Immune activation of human brain microvascular endothelial cells inhibits HIV replication in macrophages

Li, Jieliang; Wang, Yizhong; Wang, Xu; Li, Ye; Zhou, Yu; Persidsky, Yuri; Ho, Wen‐Zhe

doi:10.1182/blood-2012-08-450353

Cited by 47 publications

(48 citation statements)

References 52 publications

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“…Meanwhile, a recent study re-emphasized the significance of the antiviral role of IFN-α by showing that blocking IFN-I receptors increased viral reservoir, T cell depletion and progression to AIDS in an SIV model (Sandler et al, 2014). Furthermore, activation of brain endothelial cells through their toll-like receptor 3 (TLR3) induces release of endogenous IFNs which, in turn, appeared to suppress the ability of HIV to replicate in brain macrophages in vitro (Li et al, 2013). Thus, future research on therapeutic options to mitigate neuroinflammatory cytokine activities such as IFN-α for neuropsychiatric outcomes of HIV, should thoroughly consider such factors as blood and CSF viral load, cART regimen, HIV disease state/course, etc.…”

Section: Pathogenesis Of Handmentioning

confidence: 99%

Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications

Hong

Banks

2015

Brain, Behavior, and Immunity

303

245

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Individuals living with HIV who are optimally treated with combination antiretroviral therapy (cART) can now lead an extended life. In spite of this remarkable survival benefit from viral suppression achieved by cART in peripheral blood, the rate of mild to moderate cognitive impairment remains high. A cognitive decline that includes impairments in attention, learning and executive function is accompanied by increased rates of mood disorders that together adversely impact the daily life of those with chronic HIV infection. The evidence is clear that cells in the brain are infected with HIV that has crossed the blood-brain barrier both as cell-free virus and within infected monocytes and T cells. Viral proteins that circulate in blood can induce brain endothelial cells to release cytokines, invoking another source of neuroinflammation. The difficulty of efficient delivery of cART to the central nervous system (CNS) contributes to elevated viral load in the CNS, resulting in a persistent HIV-associated neurocognitive disorders (HAND). The pathogenesis of HAND is multifaceted, and mounting evidence indicates that immune cells play a major role. HIV-infected monocytes and T cells not only infect brain resident cells upon migration into the CNS but also produce proinflammatory cytokines such as TNF and IL-1β, which in turn, further activate microglia and astrocytes. These activated brain resident cells, along with perivascular macrophages, are the main contributors to neuroinflammation in HIV infection and release neurotoxic factors such as excitatory amino acids and inflammatory mediators, resulting in neuronal dysfunction and death. Cytokines, which are elevated in the blood of patients with HIV infection, may also contribute to brain inflammation by entering the brain from the blood. Host factors such as aging and co-morbid conditions such as cytomegalovirus co-infection and vascular pathology are important factors that affect the HIV-host immune interactions in HAND pathogenesis. By these diverse mechanisms, HIV-1 induces a neuroinflammatory response that is likely to be a major contributor to the cognitive and behavior changes seen in HIV infection.

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Section: Pathogenesis Of Handmentioning

confidence: 99%

Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications

Hong

Banks

2015

Brain, Behavior, and Immunity

303

245

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“…In addition, the HIV lentiviral vector immunogenicity has been associated with TLR3-mediated dendritic cell activation (Breckpot et al, 2010). We recently showed that the HBMECs possess functional TLR3/RIG-I signaling pathways, the activation of which could induce antiviral factors that suppressed HIV replication in macrophages (Li et al, 2013b). However, it is unclear about the intercellular communication between HBMECs and macrophages in the context of immunity against HIV.…”

mentioning

confidence: 99%

“…We previously showed the TLR3 signaling of HBMECs by PolyI:C could induce IFN-λ (Li et al, 2013b). We therefore examined whether IFN-λ is involved in the exosome-mediated antiviral activity.…”

