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Article: Improved Detection of HIV Gag p24 Protein Using a Combined Immunoprecipitation and Digital ELISA Method.

Wu, Guoxin / Cheney, Carol / Huang, Qian / Hazuda, Daria J / Howell, Bonnie J / Zuck, Paul

2021 Volume 12, Page(s) 636703

Abstract: Greater than 90% of HIV-1 proviruses are thought to be defective and incapable of viral replication. While replication competent proviruses are of primary concern with respect to disease progression or transmission, studies have shown that even defective ...

Abstract	Greater than 90% of HIV-1 proviruses are thought to be defective and incapable of viral replication. While replication competent proviruses are of primary concern with respect to disease progression or transmission, studies have shown that even defective proviruses are not silent and can produce viral proteins, which may contribute to inflammation and immune responses. Viral protein expression also has implications for immune-based HIV-1 clearance strategies, which rely on antigen recognition. Thus, sensitive assays aimed at quantifying both replication-competent proviruses and defective, yet translationally competent proviruses are needed to understand the contribution of viral protein to HIV-1 pathogenesis and determine the effectiveness of HIV-1 cure interventions. Previously, we reported a modified HIV-1 gag p24 digital enzyme-linked immunosorbent assay with single molecule array (Simoa) detection of cell-associated viral protein. Here we report a novel p24 protein enrichment method coupled with the digital immunoassay to further extend the sensitivity and specificity of viral protein detection. Immunocapture of HIV gag p24 followed by elution in a Simoa-compatible format resulted in higher protein recovery and lower background from various biological matrices and sample volumes. Quantification of as little as 1 fg of p24 protein from cell lysates from cells isolated from peripheral blood or tissues from ART-suppressed HIV participants, as well as simian-human immunodeficiency virus-infected non-human primates (NHPs), with high recovery and reproducibility is demonstrated here. The application of these enhanced methods to patient-derived samples has potential to further the study of the persistent HIV state and examine
Language	English
Publishing date	2021-03-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2021.636703
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Article ; Online: Development of a fully automated platform for agar-based measurement of viable bacterial growth.

Squadroni, Brian / Newhard, William / Carr, Donna / Trinh, Huong / Racine, Fred / Zuck, Paul / Howell, Bonnie / Hazuda, Daria J / Cassaday, Jason

SLAS technology

2022 Volume 27, Issue 4, Page(s) 247–252

Abstract: Dynamic in vitro antibacterial studies provide valuable insight on effective dosing strategies prior to translating to in vivo models. Frequent sampling is required to monitor the pharmacodynamics (PD) of these studies, leading to significant work when ... ...

Abstract	Dynamic in vitro antibacterial studies provide valuable insight on effective dosing strategies prior to translating to in vivo models. Frequent sampling is required to monitor the pharmacodynamics (PD) of these studies, leading to significant work when quantifying the bacterial load of the samples. Spreading a bacterial suspension on agar to allow colony counting is a proven process for measuring very low levels of growth, but commercial automation equipment to handle agar plating and colony counting at scale is not readily available. We describe a process to greatly decrease the hands-on time required for PD assays by utilizing general-purpose liquid handling robots to plate bacteria and a custom-made plate imager to automate colony counting. The platform developed handles the biological assay from beginning to end as well as sample tracking at each step of the process. The process relies heavily on custom automation scheduling software to enable dynamic process decisions and coordinate data flow throughout. Using the described platform, we can efficiently quantify >100 PD samples per day while maintaining the necessary dynamic range of the assay. Alleviating the main bottleneck in the dynamic antibacterial studies has allowed us to accelerate the rate of experiments to provide antibacterial dosing data within shorter timelines.
MeSH term(s)	Agar ; Anti-Bacterial Agents/pharmacology ; Automation ; Bacteria ; Software
Chemical Substances	Anti-Bacterial Agents ; Agar (9002-18-0)
Language	English
Publishing date	2022-03-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2900310-6
ISSN	2472-6311 ; 2472-6303
ISSN (online)	2472-6311
ISSN	2472-6303
DOI	10.1016/j.slast.2022.03.003
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Article ; Online: In Vitro Pharmacokinetic/Pharmacodynamic Modeling of HIV Latency Reversal by Novel HDAC Inhibitors Using an Automated Platform.

