A hallmark of HIV-1 infection is chronic inflammation, which plays a significant role in disease pathogenesis. Acute HIV infection induces robust inflammatory responses, which are insufficient to ...prevent or eliminate virus in mucosal tissues. While establishment of viral set-point is coincident with downregulation of acute innate responses, systemic inflammatory responses persist during the course of chronic HIV infection. Since the introduction of combination antiviral therapy (cART), most HIV-1
individuals can suppress viremia under detection levels for decades. However, chronic immune activation persists and has been postulated to cause HIV associated non-AIDS complications (HANA). Importantly, inflammatory cytokines and activation markers associated with macrophages are strongly and selectively correlated with the incidence of HIV-associated neurocognitive disorder (HAND), cardiovascular dysfunctions (CVD) and other HANA conditions. In this review, we discuss the roles of macrophages in facilitating viral persistence and contributing to generation of persistent inflammatory responses.
Low levels of type I interferon (IFN-I) are thought to be a driving force for immune activation and T-cell exhaustion in HIV-1 infected individuals on combination antiretroviral therapy (cART), ...though the causative mechanisms for persistent IFN-I signaling have remained unclear. Here, we show Rev-CRM1-dependent nuclear export and peripheral membrane association of intron-containing HIV-1 RNA, independent of primary viral sequence or viral protein expression, is subject to sensing and signaling via MAVS, resulting in IFN-I-dependent pro-inflammatory responses in macrophages. Additionally, HIV-1 intron-containing-RNA-induced innate immune activation of macrophages leads to upregulation of inhibitory receptor expression and functional immune exhaustion of co-cultured T cells. Our findings suggest that persistent expression of HIV-1 intron-containing RNA in macrophages contributes to chronic immune activation and T-cell dysfunction and that use of HIV RNA expression inhibitors as adjunct therapy might abrogate aberrant inflammation and restore immune function in HIV-infected individuals on cART.
A hallmark of human immunodeficiency virus type 1 (HIV-1) infection
is chronic immune activation concomitant with type I interferon (IFN) production. Although type I IFN induces an antiviral state in ...many cell types, HIV-1 can replicate
via mechanisms that have remained unclear. We have recently identified a type I IFN-inducible protein, CD169, as the HIV-1 attachment factor on dendritic cells (DCs) that can mediate robust infection of CD4
T cells in
Since CD169 expression on macrophages is also induced by type I IFN, we hypothesized that type I IFN-inducible CD169 could facilitate productive HIV-1 infection in myeloid cells in
and CD4
T cells in
and thus offset antiviral effects of type I IFN. In support of this hypothesis, infection of HIV-1 or murine leukemia virus Env (MLV-Env)-pseudotyped HIV-1 particles was enhanced in IFN-α-treated THP-1 monocytoid cells, and this enhancement was primarily dependent on CD169-mediated enhancement at the virus entry step, a phenomenon phenocopied in HIV-1 infections of IFN-α-treated primary monocyte-derived macrophages (MDMs). Furthermore, expression of CD169, a marker of type I IFN-induced immune activation
, was enhanced in lymph nodes from pigtailed macaques infected with simian immunodeficiency virus (SIV) carrying HIV-1 reverse transcriptase (RT-SHIV), compared to uninfected macaques, and interestingly, there was extensive colocalization of p27
and CD169, suggesting productive infection of CD169
myeloid cells
While cell-free HIV-1 infection of IFN-α-treated CD4
T cells was robustly decreased, initiation of infection in
via coculture with CD169
IFN-α-treated DCs restored infection, suggesting that HIV-1 exploits CD169 in
and in
to attenuate a type I IFN-induced antiviral state.
