Roles of autophagy in HIV infection

Dinkins, Christina; Pilli, Manohar; Kehrl, John H.

doi:10.1038/icb.2014.88

Cited by 59 publications

(57 citation statements)

References 86 publications

(135 reference statements)

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“…Separate reviews on this topic have appeared, and the interested reader is directed to an excellent recent article for a much more detailed analysis. (Dinkins et al, 2014) However, a brief survey of the HIV-autophagy literature is informative with respect to the very different relationships viruses and autophagy have depending on the cellular context.…”

Section: The Complex Relationship Between Hiv and Autophagymentioning

confidence: 99%

Viruses and the autophagy pathway

2015

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Studies of the cellular autophagy pathway have exploded over the past twenty years. Now appreciated as a constitutive degradative mechanism that promotes cellular homeostasis, autophagy is also required for a variety of developmental processes, cellular stress responses, and immune pathways. Autophagy certainly acts as both an anti-viral and pro-viral pathway, and the roles of autophagy depend on the virus, the cell type, and the cellular environment. The goal of this review is to summarize, in brief, what we know so far about the relationship between autophagy and viruses, particularly for those who are not familiar with the field. With a massive amount of relevant published data, it is simply not possible to be comprehensive, or to provide a complete “parade of viruses”, and apologies are offered to researchers whose work is not described herein. Rather, this review is organized around general themes regarding the relationship between autophagy and animal viruses.

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Section: The Complex Relationship Between Hiv and Autophagymentioning

confidence: 99%

Viruses and the autophagy pathway

2015

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“…Autophagosomes play a vital role in HIV-1 biogenesis (51,52). In macrophages, autophagy is stimulated by HIV-1 through the TLR8 signaling that occurs at early stages of infection, while during chronic infection, autophagy is inhibited.…”

Section: Methodsmentioning

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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“…Beclin1 can act as a positive regulator of autophagy and confers specificity to the phosphatidylinositol-3 kinase -Vps34-Atg14 complex, which is essential for autophagosome formation, and by interacting with the anti-apoptotic protein Bcl2, autophagy is inhibited (Parzych and Klionsky, 2014). In the last decade, numerous evidence has shown that autophagy is a critical target for HIV during the viral life cycle which has led to an increasing effort to understand the role of autophagy in those cells affected by HIV infection (Dinkins et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Electro-Magnetic Nano-Particle Bound Beclin1 siRNA Crosses the Blood–Brain Barrier to Attenuate the Inflammatory Effects of HIV-1 Infection in Vitro

Rodriguez

Kaushik

Lapierre

et al. 2016

J Neuroimmune Pharmacol

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The purpose of this study was to evaluate a novel drug delivery system comprised of ferric-cobalt electro-magnetic nano-material (CoFe2O4@ BaTiO3; MENP) bound to siRNA targeting Beclin1 (MENP-siBeclin1) to cross the blood-brain barrier (BBB) and attenuate the neurotoxic effects of HIV-1 infection in the central nervous system following on-demand release of siRNA using an in vitro primary human BBB model. Beclin1 is a key protein in the regulation of the autophagy pathway and we have recently demonstrated the importance of Beclin1 in regulating viral replication and viral-induced inflammation in HIV-1-infected microglia. The MENP-siBeclin1 nano-formulation did not compromise the physiological function or integrity of the BBB model. Furthermore, the in vitro BBB data revealed that MENP-siBeclin1 could efficiently attenuate viral replication, viral-induced inflammation and silence Beclin1 protein expression in HIV-1-infected microglial cells within the model system. In addition, the cytotoxic effects of direct treatment with siBeclin1 and MENP alone or in nano-formulation on primary human neuronal cells showed a minimal amount of cell death. Overall, the data shows that the nano-formulation can silence the BECN1 gene as an effective mechanism to attenuate HIV-1 replication and viral-induced inflammation in the context of the BBB.

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Roles of autophagy in HIV infection

Cited by 59 publications

References 86 publications

Viruses and the autophagy pathway

Viruses and the autophagy pathway

Autophagy facilitates macrophage depots of sustained-release nanoformulated antiretroviral drugs

Electro-Magnetic Nano-Particle Bound Beclin1 siRNA Crosses the Blood–Brain Barrier to Attenuate the Inflammatory Effects of HIV-1 Infection in Vitro

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