ApoA-I Mimetic Peptides Derived From Tomato Extract Can Reduce Intestinal Inflammation Due To HIV

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A new study by researchers from the University of California Los Angeles (UCLA) has found that ApoA-I mimetic peptides, a type of anti-inflammatory and antioxidant peptides derived from tomato extract can reduce intestinal inflammation related to being infected with HIV.

The study findings were published in the peer reviewed journal: PLOS Pathogens.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010160
 

Despite antiretroviral therapy (ART), chronic treated HIV is a state of systemic inflammation and immune activation [1]. Innate immunity biomarkers of inflammation including cytokines like interleukin-(IL)-1β[2], IL-6[3,4], tumor necrosis factor-α (TNF-α)[3,5], chemokines like C-X3-C Motif Chemokine Ligand 1 (CX3CL1)/Fractalkine [6,7] and biomarkers of monocyte/macrophage (M/M) activation such as soluble CD14 (sCD14) and sCD163[1,8,9] are predictors of morbidity in people with chronic treated HIV (PWH) [1–6,8,9].

M/M rather than T cell activation is considered a more clinically relevant predictor of morbidity in chronic treated HIV [1,8,9]. Thus, there is an enormous unmet need for novel therapeutic strategies to attenuate systemic inflammation and activation of innate immunity in chronic treated HIV.

Apolipoprotein A-I (apoA-I) mimetic peptides bind bioactive lipids and endotoxin (LPS) with higher affinity than apoA-I and may be novel therapeutic agents for treatment of inflammatory diseases including cardiovascular and inflammatory bowel disease and cancer [10–14].

We have shown that an apoA-I mimetic peptide called 4F improved ex vivo antioxidant/anti-inflammatory activities of HDL from HIV-1 infected individuals with suppressed viremia on potent ART [15]. 4F attenuates gut inflammation in murine models of gut inflammation when given orally [14].

Importantly, 4F has been tested in humans [16,17] and has a safety profile that would favor its clinical testing in HIV. Another peptide named 6F that is expressed as a transgene in tomatoes, when concentrated (Tg6F) and given orally, attenuates cancer, cardiovascular and inflammatory bowel disease in mice [11–14].

Tg6F acts in the intestine, is not absorbed intact in the blood and attenuates M/M activation and intestinal inflammation [11–14]. Preclinical studies need to validate the therapeutic use of apoA-I mimetic peptides in inflammation in HIV.

Herein, we tested at the preclinical level whether the apoA-I mimetic peptides 6F and 4F may attenuate intestinal and systemic inflammation in chronic treated HIV.

To bypass limitations of preclinical animal models of chronic treated HIV, we recently described a robust translational preclinical approach, where we used both NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) and Graft versus host disease (GVHD)-resistant C57BL/6 recombination activating gene 2 (Rag2)γcCD47 triple knockout (TKO) BLT mice [18–23] on independent ART regimens and gut explants from HIV infected participants to demonstrate that apoA-I mimetics attenuate innate immune activation, gut barrier dysfunction, plasma and intestinal oxidized lipoproteins in chronic treated HIV [24].

Herein, using murine biospecimens (blood and gut tissues) and human biospecimens (gut tissues) from our recently published study [24], we demonstrate that apoA-I mimetics consistently reduce plasma and gut tissue cytokines (TNF-α, IL-6) and chemokines (CX3CL1) and gut protein levels of the chemokine receptor CX3CR1.

ApoA-I mimetics also reduced gut protein levels of the A disintegrin and metalloprotease 17 (ADAM17), an inflammation-inducible enzyme that is responsible for the protease-driven shedding of TNF-α, CX3CL1 and sCD163 [25], one of the most robust biomarkers of innate immune activation that is strongly associated with mortality in chronic treated HIV [9].

We also show that apoA-I mimetics attenuate ex vivo lipopolysaccharide (LPS)- and oxidized lipoprotein-induced upregulation of the sheddase ADAM17 that mediates release of TNF-α and CX3CL1 in gut explants of uninfected and HIV infected participants on potent ART [25].

Collectively our pre-clinical data demonstrate the potential therapeutic use of apoA-I mimetics to target the cross-talk between oxidized lipoproteins, LPS and ADAM17 to attenuate proinflammatory intestinal and systemic responses in chronic treated HIV.


Approximately 37 million people are currently living with HIV infection globally, with about 21.7 million receiving antiretroviral treatment (ART) [1]. The use of ART has greatly reduced the incidence of AIDS-related morbidity and mortality with most HIV-infected individuals having nearly normal life expectancy [2].

