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.
Highlights
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]
Whether gp120 signals through different receptors is an important question that remains unclear. To start addressing this question, we characterized the cytokine profile produced by peripheral blood mononuclear cells (PBMCs) after stimulation with levels of recombinant gp120 that have been reported in vivo or in vitro [13, 14, 27, 28]
Using RT-qPCR on PBMC (Fig 1A), we identified 13 different cytokines significantly over-expressed upon gp120 stimulation
Summary
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]. HIV infection is 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. Gp120-mediated cytokine induction may help HIV to better escape the immune system, replicate and disseminate Consistent with this model, diverse amounts of soluble gp120 were shown to be present in plasma and tissue from HIV-1-infected individuals even under successful ART-treatment [13,14,15]. We report an extensive structure-function analysis of the requirements for primary human cell activation by gp120 leading to pro-inflammatory cytokine production
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