Browsing by Author "Perilla, Juan R."
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Item Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site(Nature Publishing Group, 2016-03-04) Liu, Chuang; Perilla, Juan R.; Ning, Jiying; Lu, Manman; Hou, Guangjin; Ramalho, Ruben; Himes, Benjamin A.; Zhao, Gongpu; Bedwell, Gregory J.; Byeon, In-Ja; Ahn, Jinwoo; Gronenborn, Angela M.; Prevelige, Peter E.; Rousso, Itay; Aiken, Christopher; Polenova, Tatyana; Schulten, Klaus; Zhang, Peijun; Chuang Liu, Juan R. Perilla, Jiying Ning, Manman Lu, Guangjin Hou, Ruben Ramalho, Benjamin A. Himes, Gongpu Zhao, Gregory J. Bedwell, In-Ja Byeon, Jinwoo Ahn, Angela M. Gronenborn, Peter E. Prevelige, Itay Rousso, Christopher Aiken, Tatyana Polenova, Klaus Schulten & Peijun Zhang; Lu, Manman; Hou, Guangjin; Polenova, TatyanaThe host cell factor cyclophilin A (CypA) interacts directly with the HIV-1 capsid and regulates viral infectivity. Although the crystal structure of CypA in complex with the N-terminal domain of the HIV-1 capsid protein (CA) has been known for nearly two decades, how CypA interacts with the viral capsid and modulates HIV-1 infectivity remains unclear. We determined the cryoEM structure of CypA in complex with the assembled HIV-1 capsid at 8-Å resolution. The structure exhibits a distinct CypA-binding pattern in which CypA selectively bridges the two CA hexamers along the direction of highest curvature. EM-guided all-atom molecular dynamics simulations and solid-state NMR further reveal that the CypA-binding pattern is achieved by single-CypA molecules simultaneously interacting with two CA subunits, in different hexamers, through a previously uncharacterized non-canonical interface. These results provide new insights into how CypA stabilizes the HIV-1 capsid and is recruited to facilitate HIV-1 infection.Item HIV-1 mutants that escape the cytotoxic T-lymphocytes are defective in viral DNA integration(PNAS Nexus, 2022-05-20) Balasubramaniam, Muthukumar; Davids, Benem-Orom; Bryer, Alex; Xu, Chaoyi; Thapa, Santosh; Shi, Jiong; Aiken, Christopher; Pandhare, Jui; Perilla, Juan R.; Dash, ChandravanuHIV-1 replication is durably controlled without antiretroviral therapy (ART) in certain infected individuals called elite controllers (ECs). These individuals express specific human leukocyte antigens (HLA) that tag HIV-infected cells for elimination by presenting viral epitopes to CD8+ cytotoxic T-lymphocytes (CTL). In HIV-infected individuals expressing HLA-B27, CTLs primarily target the viral capsid protein (CA)-derived KK10 epitope. While selection of CA mutation R264K helps HIV-1 escape this potent CTL response, the accompanying fitness cost severely diminishes virus infectivity. Interestingly, selection of a compensatory CA mutation S173A restores HIV-1 replication. However, the molecular mechanism(s) underlying HIV-1 escape from this ART-free virus control by CTLs is not fully understood. Here, we report that the R264K mutation-associated infectivity defect arises primarily from impaired HIV-1 DNA integration, which is restored by the S173A mutation. Unexpectedly, the integration defect of the R264K variant was also restored upon depletion of the host cyclophilin A. These findings reveal a nuclear crosstalk between CA and HIV-1 integration as well as identify a previously unknown role of cyclophilin A in viral DNA integration. Finally, our study identifies a novel immune escape mechanism of an HIV-1 variant escaping a CA-directed CTL response.Item Proceedings of the 2022 DARWIN Computing Symposium(Data Science Institute of the University of Delaware, 2022-03-24) Hadden-Perilla, Jodi A.; Perilla, Juan R.; Bagozzi, Benjamin E.; Eigenmann, Rudolf; Jayaraman, Arthi; Totten, William; Wu, Cathy H.The DARWIN Computing Symposium 2022—sponsored by the Data Science Institute of the University of Delaware—was held on March 24, 2022. It represented the third event in a series of Symposia motivated by a National Science Foundation (NSF) MRI Award, also known as the Delaware Advanced Research Workforce and Innovation Network (DARWIN). As part of an NSF Major Research Instrumentation award (OAC-1919839), DARWIN has the goal of catalyzing "research and education at the University of Delaware (UD) and partners by acquiring a big data and high-performance computing system and making this instrument available to the community." This third DARWIN Computing Symposium presented a wide variety of research enabled by the DARWIN machine to the Delaware community. Alongside this, it showcased additional computational and dataenabled research, provided details on accessing DARWIN for University of Delaware (UD) and partner institutions, and facilitated opportunities for forming collaborations among future users at UD and regional partners. In addition to the NSF and the Data Science Institute, the 2022 DARWIN Computing Symposium was sponsored by DELL and Nemours Children's Health. Drs. Jodi Haden-Perilla and Juan Perilla, both of the University of Delaware, served as co-chairs of the 2022 DARWIN Computing Symposium.Item The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function(mBio, 2023-02-06) Singer, Matthew R.; Dinh, Tung; Levintov, Lev; Annamalai, Arun S.; Rey, Juan S.; Briganti, Lorenzo; Cook, Nicola J.; Pye, Valerie E.; Taylor, Ian A.; Kim, Kyungjin; Engelman, Alan N.; Kim, Baek; Perilla, Juan R.; Kvaratskhelia, Mamuka; Cherepanov, PeterAllosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an emerging class of small molecules that disrupt viral maturation by inducing the aberrant multimerization of IN. Here, we present cocrystal structures of HIV-1 IN with two potent ALLINIs, namely, BI-D and the drug candidate Pirmitegravir. The structures reveal atomistic details of the ALLINI-induced interface between the HIV-1 IN catalytic core and carboxyl-terminal domains (CCD and CTD). Projecting from their principal binding pocket on the IN CCD dimer, the compounds act as molecular glue by engaging a triad of invariant HIV-1 IN CTD residues, namely, Tyr226, Trp235, and Lys266, to nucleate the CTD-CCD interaction. The drug-induced interface involves the CTD SH3-like fold and extends to the beginning of the IN carboxyl-terminal tail region. We show that mutations of HIV-1 IN CTD residues that participate in the interface with the CCD greatly reduce the IN-aggregation properties of Pirmitegravir. Our results explain the mechanism of the ALLINI-induced condensation of HIV-1 IN and provide a reliable template for the rational development of this series of antiretrovirals through the optimization of their key contacts with the viral target. IMPORTANCE Despite the remarkable success of combination antiretroviral therapy, HIV-1 remains among the major causes of human suffering and loss of life in poor and developing nations. To prevail in this drawn-out battle with the pandemic, it is essential to continue developing advanced antiviral agents to fight drug resistant HIV-1 variants. Allosteric integrase inhibitors (ALLINIs) are an emerging class of HIV-1 antagonists that are orthogonal to the current antiretroviral drugs. These small molecules act as highly specific molecular glue, which triggers the aggregation of HIV-1 integrase. In this work, we present high-resolution crystal structures that reveal the crucial interactions made by two potent ALLINIs, namely, BI-D and Pirmitegravir, with HIV-1 integrase. Our results explain the mechanism of drug action and will inform the development of this promising class of small molecules for future use in antiretroviral regimens.