HIV-1 infection in humans causes immune activation characterized by elevated levels of proinflammatory cytokines, including type I interferons (IFN). Although type I IFN induces an antiviral state in many cell types
, HIV-1 can replicate
via mechanisms that have remained unclear. In this study, we tested the hypothesis that CD169, a type I IFN-inducible HIV-1 attachment factor, offsets antiviral effects of type I IFN. Infection of HIV-1 was rescued in IFN-α-treated myeloid cells via upregulation of CD169 and a subsequent increase in CD169-dependent virus entry. Furthermore, extensive colocalization of viral Gag and CD169 was observed in lymph nodes of infected pigtailed macaques, suggesting productive infection of CD169
cells
Treatment of dendritic cell (DC)-T cell cocultures with IFN-α upregulated CD169 expression on DCs and rescued HIV-1 infection of CD4
T cells in
, suggesting that HIV-1 exploits CD169 to attenuate type I IFN-induced restrictions.
Gold nanoparticles (NPs) wrapped in a membrane can be utilized as artificial virus nanoparticles (AVNs) that combine the large nonblinking or bleaching optical cross-section of the NP core with the ...biological surface properties and functionalities provided by a self-assembled lipid membrane. We used these hybrid nanomaterials to test the roles of monosialodihexosylganglioside (GM3) and phosphatidylserine (PS) for a lipid-mediated targeting of virus-containing compartments (VCCs) in macrophages. GM3-presenting AVNs bind to CD169 (Siglec-1)–expressing macrophages, but inclusion of PS in the GM3-containing AVN membrane decreases binding. Molecular dynamics simulations of the AVN membrane and experimental binding studies of CD169 to GM3-presenting AVNs reveal Na⁺-mediated interactions between GM3 and PS as a potential cause of the antagonistic action on binding by the two negatively charged lipids. GM3-functionalized AVNs with no or low PS content localize to tetherin⁺, CD9⁺ VCC in a membrane composition-depending fashion, but increasing amounts of PS in the AVN membrane redirect the NP to lysosomal compartments. Interestingly, this compartmentalization is highly GM3 specific. Even AVNs presenting the related monosialotetrahexosylganglioside (GM1) fail to achieve an accumulation in VCC. AVN localization to VCC was observed for AVN with gold NP core but not for liposomes, suggesting that NP sequestration into VCC has additional requirements beyond ligand (GM3)–receptor (CD169) recognition that are related to the physical properties of the NP core. Our results confirm AVN as a scalable platform for elucidating the mechanisms of lipid-mediated viral entry pathways and for selective intracellular targeting.
Myeloid dendritic cells (DCs) can capture HIV-1 via the receptor CD169/Siglec-1 that binds to the ganglioside, GM3, in the virus particle membrane. In turn, HIV-1 particles captured by CD169, an ...I-type lectin, whose expression on DCs is enhanced upon maturation with LPS, are protected from degradation in CD169+ virus-containing compartments (VCCs) and disseminated to CD4⁺ T cells, a mechanism of DC-mediated HIV-1 trans-infection. In this study, we describe the mechanism of VCC formation and its role in immune evasion mechanisms of HIV-1. We find HIV-1-induced formation of VCCs is restricted to myeloid cells, and that the cytoplasmic tail of CD169 is dispensable for HIV-1 trafficking and retention within VCCs and subsequent trans-infection to CD4⁺ T cells. Interestingly, introduction of a di-aromatic endocytic motif in the cytoplasmic tail of CD169 that results in endocytosis of HIV-1 particles, suppressed CD169-mediated HIV-1 trans-infection. Furthermore, super-resolution microscopy revealed close association of CD169 and HIV-1 particles in surface-accessible but deep plasma membrane invaginations. Intriguingly, HIV-1 particles in deep VCCs were inefficiently accessed by anti-gp120 broadly neutralizing antibodies, VRC01 and NIH45-46 G54W, and thus were less susceptible to neutralization. Our study suggests that HIV-1 capture by CD169 can provide virus evasion from both innate (phagocytosis) and adaptive immune responses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human immunodeficiency virus type 1 (HIV-1) interactions with myeloid dendritic