CNS Inflammation and Macrophage/Microglial Biology Associated with HIV-1 Infection

Yadav, Anjana; Collman, Ronald G.

doi:10.1007/s11481-009-9174-2

Cited by 176 publications

(149 citation statements)

References 245 publications

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“…9,20,38 Productive infection of the CNS can be detected within days to weeks of initial infection, primarily within perivascular macrophages, but then resolves until the development of AIDS (pre-ART) or chronic infection with HIVE lesion formation (post-ART). 23,32,38e42 Productive infection of the CNS at endstage disease may represent recrudescence of virus seeded in the CNS with primary/acute infection, reintroduction of virus into the CNS terminally with AIDS, or both.…”

mentioning

confidence: 99%

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

Nowlin

Burdo

Midkiff

et al. 2015

The American Journal of Pathology

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Macrophage recruitment to the central nervous system (CNS) during AIDS pathogenesis is poorly understood. We measured the accumulation of brain perivascular (CD163 þ ) and inflammatory (MAC387 þ ) macrophages in SIV-infected monkeys. Monocyte progenitors were 5-bromo-2 0 -deoxyuridine (BrdU) labeled in bone marrow, and CNS macrophages were labeled serially with fluorescent dextrans injected into the cisterna magna. MAC387 þ macrophages accumulated in the meninges and choroid plexus in early inflammation and in the perivascular space and SIV encephalitis (SIVE) lesions late. CD163 þ macrophages accumulated in the perivascular space and SIVE lesions with late inflammation. Most of the BrdU þ cells were MAC387 þ ; however, CD163 þ BrdU þ macrophages were present in the meninges and choroid plexus with AIDS. Most (81.6% AE 1.8%) of macrophages in SIVE lesions were present in the CNS before SIVE lesion formation. There was a 2.9-fold increase in SIVp28 þ macrophages entering the CNS late compared with those entering early (P < 0.05). The rate of CD163 þ macrophage recruitment to the CNS inversely correlated with time to death (P < 0.03) and increased with SIVE. In SIVE animals, soluble CD163 correlated with CD163 þ macrophage recruitment (P Z 0.02). Most perivascular macrophages that comprise SIVE lesions and multinucleated giant cells are present in the CNS early, before SIVE lesions are formed. Most SIV-infected macrophages traffic to the CNS terminally with AIDS.

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confidence: 99%

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

Nowlin

Burdo

Midkiff

et al. 2015

The American Journal of Pathology

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“…Following sustained viral replication in brain mononuclear phagocytes (MP) (blood-borne macrophages and microglia) and progressive immune suppression, HIV incites glial inflammation and injures neurons (for recent reviews, see 1,2 ). Such pathobiologic events result in behavioral, motor, and cognitive impairments that range from clinically asymptomatic to frank dementia, referred to as HIV-associated neurocognitive disorders (HAND).…”

Section: Introductionmentioning

confidence: 99%

Mononuclear phagocyte intercellular crosstalk facilitates transmission of cell-targeted nanoformulated antiretroviral drugs to human brain endothelial cells

Kanmogne¹,

Singh²,

Roy³

et al. 2012

IJN

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Despite the successes of antiretroviral therapy (ART), HIV-associated neurocognitive disorders remain prevalent in infected people. This is due, in part, to incomplete ART penetration across the blood-brain barrier (BBB) and lymph nodes and to the establishment of viral sanctuaries within the central nervous system. In efforts to improve ART delivery, our laboratories developed a macrophage-carriage system for nanoformulated crystalline ART (nanoART) (atazanavir, ritonavir, indinavir, and efavirenz). We demonstrate that nanoART transfer from mononuclear phagocytes (MP) to human brain microvascular endothelial cells (HBMEC) can be realized through cell-to-cell contacts, which can facilitate drug passage across the BBB. Coculturing of donor MP containing nanoART with recipient HBMEC facilitates intercellular particle transfer. NanoART uptake was observed in up to 52% of HBMEC with limited cytotoxicity. Folate coating of nanoART increased MP to HBMEC particle transfer by up to 77%. To translate the cell assays into relevant animal models of disease, ritonavir and atazanavir nanoformulations were injected into HIV-1-infected NOD/scid-γ c null mice reconstituted with human peripheral blood lymphocytes. Atazanavir and ritonavir levels in brains of mice treated with folate-coated nanoART were three-to four-fold higher than in mice treated with noncoated particles. This was associated with decreased viral load in the spleen and brain, and diminished brain CD11b-associated glial activation. We postulate that monocyte-macrophage transfer of nanoART to brain endothelial cells could facilitate drug entry into the brain.

