Challenges and strategies for the eradication of the HIV reservoir

Kimata, Jason T.; Rice, Andrew P.; Wang, Jin

doi:10.1016/j.coi.2016.05.015

Cited by 52 publications

(50 citation statements)

References 57 publications

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“…Detection of virus in such body tissues remains a major challenge in viral eradication [11, 22, 24, 25, 54, 55]. HIV-1 infection is continuous at low levels in lymphoid, gut and central nervous system compartments but exists as a source to propagate progeny infection [11, 22, 24, 25].…”

Section: Discussionmentioning

confidence: 99%

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Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging

et al. 2017

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The size, shape and chemical composition of europium (Eu3+) cobalt ferrite (CFEu) nanoparticles were optimized for use as a “multimodal imaging nanoprobe” for combined fluorescence and magnetic resonance bioimaging. Doping Eu3+ ions into a CF structure imparts unique bioimaging and magnetic properties to the nanostructure that can be used for real-time screening of targeted nanoformulations for tissue biodistribution assessment. The CFEu nanoparticles (size ~7.2 nm) were prepared by solvothermal techniques and encapsulated into poloxamer 407-coated mesoporous silica (Si-P407) to form superparamagnetic monodisperse Si-CFEu nanoparticles with a size of ~ 140 nm. Folic acid (FA) nanoparticle decoration (FA-Si-CFEu, size ~ 140 nm) facilitated monocyte-derived macrophage (MDM) targeting. FA-Si-CFEu MDM uptake and retention was higher than seen with Si-CFEu nanoparticles. The transverse relaxivity of both Si-CFEu and FA-Si-CFEu particles were r2= 433.42 mM−1s−1 and r2= 419.52 mM−1s−1 (in saline) and r2= 736.57 mM−1s−1 and r2= 814.41 mM−1s−1 (in MDM), respectively. The results were greater than a log order-of-magnitude than what was observed at replicate iron concentrations for ultrasmall superparamagnetic iron oxide (USPIO) particles (r2= 31.15 mM−1s−1 in saline) and paralleled data sets obtained for T2 magnetic resonance imaging. We now provide a developmental opportunity to employ these novel particles for theranostic drug distribution and efficacy evaluations.

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Section: Discussionmentioning

confidence: 99%

“…HIV-1 infection is continuous at low levels in lymphoid, gut and central nervous system compartments but exists as a source to propagate progeny infection [11, 22, 24, 25]. Thus, innovations that improve penetrance of ARV into HIV sanctuaries have remained a major focus in HIV cure strategies [25, 55]. …”

Section: Discussionmentioning

confidence: 99%

Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging

et al. 2017

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“…These persistently infected cells form virus reservoirs for resupply of circulating virus and contribute to virus pathogenicity by producing toxic viral products. While current antiviral treatments can block virus replication, there is no established treatment to inactivate persisting viral genomes (Kimata, Rice, & Wang, ).…”

Section: Introductionmentioning

confidence: 99%

Synthetic AAV/CRISPR vectors for blocking HIV‐1 expression in persistently infected astrocytes

Kunze

Börner

Kienle

et al. 2017

Glia

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Astrocytes, the most abundant cells in the mammalian brain, perform key functions and are involved in several neurodegenerative diseases. The human immunodeficiency virus (HIV) can persist in astrocytes, contributing to the HIV burden and neurological dysfunctions in infected individuals. While a comprehensive approach to HIV cure must include the targeting of HIV-1 in astrocytes, dedicated tools for this purpose are still lacking. Here we report a novel Adeno-associated virus-based vector (AAV9P1) with a synthetic surface peptide for transduction of astrocytes. Analysis of AAV9P1 transduction efficiencies with single brain cell populations, including primary human brain cells, as well as human brain organoids demonstrated that AAV9P1 targeted terminally differentiated human astrocytes much more efficiently than neurons. We then investigated whether AAV9P1 can be used to deliver HIV-inhibitory genes to astrocytes. To this end we generated AAV9P1 vectors containing genes for HIV-1 proviral editing by CRISPR/Cas9. Latently HIV-1 infected astrocytes transduced with these vectors showed significantly diminished reactivation of proviruses, compared with untransduced cultures. Sequence analysis identified mutations/deletions in key HIV-1 transcriptional control regions. We conclude that AAV9P1 is a promising tool for gene delivery to astrocytes and may facilitate inactivation/destruction of persisting HIV-1 proviruses in astrocyte reservoirs.