Newhard, William / Patel, Munjal / Cassaday, Jason / Ballard, Jeanine / Squadroni, Brian / Wu, Guoxin / Liu, Jian / Yu, Wensheng / Kozlowski, Joe / Zuck, Paul / Howell, Bonnie / Hazuda, Daria / Vargo, Ryan / Barnard, Richard

SLAS discovery : advancing life sciences R & D

2021 Volume 26, Issue 5, Page(s) 642–654

Abstract: Antiretroviral therapy is able to effectively control but not eradicate HIV infection, which can persist, leading to the need for lifelong therapy. The existence of latently HIV-infected cells is a major barrier to the eradication of chronic HIV ... ...

Abstract	Antiretroviral therapy is able to effectively control but not eradicate HIV infection, which can persist, leading to the need for lifelong therapy. The existence of latently HIV-infected cells is a major barrier to the eradication of chronic HIV infection. Histone deacetylase inhibitors (HDACis), small molecules licensed for oncology indications, have shown the ability to produce HIV transcripts in vitro and in vivo. The pharmacologic parameters that drive optimal HIV latency reversal in vivo are unknown and could be influenced by such factors as the HDACi binding kinetics, concentration of compound, and duration of exposure. This study evaluates how these parameters affect HIV latency reversal for a series of novel HDACis that differ in their enzymatic on and off rates. Varying cellular exposure, using automated washout methods of HDACi in a Jurkat cell model of HIV latency, led to the investigation of the relationship between pharmacokinetic (PK) properties, target engagement (TE), and pharmacodynamic (PD) responses. Using an automated robotic platform enabled miniaturization of a suspension cell-based washout assay that required multiple manipulations over the 48 h duration of the assay. Quantification of histone acetylation (TE) revealed that HDACis showed early peaks and differences in the durability of response between different investigated HDACis. By expanding the sample times, the shift between TE and PD, as measured by green fluorescent protein, could be fully characterized. The comprehensive data set generated by automating the assays described here was used to establish a PK/PD model for HDACi-induced HIV latency reversal.
MeSH term(s)	Automation, Laboratory ; Cell Culture Techniques ; Cells, Cultured ; Gene Expression Regulation, Viral/drug effects ; HIV/drug effects ; HIV/genetics ; HIV Infections/drug therapy ; HIV Infections/virology ; Histone Deacetylase Inhibitors/pharmacokinetics ; Humans ; Jurkat Cells ; Models, Theoretical ; Virus Latency/drug effects ; Virus Replication/drug effects
Chemical Substances	Histone Deacetylase Inhibitors
Language	English
Publishing date	2021-01-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2885123-7
ISSN	2472-5560 ; 2472-5552
ISSN (online)	2472-5560
ISSN	2472-5552
DOI	10.1177/2472555220983810
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Article ; Online: Gag p24 Is a Marker of Human Immunodeficiency Virus Expression in Tissues and Correlates With Immune Response.

Wu, Guoxin / Zuck, Paul / Goh, Shih Lin / Milush, Jeffrey M / Vohra, Poonam / Wong, Joseph K / Somsouk, Ma / Yukl, Steven A / Shacklett, Barbara L / Chomont, Nicolas / Haase, Ashley T / Hatano, Hiroyu / Schacker, Timothy W / Deeks, Steven G / Hazuda, Daria J / Hunt, Peter W / Howell, Bonnie J

The Journal of infectious diseases

2021 Volume 224, Issue 9, Page(s) 1593–1598

Abstract: We demonstrate that human immunodeficiency virus (HIV) gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also ... ...

