Daniel A. Donahue

Department of Virology

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Stage-Dependent Inhibition of HIV-1 Replication by Antiretroviral Drugs in Cell Culture

Antimicrobial Agents and Chemotherapy (2009)

Daniel A. Donahue Richard D. Sloan Björn D. Kuhl Tamara Bar-Magen Susan M. Schader

ABSTRACT Recent clinical trials have shown that the use of the HIV-1 integrase (IN) inhibitor raltegravir (RAL) results in drops in the viral load that are more rapid than those achieved by use of the reverse transcriptase (RT) inhibitor efavirenz. Previously, mathematical modeling of viral load decay that takes into account the stage of viral replication targeted by a drug has yielded data that closely approximate the clinical trial results. This model predicts greater inhibition of viral replication by drugs that act later in the viral replication cycle. In the present study, we have added drugs that target entry, reverse transcription, integration, or proteolytic processing to acutely infected cells and have shown modest viral inhibition by entry inhibitors, intermediate levels of inhibition by RT and IN inhibitors, and high levels of inhibition by protease inhibitors relative to the levels of growth for the no-drug controls. When dual or triple combinations of these drugs were added to acutely infected cells, we found that the levels of inhibition achieved by any given combination were comparable to those achieved by the latest-acting drug in the combination. In single-round infections in which the kinetics of reverse transcription and integration had been determined by quantitative PCR, addition of IN inhibitors at various times postinfection resulted in levels of inhibition equal to or greater than those achieved by addition of RT inhibitors. Collectively, our data provide in vitro evidence of the stage-dependent inhibition of HIV-1 by clinically relevant drugs. We discuss how stage-dependent inhibition helps to explain the unique viral load decay dynamics observed clinically with RAL.

Raltegravir

Integrase inhibitor

Efavirenz

Protease inhibitor (pharmacology)

Reverse-transcriptase inhibitor

10.1128/aac.01537-09

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Citations (49)

Induction of ecotropic endogenous murine leukemia virus in long-term bone marrow cultures from mouse strains of varying natural leukemia incidence.

PubMed (1979)

Joel S. Greenberger Daniel A. Donahue Mary Ann Sakakeeny

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Citations (14)

Nuclear restriction of HIV-1 infection by SUN1

Scientific Reports (2021)

Mirjana Persaud Anastasia Selyutina Cindy Buffone Silvana Opp Daniel A. Donahue

Abstract Overexpression of the human S ad-1- Un c-84 homology protein 2 (SUN2) blocks HIV-1 infection in a capsid-dependent manner. In agreement, we showed that overexpression of SUN1 (Sad1 and UNC-84a) also blocks HIV-1 infection in a capsid-dependent manner. SUN2 and the related protein SUN1 are transmembrane proteins located in the inner membrane of the nuclear envelope. The N-terminal domains of SUN1/2 localizes to the nucleoplasm while the C-terminal domains are localized in the nuclear lamina. Because the N-terminal domains of SUN1/2 are located in the nucleoplasm, we hypothesized that SUN1/2 might be interacting with the HIV-1 replication complex in the nucleus leading to HIV-1 inhibition. Our results demonstrated that SUN1/2 interacts with the HIV-1 capsid, and in agreement with our hypothesis, the use of N-terminal deletion mutants showed that SUN1/2 proteins bind to the viral capsid by using its N-terminal domain. SUN1/2 deletion mutants correlated restriction of HIV-1 with capsid binding. Interestingly, the ability of SUN1/2 to restrict HIV-1 also correlated with perinuclear localization of these proteins. In agreement with the notion that SUN proteins interact with the HIV-1 capsid in the nucleus, we found that restriction of HIV-1 by overexpression of SUN proteins do not block the entry of the HIV-1 core into the nucleus. Our results showed that HIV-1 restriction is mediated by the interaction of SUN1/2N-terminal domains with the HIV-1 core in the nuclear compartment.

10.1038/s41598-021-98541-4

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Citations (3)

Cellular and molecular mechanisms involved in the establishment of HIV-1 latency

Retrovirology (2013)

Daniel A. Donahue Mark A. Wainberg

Latently infected cells represent the major barrier to either a sterilizing or a functional HIV-1 cure. Multiple approaches to reactivation and depletion of the latent reservoir have been attempted clinically, but full depletion of this compartment remains a long-term goal. Compared to the mechanisms involved in the maintenance of HIV-1 latency and the pathways leading to viral reactivation, less is known about the establishment of latent infection. This review focuses on how HIV-1 latency is established at the cellular and molecular levels. We first discuss how latent infection can be established following infection of an activated CD4 T-cell that undergoes a transition to a resting memory state and also how direct infection of a resting CD4 T-cell can lead to latency. Various animal, primary cell, and cell line models also provide insights into this process and are discussed with respect to the routes of infection that result in latency. A number of molecular mechanisms that are active at both transcriptional and post-transcriptional levels have been associated with HIV-1 latency. Many, but not all of these, help to drive the establishment of latent infection, and we review the evidence in favor of or against each mechanism specifically with regard to the establishment of latency. We also discuss the role of immediate silent integration of viral DNA versus silencing of initially active infections. Finally, we discuss potential approaches aimed at limiting the establishment of latent infection.

Virus latency

Latent Virus

10.1186/1742-4690-10-11

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Citations (109)

Comparative biochemical analysis of wildtype and drug resistant HIV-1 integrase subtypes B and C

Retrovirology (2009)

Tamara Bar-Magen Richard D. Sloan Emily I McDonough Verena Faltenbacher Daniel A. Donahue

retroviruses, retroelements and their hosts Meet ing abstracts - A single PDF containing all abstracts in this Supplement is available here . http://www. biomedcentral.co m/content/pdf/17 42-4690-6-S2-inf o.pdf

Integrase inhibitor

10.1186/1742-4690-6-s2-p6

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Faculty Opinions recommendation of Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature (2013)

Mark A. Wainberg Daniel A. Donahue

Read the full review for this Faculty Opinions recommended article: Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study.

Antiretroviral treatment

10.3410/f.718004234.793475795

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