Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy
Abstract
:1. Introduction
1.1. HIV Latency and the Latent Reservoir
1.2. Post-Treatment Control: A Blueprint for “Reduce and Control?”
1.3. An Overview of HIV Cure Approaches
1.4. Facilitating Immunological Control of HIV Infections
2. In Vitro and In Vivo Reactivation of Latent HIV
2.1. Histone Deacetylase (HDAC) and Histone Methytransferase (HMT) Inhibitors
2.2. BET Inhibitors
2.3. Disulfiram
2.4. PKC Agonists
2.5. Toll-like Receptor (TLR) Agonists
2.6. SMAC Mimetics
2.7. Summary and Conclusions
3. “Block and Lock”: An Alternative Strategy for A Functional Cure
3.1. Pharmacologic Inhibition of Host Factors
3.2. Small Molecule Inhibition of HIV Tat
3.3. Targeting HIV-1 mRNAs
4. Gene Editing Strategies to Attack Latent HIV Proviruses
4.1. Homing Endonucleases
4.2. Zinc Finger Proteins
4.3. TALEs
4.4. CRISPR
4.5. Summary and Conclusions
4.6. Challenges
5. Concluding Thoughts
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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HE | ZFP | TALE | CRISPR | |
---|---|---|---|---|
Target sequence constraints | High (pre-defined targets) | No constraints (any sequence) | No constraints (any sequence) | Low (PAM required) |
Target size [213,254] | 12–44 | 18–36 | 24–40 | 17–23 |
Design and assembly [213] | Difficult | Moderate | Easy | Very easy |
Toxicity [206,211,255] | Low | High | Low | Unclear, high in some cell lineages |
Specificity [211,254,256,257] | High | Low to Moderate | Moderate to High | Low to Moderate |
Multiplexing suitability [254] | Low | Low | Moderate | High |
Source [254] | Organelles, Bacteria, Phages | Bacteria, Eukaryotes | Bacteria | Bacteria |
Cost to generate knockout reagent [254] | 4000–5000 USD | 5000–10,000 USD | <1000 USD | <100 USD |
Immunogenicity [218,254] | Unknown | Low | Unknown | Prevalent pre-existing immunity |
Size of effector protein in kDa [258,259] | <40 | ~40 | ~105 | ~160 |
Average length of effector protein [258,260] | 200–300 aa | 120–180 aa | 660–700 aa | 1400 aa |
Sensitivity to chromatin condensation [261,262] | Sensitive to chromatin compactation and CpG Methylation | Binds condensed and hypermethylated DNA | Potentially decreased binding of condensed DNA | Targeting of hypermethylated CpG islands may be limited |
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Schwarzer, R.; Gramatica, A.; Greene, W.C. Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy. Viruses 2020, 12, 188. https://doi.org/10.3390/v12020188
Schwarzer R, Gramatica A, Greene WC. Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy. Viruses. 2020; 12(2):188. https://doi.org/10.3390/v12020188
Chicago/Turabian StyleSchwarzer, Roland, Andrea Gramatica, and Warner C. Greene. 2020. "Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy" Viruses 12, no. 2: 188. https://doi.org/10.3390/v12020188
APA StyleSchwarzer, R., Gramatica, A., & Greene, W. C. (2020). Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy. Viruses, 12(2), 188. https://doi.org/10.3390/v12020188