Abstract	We demonstrate that human immunodeficiency virus (HIV) gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also measurably decline with ART in natural controllers. During ART, gut p24 expression is more strongly associated both with HIV-specific CD8+ T-cell frequency and plasma soluble CD14 levels than gut HIV RNA expression. This study supports using gag p24 as a marker of HIV expression in HIV+ tissues to study effects of viral persistence and to monitor efficacy of treatment in HIV-based clearance studies.
MeSH term(s)	Biomarkers/blood ; Biopsy ; CD4 Lymphocyte Count ; CD4-Positive T-Lymphocytes/immunology ; Female ; HIV Core Protein p24/genetics ; HIV Core Protein p24/immunology ; HIV Infections/drug therapy ; HIV Infections/genetics ; HIV Infections/immunology ; HIV-1/immunology ; Humans ; Lymphocyte Activation ; gag Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	Biomarkers ; HIV Core Protein p24 ; gag Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2021-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiab121
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Article ; Online: Detecting Sources of Immune Activation and Viral Rebound in HIV Infection.

Journal of virology

2022 Volume 96, Issue 15, Page(s) e0088522

Abstract: Anti-retroviral therapy (ART) generally suppresses HIV replication to undetectable levels in peripheral blood, but immune activation associated with increased morbidity and mortality is sustained during ART, and infection rebounds when treatment is ... ...

Abstract	Anti-retroviral therapy (ART) generally suppresses HIV replication to undetectable levels in peripheral blood, but immune activation associated with increased morbidity and mortality is sustained during ART, and infection rebounds when treatment is interrupted. To identify drivers of immune activation and potential sources of viral rebound, we modified RNAscope in situ hybridization to visualize HIV-producing cells as a standard against which to compare the following assays of potential sources of immune activation and virus rebound following treatment interruption: (i) envelope detection by induced transcription-based sequencing (EDITS) assay; (ii) HIV-Flow; (iii) Flow-FISH assays that can scan tissues and cell suspensions to detect rare cells expressing env mRNA, gag mRNA/Gag protein and p24; and (iv) an ultrasensitive immunoassay that detects p24 in cell/tissue lysates at subfemtomolar levels. We show that the sensitivities of these assays are sufficient to detect one rare HIV-producing/env mRNA
MeSH term(s)	Anti-HIV Agents/administration & dosage ; Anti-HIV Agents/therapeutic use ; Antigens, Viral/analysis ; Antigens, Viral/genetics ; Antigens, Viral/metabolism ; CD4-Positive T-Lymphocytes ; HIV Core Protein p24/genetics ; HIV Infections/immunology ; HIV Infections/virology ; HIV-1/genetics ; HIV-1/growth & development ; HIV-1/immunology ; Humans ; Immunoassay ; In Situ Hybridization, Fluorescence ; RNA, Messenger/analysis ; RNA, Viral/analysis ; Reproducibility of Results ; Sensitivity and Specificity ; Viral Tropism ; Virus Activation ; env Gene Products, Human Immunodeficiency Virus/genetics
Chemical Substances	Anti-HIV Agents ; Antigens, Viral ; HIV Core Protein p24 ; RNA, Messenger ; RNA, Viral ; env Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2022-07-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/jvi.00885-22
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Article ; Online: Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1.

Balibar, Carl J / Klein, Daniel J / Zamlynny, Beata / Diamond, Tracy L / Fang, Zhiyu / Cheney, Carol A / Kristoff, Jan / Lu, Meiqing / Bukhtiyarova, Marina / Ou, Yangsi / Xu, Min / Ba, Lei / Carroll, Steven S / El Marrouni, Abdellatif / Fay, John F / Forster, Ashley / Goh, Shih Lin / Gu, Meigang / Krosky, Daniel /

Rosenbloom, Daniel I S / Sheth, Payal / Wang, Deping / Wu, Guoxin / Zebisch, Matthias / Zhao, Tian / Zuck, Paul / Grobler, Jay / Hazuda, Daria J / Howell, Bonnie J / Converso, Antonella

Science translational medicine

2023 Volume 15, Issue 684, Page(s) eabn2038

Abstract: Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside ...

Abstract	Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1-infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1
MeSH term(s)	Humans ; HIV-1 ; HIV Infections/drug therapy ; Antiviral Agents/therapeutic use ; Apoptosis ; Cell Death ; CD4-Positive T-Lymphocytes ; Virus Replication
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2023-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.abn2038
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Article ; Online: Initial productive and latent HIV infections originate in vivo by infection of resting T cells.