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“…47 In addition to IFN␣2 enforced TNF␣ generation, HIV-induced macrophages produce TNF␣, 48 and elevated levels of this inflammatory mediator are detected in HAD patient CNS, further contributing to HIV entry into the brain. 49 Although detection of CaMKII activation was more challenging to assess in our cultures, this pathway can potentially enhance NFB signaling, 50 contributing to a selfperpetuating response for parental IFNs with a lesser role of CaMKII in the case of SDM1, which may explain lower phosphorylation levels of STAT1(S727). Increased STAT1(S727) phosphorylation, known to be important for most IFN transcriptional activity, may favor IDO by parental IFN compared with SDM1.…”

Section: Discussionmentioning

confidence: 99%

Structural variants of IFNα preferentially promote antiviral functions

Vázquez

Schmeisser

Dolan

et al. 2011

Blood

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IFN␣, a cytokine with multiple functions in innate and adaptive immunity and a potent inhibitor of HIV, exerts antiviral activity, in part, by enhancing apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3 (APOBEC3) family members. Although IFN␣ therapy is associated with reduced viral burden, this cytokine also mediates immune dysfunction and toxicities. Through detailed mapping of IFN␣ receptor binding sites, we generated IFN␣ hybrids and mutants and determined that structural changes in the C-helix alter the ability of IFN to limit retroviral activity. Selective IFN␣ constructs differentially block HIV replication and their directional magnitude of inhibition correlates with APOBEC3 levels. Importantly, certain mutants exhibited reduced toxicity as reflected by induced indoleamine 2,3-dioxygenase (IDO), suggesting discreet and shared intracellular signaling pathways. Defining IFN structure and function relative to APOBEC and other antiviral genes may enable design of novel IFN-related molecules preserving beneficial antiviral roles while minimizing negative effects. (Blood. 2011;118(9): 2567-2577) IntroductionHighly active antiretroviral therapy (HAART) may not eradicate all long-lived and productive reservoirs of HIV, including macrophages, 1-3 and additional approaches to viral suppression continue to center on host cell-derived molecules that antagonize the virus life cycle. Although hundreds of host cell factors are required by HIV for successful infection 4 and may serve as potential intervention targets, considerable effort has focused on those endogenous factors that contribute to cellular resistance to HIV. Among the innate intracellular HIV antagonists are the apolipoprotein-B mRNA-editing enzyme-catalytic polypeptide-like 3 (APOBEC3) family of cytidine deaminases, 5,6 and members of the tripartite motif family (TRIM), 7 but HIV has the potential to effectively eliminate or neutralize these resistance factors.In vitro studies demonstrated that IFN␣ enhances innate antiviral molecules including APOBEC family members as a counter-maneuver to HIV viral infectivity factor (VIF). 8,9 Importantly, treatment of HIV and HCV coinfected patients with pegylated-IFN␣-2a (peg-IFN␣) and Ribavirin or HIV monoinfected patients with peg-IFN␣ only 10 resulted in enhanced APOBEC expression in PBMCs along with other IFN stimulated genes (ISGs). 10 These studies illustrate the potential to alter the virus-host imbalance and suppression of de novo synthesis of HIV. Despite these promising findings, the use of IFN␣ therapeutically is fraught with potential side effects, including cytotoxicity, immune dysregulation, neuropathicity and apoptosis. [11][12][13][14] Although the use of peg-IFN␣ with its longer half-life has enabled reductions in levels of administered cytokine on a less frequent regimen, toxicity remains a deterrent.Based on the potential utility of IFN␣ in the arsenal of anti-HIV therapies, we have attempted to determine whether its antiviral capacities can be dissociated from its toxic functions....

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CNS Inflammation and Macrophage/Microglial Biology Associated with HIV-1 Infection

Cited by 176 publications

References 245 publications

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

SIV Encephalitis Lesions Are Composed of CD163+ Macrophages Present in the Central Nervous System during Early SIV Infection and SIV-Positive Macrophages Recruited Terminally with AIDS

Mononuclear phagocyte intercellular crosstalk facilitates transmission of cell-targeted nanoformulated antiretroviral drugs to human brain endothelial cells

Structural variants of IFNα preferentially promote antiviral functions

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