A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy

Araínga, Mariluz; Edagwa, Benson; Mosley, R. Lee; Poluektova, Larisa Y.; Gorantla, Santhi; Gendelman, Howard E.

doi:10.1186/s12977-017-0344-7

Cited by 91 publications

(92 citation statements)

References 83 publications

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“…In addition to serving as a screening tool, these particles can facilitate drug penetrance into reservoir sites by a “Trojan horse” mechanism by creating drug depots [86]. The ability to deliver therapeutics to the exact subcellular site of HIV infection provides opportunities for disease prevention and treatment.…”

Section: Discussionmentioning

confidence: 99%

Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

et al. 2018

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Antiretroviral therapy (ART) has changed the outcome of human immunodeficiency virus type one (HIV-1) infection from certain death to a life free of disease co-morbidities. However, infected people must remain on life-long daily ART. ART reduces but fails to eliminate the viral reservoir. In order to improve upon current treatment regimens, our laboratory created long acting slow effective release (LASER) ART nanoformulated prodrugs from native medicines. LASER ART enables antiretroviral drugs (ARVs) to better reach target sites of HIV-1 infection while, at the same time, improve ART's half-life and potency. However, novel ARV design has been slowed by prolonged pharmacokinetic testing requirements. To such ends, tri-modal theranostic nanoparticles were created with single-photon emission computed tomography (SPECT/CT), magnetic resonance imaging (MRI) and fluorescence capabilities to predict LASER ART biodistribution. The created theranostic ARV probes were then employed to monitor drug tissue distribution and potency. Intrinsically Indium (In) radiolabeled, europium doped cobalt-ferrite particles and rilpivirine were encased in a polycaprolactone core surrounded by a lipid shell (InEuCF-RPV). Particle cell and tissue distribution, and antiretroviral activities were sustained in macrophage tissue depots. InEuCF-PCL/RPV particles injected into mice demonstrated co-registration of MRI and SPECT/CT tissue signals with RPV and cobalt. Cell and animal particle biodistribution paralleled ARV activities. We posit that particle selection can predict RPV distribution and potency facilitated by multifunctional theranostic nanoparticles.

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Section: Discussionmentioning

confidence: 99%

Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

et al. 2018

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“…Despite the ability of long‐acting RPV and CAB used in combination to decrease the viral load in mouse animal models and their progression to phase III clinical trials, viral replication was reported in macrophages in vitro . One solution to this lack of penetration is to improve viral reserve accumulation by modifying the nanoformulations to enhance uptake by macrophages .…”

Section: Nanostructured Systems For the Treatment Of Hivmentioning

confidence: 99%

“…99 Despite the ability of long-acting RPV and CAB used in combination to decrease the viral load in mouse animal models and their progression to phase III clinical trials, viral replication was reported in macrophages in vitro. 106 One solution to this lack of penetration is to improve viral reserve accumulation by modifying the nanoformulations to enhance uptake by macrophages. 105 The Gendelman lab demonstrated improved lymph node and spleen accumulation and increased off-site accumulation in the liver and lungs of an IDV NP delivered via bone marrow-derived macrophages in humanized mice.…”

Section: Nanosuspensions/drug Npsmentioning

confidence: 99%

Harnessing nanostructured systems for improved treatment and prevention of HIV disease

Monroe

Flexner

Cui

2018

Bioengineering & Transla Med

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Combination antiretroviral therapy effectively controls human immunodeficiency virus (HIV) viral replication, delaying the progression to acquired immune deficiency syndrome and improving and extending quality of life of patients. However, the inability of antiretroviral therapeutics to target latent virus and their poor penetration of viral reserve tissues result in the need for continued treatment for the life of the patient. Side effects from long‐term antiretroviral use and the development of drug resistance due to patient noncompliance are also continuing problems. Nanostructured systems of antiretroviral therapeutics have the potential to improve targeted delivery to viral reservoirs, reduce drug toxicity, and increase dosing intervals, thereby improving treatment outcomes and enhancing patient adherence. Despite these advantages, very few nanostructured antiretroviral delivery systems have made it to clinical trials due to challenges in preclinical and clinical development. In this context, we review the current challenges in HIV disease management, and the recent progress in leveraging the unique performance of nanostructured systems in therapeutic delivery for improved treatment and prevention of this incurable human disease.

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“…Macrophages (Mφ) are permissive to productive infection with HIV and a source of viral progeny for transmission to other cell types such as T cells [1][2][3][4][5][6][7]. HIV-infected Mφ are widely distributed in tissues such as gastrointestinal and other mucosal tissues, lymph nodes and within the central nervous system where they have a life span extending from months to years [8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages

Kumar

Reh

Sxm

et al. 2019

Preprint

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Latent viral reservoirs of HIV-1 that persist despite antiretroviral therapy (ART) are major barriers for a successful cure. Macrophages serve as viral reservoirs due to their resistance to apoptosis and HIV-cytopathic effects. We have previously shown that inhibitor of apoptosis proteins (IAPs) confer resistance to HIV-Vpr-induced apoptosis in normal macrophages. Herein, we show that second mitochondrial activator of caspases (SMAC)-mimetics (SM) specifically induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, and GFP-expressing HIV, chronically infected U1 cells, and ex-vivo derived MDMs from naïve and ART-treated HIV patients. SM-induced cell death was found to be mediated by IAPs using IAP siRNAs, was independent of endogenously produced TNFα and was attributed to the concomitant downregulation of IAP-1/2 and the receptor interacting protein kinase-1 degradation following HIV infection. Altogether, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.

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A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy

Cited by 91 publications

References 83 publications

Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

Bioimaging predictors of rilpivirine biodistribution and antiretroviral activities

Harnessing nanostructured systems for improved treatment and prevention of HIV disease

Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages

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