Wietgrefe, Stephen W / Anderson, Jodi / Duan, Lijie / Southern, Peter J / Zuck, Paul / Wu, Guoxin / Howell, Bonnie J / Reilly, Cavan / Kroon, Eugène / Chottanapund, Suthat / Buranapraditkun, Supranee / Sacdalan, Carlo / Tulmethakaan, Nicha / Colby, Donn J / Chomchey, Nitiya / Prueksakaew, Peeriya / Pinyakorn, Suteeraporn / Trichavaroj, Rapee / Mitchell, Julie L /

Trautmann, Lydie / Hsu, Denise / Vasan, Sandhya / Manasnayakorn, Sopark / de Souza, Mark / Tovanabutra, Sodsai / Schuetz, Alexandra / Robb, Merlin L / Phanuphak, Nittaya / Ananworanich, Jintanat / Schacker, Timothy W / Haase, Ashley T

The Journal of clinical investigation

2023 Volume 133, Issue 22

Abstract: Productively infected cells are generally thought to arise from HIV infection of activated CD4+ T cells, and these infected activated cells are thought to be a recurring source of latently infected cells when a portion of the population transitions to a ... ...

Abstract	Productively infected cells are generally thought to arise from HIV infection of activated CD4+ T cells, and these infected activated cells are thought to be a recurring source of latently infected cells when a portion of the population transitions to a resting state. We discovered and report here that productively and latently infected cells can instead originate from direct infection of resting CD4+ T cell populations in lymphoid tissues in Fiebig I, the earliest stage of detectable HIV infection. We found that direct infection of resting CD4+ T cells was correlated with the availability of susceptible target cells in lymphoid tissues largely restricted to resting CD4+ T cells in which expression of pTEFb enabled productive infection, and we documented persistence of HIV-producing resting T cells during antiretroviral therapy (ART). Thus, we provide evidence of a mechanism by which direct infection of resting T cells in lymphoid tissues to generate productively and latently infected cells creates a mechanism by which the productively infected cells can replenish both populations and maintain two sources of virus from which HIV infection can rebound, even if ART is instituted at the earliest stage of detectable infection.
MeSH term(s)	Humans ; HIV Infections ; Virus Latency ; Virus Replication ; CD4-Positive T-Lymphocytes
Language	English
Publishing date	2023-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI171501
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Article ; Online: Dynamic Compound-Dependent Acoustic Transfer to Investigate Inhibitor Reversibility.

Nothstein, Jennifer / MacColl, Elisabeth / Zuck, Paul / Cassaday, Jason / Uebele, Victor N / Hermes, Jeffrey D / Homsher, Michelle F

SLAS technology

2016 Volume 22, Issue 5, Page(s) 485–492

Abstract: Automated mechanism of action studies are introducing the need for tailored compound delivery, which can be challenging for standard compound management procedures. Jump dilution assays investigating inhibitor reversibility require compound delivery at ... ...

Abstract	Automated mechanism of action studies are introducing the need for tailored compound delivery, which can be challenging for standard compound management procedures. Jump dilution assays investigating inhibitor reversibility require compound delivery at specific volumes to assay specific concentrations of 10 × IC
MeSH term(s)	Acoustics ; Dipeptidyl Peptidase 4/metabolism ; Dipeptidyl-Peptidase IV Inhibitors/pharmacology ; Drug Discovery/methods ; Indicator Dilution Techniques ; Inhibitory Concentration 50
Chemical Substances	Dipeptidyl-Peptidase IV Inhibitors ; Dipeptidyl Peptidase 4 (EC 3.4.14.5)
Language	English
Publishing date	2016-12-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2900310-6
ISSN	2472-6311 ; 2472-6303
ISSN (online)	2472-6311
ISSN	2472-6303
DOI	10.1177/2472630316684807
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Article ; Online: Development of a Platform to Enable Fully Automated Cross-Titration Experiments.