cells (DCs) can result in virus dissemination to CD4⁺ T cells via a trans infection pathway dependent on virion ...incorporation of the host cell derived glycosphingolipid (GSL), GM3. The mechanism of DC-mediated trans infection is extremely efficacious and can result in infection of multiple CD4⁺ T cells as these cells make exploratory contacts on the DC surface. While it has long been appreciated that activation of DCs with ligands that induce type I IFN signaling pathway dramatically enhances DC-mediated T cell trans infection, the mechanism by which this occurs has remained unclear until now. Here, we demonstrate that the type I IFN-inducible Siglec-1, CD169, is the DC receptor that captures HIV in a GM3-dependent manner. Selective downregulation of CD169 expression, neutralizing CD169 function, or depletion of GSLs from virions, abrogated DC-mediated HIV-1 capture and trans infection, while exogenous expression of CD169 in receptor-naïve cells rescued GSL-dependent capture and trans infection. HIV-1 particles co-localized with CD169 on DC surface immediately following capture and subsequently within non-lysosomal compartments that redistributed to the DC--T cell infectious synapses upon initiation of T cell contact. Together, these findings describe a novel mechanism of pathogen parasitization of host encoded cellular recognition machinery (GM3--CD169 interaction) for DC-dependent HIV dissemination.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Exacerbated and persistent innate immune response marked by pro-inflammatory cytokine expression is thought to be a major driver of chronic COVID-19 pathology. Although macrophages are not the ...primary target cells of SARS-CoV-2 infection in humans, viral RNA and antigens in activated monocytes and macrophages have been detected in post-mortem samples, and dysfunctional monocytes and macrophages have been hypothesized to contribute to a protracted hyper-inflammatory state in COVID-19 patients. In this study, we demonstrate that CD169, a myeloid cell specific I-type lectin, facilitated ACE2-independent SARS-CoV-2 fusion and entry in macrophages. CD169-mediated SARS-CoV-2 entry in macrophages resulted in expression of viral genomic and subgenomic RNAs with minimal viral protein expression and no infectious viral particle release, suggesting a post-entry restriction of the SARS-CoV-2 replication cycle. Intriguingly this post-entry replication block was alleviated by exogenous ACE2 expression in macrophages. Restricted expression of viral genomic and subgenomic RNA in CD169+ macrophages elicited a pro-inflammatory cytokine expression (TNFα, IL-6 and IL-1β) in a RIG-I, MDA-5 and MAVS-dependent manner, which was suppressed by remdesivir treatment. These findings suggest that de novo expression of SARS-CoV-2 RNA in macrophages contributes to the pro-inflammatory cytokine signature and that blocking CD169-mediated ACE2 independent infection and subsequent activation of macrophages by viral RNA might alleviate COVID-19-associated hyperinflammatory response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ganglioside GM3, a host-derived glycosphingolipid incorporated in the membrane of human immunodeficiency virus-1 (HIV-1) viral particles, mediates interactions between HIV-1 and Siglec1/CD169, a ...protein expressed on dendritic cells (DCs). Such interactions, which seem to be independent of viral envelope glycoprotein gp120, are poorly understood. Here we develop a model system consisting of self-assembled artificial virus nanoparticles (AVNs) that are free of viral glycoproteins or other host-derived glycolipids and glycoproteins. These plasmonic AVNs contain a membrane of defined composition wrapped around a solid metal core. GM3-containing AVNs are captured by CD169-expressing HeLa cells or mature DCs, and are sequestered within non-lysosomal tetraspanin-positive compartments. This distribution is reminiscent of CD169-dependent HIV-1 sequestration in mature DCs. Our results highlight GM3-CD169 binding as a gp120-independent signal for sequestration and preservation of HIV-1 infectivity. They also indicate that plasmonic AVNs offer improved features over liposome-based systems and represent a versatile tool for probing specific virus-cell interactions.