mentioning

confidence: 99%

Exosomes contribute to the transmission of anti-HIV activity from TLR3-activated brain microvascular endothelial cells to macrophages

et al. 2016

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Human brain microvascular endothelial cells (HBMECs), the major cell type in the blood-brain barrier (BBB), play a key role in maintaining brain homeostasis. However, their role in the BBB innate immunity against HIV invasion of the central nervous system (CNS) remains to be determined. Our early work showed that TLR3 signaling of HBMECs could produce the antiviral factors that inhibit HIV replication in macrophages. The present study examined whether exosomes from TLR3-activated HBMECs mediate the intercellular transfer of antiviral factors to macrophages. Primary human macrophages could take up exosomes from TLR3-activated HBMECs. HBMECs-derived exosomes contained multiple antiviral factors, including several key IFN-stimulated genes (ISGs; ISG15, ISG56, and Mx2) at mRNA and protein levels. The depletion of exosomes from TLR3-activated HBMECs culture supernatant diminished HBMECs-mediated anti-HIV activity in macrophages. In conclusion, we demonstrate that exosomes shed by HBMECs are able to transport the antiviral molecules to macrophages. This finding suggests the possibility that HIV nonpermissive BBB cells (HBMECs) can help to restore the antiviral state in HIV-infected macrophages, which may be a defense mechanism against HIV neuroinvasion.

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“…Blood-derived exosomes promote HIV-1 infection via CCR5/CXCR4, Gag, viral mRNA/ miRNA, TAR RNA, CD45/CD86, and tumor necrosis factor-α (TNF-α); [38][39][40][41][42][43][44] HIV-1 infection can be inhibited by the same exosomes via APOBEC3G, CD4, interferon (IFN)-α, IFN-β, and various interleukins. [45][46][47][48][49][50] Exosomes derived from breast milk or semen can also inhibit HIV-1 infection via IgA, IgG, mucin 1, and oligosaccharides, 51-53 although semenderived exosomes only inhibit HIV-1 entry specifically via mucin 6. 54 The effects of exosomes from other body fluids, such as urine, saliva, bronchoalveolar lavage, and cerebrospinal fluid, on HIV-1 entry are currently unexplored.…”

Section: Discussionmentioning

confidence: 99%

Role of TIM-4 in exosome-dependent entry of HIV-1 into human immune cells

Sims

Farrow

Williams

et al. 2017

IJN

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Exosomes, 30–200 nm nanostructures secreted from donor cells and internalized by recipient cells, can play an important role in the cellular entry of some viruses. These microvesicles are actively secreted into various body fluids, including blood, urine, saliva, cerebrospinal fluid, and breast milk. We successfully isolated exosomes from human breast milk and plasma. The size and concentration of purified exosomes were measured by nanoparticle tracking, while Western blotting confirmed the presence of the exosomal-associated proteins CD9 and CD63, clathrin, and T cell immunoglobulin and mucin proteins (TIMs). Through viral infection assays, we determined that HIV-1 utilizes an exosome-dependent mechanism for entry into human immune cells. The virus contains high amounts of phosphatidylserine (PtdSer) and may bind PtdSer receptors, such as TIMs. This mechanism is supported by our findings that exosomes from multiple sources increased HIV-1 entry into T cells and macrophages, and viral entry was potently blocked with anti-TIM-4 antibodies.

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Immune activation of human brain microvascular endothelial cells inhibits HIV replication in macrophages

Abstract: Key Points Brain ECs possess a functional TLR3/RIG-I system that is able to mount an effective IFN induction upon immune activation. Brain ECs may be a key regulatory bystander, playing a crucial role in the BBB innate immunity against HIV infection.

Cited by 47 publications

References 52 publications

Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications

Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications

Exosomes contribute to the transmission of anti-HIV activity from TLR3-activated brain microvascular endothelial cells to macrophages

Role of TIM-4 in exosome-dependent entry of HIV-1 into human immune cells

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