However, ART does not eradicate HIV [3]. People living with HIV, even after suppressive ART, experience high incidence of non-AIDS associated comorbidities, including cardiovascular disease (CVD), frailty, and osteoporosis, liver and kidney disease, and non-AIDS-associated cancers [2,[4], [5], [6], [7]]. Chronic immune activation and inflammation have been identified as the most common risk factor underlying these co-morbidities [[8], [9], [10]]. Chronic inflammation during suppressive ART is multi-factorial, with microbial translocation through the gut barrier being a significant contributor [7].

The gastrointestinal (GI) tract is the major site of HIV replication and persistence of the HIV reservoir [11,12], with early events following HIV infection resulting in rapid loss of GI mucosal integrity. These alterations lead to an increase in GI permeability and translocation of microbial products from the gut lumen across the damaged mucosa into the circulation leading to chronic systemic inflammation [7].

The significance of gut microbiota and gut integrity in HIV pathogenesis is underpinned by clinical trials showing that daily probiotic supplementation to ART-naïve HIV+ persons, decreased immune cell activation, lowered levels of serum inflammatory markers [13], and reduced microbial translocation [14]. The benefits were recapitulated in ART-suppressed HIV+ persons [15], highlighting the potential beneficial effects of some probiotic species in modulating GI disorders and impacting HIV disease progression.

However, a lack of understanding of the underlying molecular and biochemical pathways mediating chronic immune activation and inflammation in HIV+ persons precludes the discovery of novel and more specific therapeutics to eradicate gut-resident HIV-reservoir cells, and prevent non-AIDS associated comorbidities.

The causes for the “leaky gut syndrome” are multifactorial and in this review, we will showcase how lessons learnt from HIV and inflammatory bowel diseases (IBD) can enable greater understanding of etiology and mechanisms of gut dysfunction in each condition. We will also highlight how IBD itself is a potentially serious non-modifiable risk factor for the development of non-AIDS co-morbidities.

Microbial dysbiosis “the Achilles heel” of “leaky gut” associated syndromes

The complex intestinal ecosystem is comprised of trillions of bacteria performing crucial homeostatic functions [16]. Several lines of evidence have implicated alterations in the intestinal microbiota (dysbiosis) to infectious diseases and metabolic disorders such as HIV infection, obesity, and CVD, elegantly reviewed by Godfrey and colleagues [7].

In the context of HIV, disease progression is strongly associated with changes in the enteric microbiota and systemic abnormalities, a concept described as a “two-way street” [17]. This vicious pathological cycle exacerbates HIV-associated immune activation and inflammation [18]. Based on observations regarding the beneficial effects of restoring gut microbial homeostasis and immune functions in metabolic disorders and HIV, deciphering the precise molecular mechanisms is paramount.

The composition of gut bacteria varies significantly between HIV+ ART-suppressed, and HIV uninfected persons [19]. However, there is no consensus about specific bacterial diversity at genus or species level [19]. In clinical studies, several factors could act as confounders, affecting the reliability of microbiome data including: sampling differences such as mucosal versus luminal, lack of standardization in sample collection and analysis, and biological effect of diet, medications and geographic location [19].

Additionally, ART regimens, MSM (men who have sex with men) versus heterosexual males [20], level of immune activation and CD4 T cell recovery status on ART [21], as well as the use of Truvada (emtricitabine, tenofovir disoproxil fumarate) as HIV pre-exposure prophylaxis (PreP) in HIV-negative persons [22] have profound effects on the gut microbiome. Notwithstanding, an increase in members of the genus Prevotella in HIV+ versus HIV-negative healthy controls has been reported [18,21,23].

At the biochemical level, enrichment of Lactobacillales in HIV+ persons may result in catabolism of tryptophan to indole-3-aldehyde by way of the tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) [24]. This could create a vicious cycle linking dysbiosis with activation of the kynurenine/IDO pathway and pro-inflammatory cytokine production. It could further lead to a loss of Th17 cells from the gut mucosa, further compromising the integrity of the GI tract [25]. A similar increase in Proteobacteria [26] and Actinetobacteria and a decrease in Firmicutes has been reported in IBD, as well as an increased expression of IDO in intestinal biopsies [27].

Interestingly, microbial dysbiosis did not promote disease progression in simian immunodeficiency virus (SIV)-infected macaques [28], highlighting the importance of being aware of model-specific outcomes when trying to understand the mechanism of diseases in humans.

Immune cells themselves also regulate tryptophan biogenesis. In this regard, LPS-conditioned dendritic cells induce IDO isoforms that preferentially induce NF-κB inflammatory pathway, which may contribute to an immunosuppressive gut environment [29,30]. Similar immunosuppressive and tolerogenic response has been described in macrophages over-expressing IDO via Interleukin-32 (IL-32) and Toll-like receptor 9 (TLR9) stimulation [31,32].

reference link : https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6710907/

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