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“…The next frontier for antiretroviral therapy (ART) rests in easing drug use, targeting viral reservoirs, extending drug half-life, reducing viral mutations, and overcoming systemic toxicity (1)(2)(3). We previously developed, characterized, and tested therapeutic responses of long-acting nanoformulated ART (nanoART) (4)(5)(6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Gnanadhas¹,

Dash²,

Sillman³

et al. 2017

Journal of Clinical Investigation

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Long-acting anti-HIV products can substantively change the standard of care for patients with HIV/AIDS. To this end, hydrophobic antiretroviral drugs (ARVs) were recently developed for parenteral administration at monthly or longer intervals. While shorter-acting hydrophilic drugs can be made into nanocarrier-encased prodrugs, the nanocarrier encasement must be boosted to establish long-acting ARV depots. The mixed-lineage kinase 3 (MLK-3) inhibitor URMC-099 provides this function by affecting autophagy. Here, we have shown that URMC-099 facilitates ARV sequestration and its antiretroviral responses by promoting the nuclear translocation of the transcription factor EB (TFEB). In monocyte-derived macrophages, URMC-099 induction of autophagy led to retention of nanoparticles containing the antiretroviral protease inhibitor atazanavir. These nanoparticles were localized within macrophage autophagosomes, leading to a 4-fold enhancement of mitochondrial and cell vitality. In rodents, URMC-099 activation of autophagy led to 50-fold increases in the plasma drug concentration of the viral integrase inhibitor dolutegravir. These data paralleled URMC-099-mediated induction of autophagy and the previously reported antiretroviral responses in HIV-1-infected humanized mice. We conclude that pharmacologic induction of autophagy provides a means to extend the action of a long-acting, slow, effective release of antiretroviral therapy. Center for Neural Development and Disease, University of Rochester Medical Center (URMC), Rochester, New York, USA. Conflict of interest:H.A. Gelbard and H.E. Gendelman are members of the scientific advisory board for WavoDyne Therapeutics Inc., which is developing URMC-099 as a firstin-class MLK-3 inhibitor for clinical trials. URMC-099 is owned by URMC (patent nos. US 8,846,909 B2;8,877,772;and 9,181,247 and associated international patents). tion of TFEB mRNA by approximately 4-to 8-fold under different treatment conditions ( Figure 2F). With HIV-1 infection, TFEB mRNA levels were reduced by 2-to 3-fold compared with levels in uninfected controls, and URMC-099 could recover the phenotype. Increased TFEB translocation was delayed and did not reach significant levels until day 7 after URMC-099 treatment (Supplemental Figure 2B). These data confirm that URMC-099 regulates TFEB nuclear translocation in an mTORC1-dependent manner. URMC-099 stimulates autophagy in human MDMs. On the basis of the preceding data sets, we theorized that nuclear translocation of TFEB induces autophagy and lysosomal biogenesis. TFEB serves as the master regulator of both autophagy and lysosomal biogenesis (26), and such regulation could have a profound role in nanoART intracellular sequestration in MDMs. Thus, we examined the autophagosome markers microtubule-associated protein 1 light chain 3 β (LC3B, also known as MAP1LC3B) and beclin 1 (BECN1). Using Western blot assays, we found that each marker was significantly upregulated by URMC-099 ( Figure 3, A-C and Supplemental Figure 3A). URMC-099 increased the expression ...

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Challenges and strategies for the eradication of the HIV reservoir

Cited by 52 publications

References 57 publications

Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging

Development of europium doped core-shell silica cobalt ferrite functionalized nanoparticles for magnetic resonance imaging

Synthetic AAV/CRISPR vectors for blocking HIV‐1 expression in persistently infected astrocytes

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

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