Background
Despite the anticipated efficacy of escitalopram in treating depression and anxiety in individuals with preexisting cardiovascular conditions, persistent concerns regarding its adverse ...effects have emerged. In this systematic review, we aimed to evaluate the cardiovascular safety profile of escitalopram compared with that of placebo in patients with underlying cardiovascular disease.
Methods
We used a predefined search strategy in PubMed, Cochrane Central Register of Controlled Trials, Embase, International Clinical Trials Registry Platform, and
ClinicalTrials.gov
to identify studies evaluating adverse cardiovascular reactions to escitalopram in patients with underlying cardiovascular disease. Randomized controlled trials (RCTs) that provided results on cardiovascular safety outcomes were included. Two independent reviewers screened the abstracts and full texts of the individual studies. The risk of bias was assessed using version 2 of the Cochrane risk-of-bias tool for randomized trials. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach.
Results
The primary outcomes were the frequency of major adverse cardiovascular events (MACE), QTc prolongation, and discontinuation of study medication. We identified 5 RCTs with 773 participants who met the inclusion criteria. Escitalopram was not associated with significantly increased risk of MACE (risk ratio RR = 1.85; 95% confidence interval CI 0.80 to 4.26;
I
2
0%; 5 RCTs;
n
= 773, moderate certainty of evidence), discontinuation of study medication (RR = 1.03; 95% CI 0.84–1.26;
I
2
0%; 5 RCTs;
n
= 773, low certainty of evidence), and QTc prolongation (RR = 1.20; 95% CI 0.76–1.90;
I
2
0%; 4 RCTs;
n
= 646, low certainty of evidence).
Conclusion
Escitalopram does not significantly increase the risk of cardiovascular adverse reactions compared with placebo in patients with underlying cardiovascular disease. However, the presence of wide CIs and the limited number of included studies highlight the need for further studies with larger sample sizes to enhance the precision and reliability of these findings.
Systematic review registration
: International Prospective Register of Systematic Reviews CRD42022298181.
The monosialodihexosylganglioside, GM3, and its binding to CD169 (Siglec‐1) have been indicated as key factors in the glycoprotein‐independent sequestration of the human immunodeficiency virus‐1 ...(HIV‐1) in virus‐containing compartments (VCCs) in myeloid cells. Here, lipid‐wrapped polymer nanoparticles (NPs) are applied as a virus‐mimicking model to characterize the effect of core stiffness on NP uptake and intracellular fate triggered by GM3‐CD169 binding in macrophages. GM3‐functionalized lipid‐wrapped NPs are assembled with poly(lactic‐co‐glycolic) acid (PLGA) as well as with low and high molecular weight polylactic acid (PLAlMW and PLAhMW) cores. The NPs have an average diameter of 146 ± 17 nm and comparable surface properties defined by the self‐assembled lipid layer. Due to differences in the glass transition temperature, the Young's modulus (E) differs substantially under physiological conditions between PLGA (EPLGA = 60 ± 32 MPa), PLAlMW (EPLAlMW = 86 ± 25 MPa), and PLAhMW (EPLAhMW = 1.41 ± 0.67 GPa) NPs. Only the stiff GM3‐presenting PLAhMW NPs but not the softer PLGA or PLAlMW NPs avoid a lysosomal pathway and localize in tetraspanin (CD9)‐positive compartments that resemble VCCs. These observations suggest that GM3‐CD169‐induced sequestration of NPs in nonlysosomal compartments is not entirely determined by ligand–receptor interactions but also depends on core stiffness.
Human immunodeficiency virus‐1 mimicking monosialodihexosylganglioside‐presenting polymeric nanoparticles with different core stiffnesses are generated, and their intracellular fate in CD169‐expressing macrophages is monitored. It is found that ligand and core stiffness together determine the intracellular fate of the lipid‐wrapped nanoparticles. These findings provide new insights into the importance of the mechanical properties of the virus particle for its function in infection.
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