Publications by authors named "Janet M Siliciano"

8 Publications

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Heightened resistance to host type 1 interferons characterizes HIV-1 at transmission and after antiretroviral therapy interruption.

Sci Transl Med 2021 01;13(576)

Laboratory of Molecular Immunology, Rockefeller University, New York, NY 10065, USA.

Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4 T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFNα2 and IFNβ that reduced viral replication in vitro by 50% (IC) and found consistent changes in the sensitivity of HIV-1 to IFN-I inhibition both across individuals and over time. Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4 T cell loss, and remained elevated in individuals with accelerated disease. HIV-1 isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just before ART initiation. However, viruses that rebounded after treatment interruption displayed the highest degree of IFNα2 and IFNβ resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption. Although elevated at transmission, host innate pressures are the highest during viral rebound, limiting the viruses that successfully become reactivated from latency to those that are IFN-I resistant.
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http://dx.doi.org/10.1126/scitranslmed.abd8179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923595PMC
January 2021

Distinct viral reservoirs in individuals with spontaneous control of HIV-1.

Nature 2020 09 26;585(7824):261-267. Epub 2020 Aug 26.

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.

Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed 'elite controllers'), despite the presence of a replication-competent viral reservoir. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation, may be feasible in rare instances.
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http://dx.doi.org/10.1038/s41586-020-2651-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837306PMC
September 2020

HIV-1 latent reservoir size and diversity are stable following brief treatment interruption.

J Clin Invest 2018 07 18;128(7):3102-3115. Epub 2018 Jun 18.

University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: The effect of a brief analytical treatment interruption (ATI) on the HIV-1 latent reservoir of individuals who initiate antiretroviral therapy (ART) during chronic infection is unknown.

Methods: We evaluated the impact of transient viremia on the latent reservoir in participants who underwent an ATI and at least 6 months of subsequent viral suppression in a clinical trial testing the effect of passive infusion of the broadly neutralizing Ab VRC01 during ATI.

Results: Measures of total HIV-1 DNA, cell-associated RNA, and infectious units per million cells (IUPM) (measured by quantitative viral outgrowth assay [QVOA]) were not statistically different before or after ATI. Phylogenetic analyses of HIV-1 env sequences from QVOA and proviral DNA demonstrated little change in the composition of the virus populations comprising the pre- and post-ATI reservoir. Expanded clones were common in both QVOA and proviral DNA sequences. The frequency of clonal populations differed significantly between QVOA viruses, proviral DNA sequences, and the viruses that reactivated in vivo.

Conclusions: The results indicate that transient viremia from ATI does not substantially alter measures of the latent reservoir, that clonal expansion is prevalent within the latent reservoir, and that characterization of latent viruses that can reactivate in vivo remains challenging.

Trial Registration: ClinicalTrials.gov NCT02463227FUNDING. Funding was provided by the NIH.
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http://dx.doi.org/10.1172/JCI120194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026010PMC
July 2018

Diverse fates of uracilated HIV-1 DNA during infection of myeloid lineage cells.

Elife 2016 09 20;5. Epub 2016 Sep 20.

Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, United States.

We report that a major subpopulation of monocyte-derived macrophages (MDMs) contains high levels of dUTP, which is incorporated into HIV-1 DNA during reverse transcription (U/A pairs), resulting in pre-integration restriction and post-integration mutagenesis. After entering the nucleus, uracilated viral DNA products are degraded by the uracil base excision repair (UBER) machinery with less than 1% of the uracilated DNA successfully integrating. Although uracilated proviral DNA showed few mutations, the viral genomic RNA was highly mutated, suggesting that errors occur during transcription. Viral DNA isolated from blood monocytes and alveolar macrophages (but not T cells) of drug-suppressed HIV-infected individuals also contained abundant uracils. The presence of viral uracils in short-lived monocytes suggests their recent infection through contact with virus producing cells in a tissue reservoir. These findings reveal new elements of a viral defense mechanism involving host UBER that may be relevant to the establishment and persistence of HIV-1 infection.
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http://dx.doi.org/10.7554/eLife.18447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030084PMC
September 2016

Designing and Interpreting Limiting Dilution Assays: General Principles and Applications to the Latent Reservoir for Human Immunodeficiency Virus-1.

Open Forum Infect Dis 2015 Dec 26;2(4):ofv123. Epub 2015 Aug 26.

Department of Medicine , Johns Hopkins University School of Medicine ; Howard Hughes Medical Institute , Baltimore, Maryland.

Limiting dilution assays are widely used in infectious disease research. These assays are crucial for current human immunodeficiency virus (HIV)-1 cure research in particular. In this study, we offer new tools to help investigators design and analyze dilution assays based on their specific research needs. Limiting dilution assays are commonly used to measure the extent of infection, and in the context of HIV they represent an essential tool for studying latency and potential curative strategies. Yet standard assay designs may not discern whether an intervention reduces an already miniscule latent infection. This review addresses challenges arising in this setting and in the general use of dilution assays. We illustrate the major statistical method for estimating frequency of infectious units from assay results, and we offer an online tool for computing this estimate. We recommend a procedure for customizing assay design to achieve desired sensitivity and precision goals, subject to experimental constraints. We consider experiments in which no viral outgrowth is observed and explain how using alternatives to viral outgrowth may make measurement of HIV latency more efficient. Finally, we discuss how biological complications, such as probabilistic growth of small infections, alter interpretations of experimental results.
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http://dx.doi.org/10.1093/ofid/ofv123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602119PMC
December 2015

The Remarkable Stability of the Latent Reservoir for HIV-1 in Resting Memory CD4+ T Cells.

J Infect Dis 2015 Nov 15;212(9):1345-7. Epub 2015 Apr 15.

Department of Medicine, Johns Hopkins University School of Medicine Howard Hughes Medical Institute, Baltimore, Maryland.

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http://dx.doi.org/10.1093/infdis/jiv219DOI Listing
November 2015

Targeting HIV reservoirs with valproic acid.

Hopkins HIV Rep 2005 Sep;17(5):8-9

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September 2005

Latency in human immunodeficiency virus type 1 infection: no easy answers.

J Virol 2003 Feb;77(3):1659-65

Departments of Medicine and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC140995PMC
http://dx.doi.org/10.1128/jvi.77.3.1659-1665.2003DOI Listing
February 2003