Cassaday, Jason / Finley, Michael / Squadroni, Brian / Jezequel-Sur, Sylvie / Rauch, Albert / Gajera, Bharti / Uebele, Victor / Hermes, Jeffrey / Zuck, Paul

SLAS technology

2016 Volume 22, Issue 2, Page(s) 195–205

Abstract: In the triage of hits from a high-throughput screening campaign or during the optimization of a lead compound, it is relatively routine to test compounds at multiple concentrations to determine potency and maximal effect. Additional follow-up experiments, ...

Abstract	In the triage of hits from a high-throughput screening campaign or during the optimization of a lead compound, it is relatively routine to test compounds at multiple concentrations to determine potency and maximal effect. Additional follow-up experiments, such as agonist shift, can be quite valuable in ascertaining compound mechanism of action (MOA). However, these experiments require cross-titration of a test compound with the activating ligand of the receptor requiring 100-200 data points, severely limiting the number tested in MOA assays in a screening triage. We describe a process to enhance the throughput of such cross-titration experiments through the integration of Hewlett Packard's D300 digital dispenser onto one of our robotics platforms to enable on-the-fly cross-titration of compounds in a 1536-well plate format. The process handles all the compound management and data tracking, as well as the biological assay. The process relies heavily on in-house-built software and hardware, and uses our proprietary control software for the platform. Using this system, we were able to automate the cross-titration of compounds for both positive and negative allosteric modulators of two different G protein-coupled receptors (GPCRs) using two distinct assay detection formats, IP1 and Ca
MeSH term(s)	Automation, Laboratory/instrumentation ; Automation, Laboratory/methods ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical/instrumentation ; Drug Evaluation, Preclinical/methods ; High-Throughput Screening Assays ; Humans ; Receptors, G-Protein-Coupled/agonists ; Titrimetry/instrumentation ; Titrimetry/methods
Chemical Substances	Receptors, G-Protein-Coupled
Language	English
Publishing date	2016-11-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2900310-6
ISSN	2472-6311 ; 2472-6303
ISSN (online)	2472-6311
ISSN	2472-6303
DOI	10.1177/2211068216679805
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Article ; Online: Neurotoxicity with high-dose disulfiram and vorinostat used for HIV latency reversal.

McMahon, James H / Evans, Vanessa A / Lau, Jillian S Y / Symons, Jori / Zerbato, Jennifer M / Chang, Judy / Solomon, Ajantha / Tennakoon, Surekha / Dantanarayana, Ashanti / Hagenauer, Michelle / Lee, Sulggi / Palmer, Sarah / Fisher, Katie / Bumpus, Namandje / Heck, Carley J S / Burger, David / Wu, Guoxin / Zuck, Paul / Howell, Bonnie J /

Zetterberg, Henrik H / Blennow, Kaj / Gisslen, Magnus / Rasmussen, Thomas A / Lewin, Sharon R

AIDS (London, England)

2021 Volume 36, Issue 1, Page(s) 75–82

Abstract: Objective: The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and can enhance HIV latency reversal.: Design: Vorinostat and disulfiram ... ...

Abstract	Objective: The aim of this study was to examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is well tolerated and can enhance HIV latency reversal. Design: Vorinostat and disulfiram can increase HIV transcription in PWH on ART. Together, these agents may lead to significant HIV latency reversal. Methods: Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated unspliced RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA, and plasma concentrations of ART, vorinostat, and disulfiram. Results: The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia, and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4-fold and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8 to 37 (peak 81 copies ml-1) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1. Conclusion: The combination of prolonged high-dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal.
MeSH term(s)	Disulfiram/administration & dosage ; Drug Therapy, Combination/adverse effects ; HIV Infections/drug therapy ; Humans ; Virus Latency/physiology ; Vorinostat/administration & dosage
Chemical Substances	Vorinostat (58IFB293JI) ; Disulfiram (TR3MLJ1UAI)
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639076-6
ISSN	1473-5571 ; 0269-9370 ; 1350-2840
ISSN (online)	1473-5571
ISSN	0269-9370 ; 1350-2840
DOI	10.1097/QAD.0000000000003091
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