviral treatment (ART) regimens are very effective in controlling viral replication and bringing plasma viral loads below detection limits. HIV infection leads to major perturbations on immune system regulatory mechanisms as CD4 T cells depletion, maturation and exhaustion of T cells and a constant immune activation are hallmarks of this infection. Previous studies have shown that chronic immune activation plays a critical role in HIV pathogenesis, contributing, besides direct infection, to progressive destruction of the CD4 T cell compartment and to the dysfunction of multiple immune cell subsets [2, 3]. HIV-induced inflammation is also described in the gastro-intestinal mucosa, leading to translocation of bacterial products [4, 5] which create an inflammatory loop that impairs epithelium integrity. Moreover, systemic inflammation and immune dysregulation persist in a significant fraction of the ART-suppressed individuals and is associated with non-AIDS defining clinical complications such as cardiovascular disease and cancer, as well as increased morbidity and mortality [2]. HIV infection is then associated with multifactorial pathogenic mechanisms, patients still present evidence of immune impairment such as expansion of myeloid derived suppressor. This inflammatory response occurs despite IL-10 production, a well-known anti-inflammatory cytokine. IL-10 is up-regulated in multiple cell types during HIV virus infection [6, 7] and blockade of IL-10 improves HIV-specific CD4 and CD8 T cells function, showing that this pathway contributes to virus-specific immune impairment.

HIV-1 enters the host cells by engaging two receptors, CD4 and one G protein coupled chemokine receptor, CCR5 or CXCR4. In this study, we focused on the importance of these receptors in the HIV envelope protein gp120 induction of cytokines. Using PBMCs from healthy donors, we identified a strong and diverse cytokine burst in response to gp120 mainly due to monocytes. Using different approaches, we identified monocytes as significant producers of IL-10, IL-1, IL-6 and CCL2 upon gp120 stimulation. These results were in accordance with previous work reporting cytokine production in the context of HIV infection [14, 39]. This burst includes IL-6, a cytokine necessary in gp120 suppressive induction as previously reported [40] but also IL-10 [6, 41]. Although monocytes were the primary responding cells, we cannot exclude the contribution of other cell populations. For example, T cells produce a lot less IL-10 than monocytes, even though IL-10 mRNA is up-regulated in T cells [6]. Our results point out to an essential role of monocytes in HIV pathogenesis and support the need of further investigation on HIV gp120 protein interaction with monocytes.

 

Source:

http://doi.org/10.1371/journal.pone.0174550

 

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