Actions of Retinoic Acid in the Pathophysiology of HIV Infection

Abstract

The vitamin A metabolite all-trans retinoic acid (RA) plays a key role in tissue homeostasis and mucosal immunity. RA is produced by gut-associated dendritic cells, which are among the first cells encountered by HIV. Acute HIV infection results in rapid reduction of RA levels and dysregulation of immune cell populations whose identities and function are largely controlled by RA. Here, we discuss the potential link between the roles played by RA in shaping intestinal immune responses and the manifestations and pathogenesis of HIV-associated enteropathy and similar conditions observed in SIV-infected non-human primate models. We also present data demonstrating the ability of RA to enhance the activation of replication-competent viral reservoirs from subjects on suppressive anti-retroviral therapy. The data suggest that retinoid supplementation may be a useful adjuvant for countering the pathologic condition of the gastro-intestinal tract associated with HIV infection and as part of a strategy for reactivating viral reservoirs as a means of depleting latent viral infection.

Dual role for microbial short-chain fatty acids in modifying SIV disease trajectory following anti-α4β7 antibody administration

“…To test this hypothesis, biologically relevant retinoids were quantified in the RM plasma across several time points, including baseline (prior to CD8 depletion and infection), day 14 (acute infection), day 98 (therapy), and day 161 (63 days post-cART interruption) ( Figure 4(a) ). Consistent with results from previous studies, acute infection was associated with a significant decrease in plasma atRA levels in both control and anti-α4β7-treated groups [ 22 , 40 ]. Plasma atRA levels remained depressed in the control animals during subsequent sampling.…”

“…atRA plays a pleiotropic role in the gut mucosa. Produced by both the intestinal epithelium and CD103+ dendritic cells (DCs), its generation and release signals for a significant immunomodulatory response, including the differentiation of pro-tolerogenic T-reg cells, IgA class-switching, and regulation of lymphocyte effector function [ 22 ]. Additionally, atRA induces the expression of both CCR9 and the aforementioned α4β7 integrin on diverse immune cell subsets [ 23 ].…”

MAdCAM-1 costimulation in the presence of retinoic acid and TGF-β promotes HIV infection and differentiation of CD4+ T cells into CCR5+ TRM-like cells

“…In the course of these studies we determined that, in the presence of RA, signaling by both HIV gp120 and MAdCAM-1 activates cells in a way that supports HIV infection [ 1 , 9 , 11 ]. Both RA and MAdCAM-1 are modulated in the context of HIV and SIV infection [ 72 , 73 ]. These observations raise the question as to how signaling through α 4 β 7 impacts CD4 + T cell differentiation.…”

Insilico discovering of STRA6 as a Novel Binding Receptor of Human Immunodeficiency (HIV)

“…The plasma retinoid assays showed that HIV infection did not affect the generation of RA substrates (retinol) or stored retinoids, indicating that RA decreases were driven by a metabolic malfunction 9 . According to preliminary in vitro investigations done using human CD4+ T-cell line, HIV infection was found to lower RA production, although plasma RA levels in HIV-infected patients were similar to those of NHP 9,10 . HIV-1 transgenic mice (Tg26) glomeruli also found to have poor RA metabolism 11 .…”

“…HIV-infected people are reported to have decreased plasma RA levels 8,9 . In an NHP (nonhuman primate) HIV model, plasma Retinoic Acid dropped, indicating acute VitA deficiency (VAD).…”