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Complex decay dynamics of HIV virions, intact and defective proviruses, and 2LTR circles following initiation of antiretroviral therapy

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
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  1. Johns Hopkins Univ., Baltimore, MD (United States)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Johns Hopkins Univ., Baltimore, MD (United States); Howard Hughes Medical Inst., Baltimore, MD (United States)
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In persons living with HIV-1 (PLWH) who start antiretroviral therapy (ART), plasma virus decays in a biphasic fashion to below the detection limit. The first phase reflects the short half-life (<1 d) of cells that produce most of the plasma virus. The second phase represents the slower turnover (t1/2 = 14 d) of another infected cell population, whose identity is unclear. Using the intact proviral DNA assay (IPDA) to distinguish intact and defective proviruses, we analyzed viral decay in 17 PLWH initiating ART. Circulating CD4+ T cells with intact proviruses include few of the rapidly decaying first-phase cells. Instead, this population initially decays more slowly (t1/2 = 12.9 d) in a process that largely represents death or exit from the circulation rather than transition to latency. This more protracted decay potentially allows for immune selection. After ~3 mo, the decay slope changes, and CD4+ T cells with intact proviruses decay with a half-life of 19 mo, which is still shorter than that of the latently infected cells that persist on long-term ART. Two-long-terminal repeat (2LTR) circles decay with fast and slow phases paralleling intact proviruses, a finding that precludes their use as a simple marker of ongoing viral replication. Proviruses with defects at the 5' or 3' end of the genome show equivalent monophasic decay at rates that vary among individuals. Understanding these complex early decay processes is important for correct use of reservoir assays and may provide insights into properties of surviving cells that can constitute the stable latent reservoir.
Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
Bill and Melinda Gates Foundation; Fundacao para a Ciencia e Tecnologia, Portugal; Johns Hopkins Center for AIDS Research; National Institutes of Health (NIH); USDOE National Nuclear Security Administration (NNSA)
Grant/Contract Number:
89233218CNA000001
OSTI ID:
1868256
Report Number(s):
LA-UR-21-32238
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 6 Vol. 119; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
English

References (90)

HIV-1 entry into quiescent primary lymphocytes: Molecular analysis reveals a labile, latent viral structure journal April 1990
Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial journal October 2014
Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure journal October 2013
Identification of Genetically Intact HIV-1 Proviruses in Specific CD4 + T Cells from Effectively Treated Participants journal October 2017
Combined single-cell transcriptional, translational, and genomic profiling reveals HIV-1 reservoir diversity journal August 2021
Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral Landscape journal April 2017
The Landscape of Persistent Viral Genomes in ART-Treated SIV, SHIV, and HIV-2 Infections journal July 2019
Extension of the SAEM algorithm to left-censored data in nonlinear mixed-effects model: Application to HIV dynamics model journal December 2006
Human Immunodeficiency Virus Controllers: Mechanisms of Durable Virus Control in the Absence of Antiretroviral Therapy journal September 2007
HIV replication and latency in monocytes and macrophages journal January 2021
HIV-specific cytotoxic T lymphocytes in seropositive individuals journal July 1987
Viral dynamics in human immunodeficiency virus type 1 infection journal January 1995
Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection journal January 1995
Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection journal May 1997
Decay characteristics of HIV-1-infected compartments during combination therapy journal May 1997
Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy journal January 2000
Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy journal May 1999
Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy journal July 2012
Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection journal December 2013
Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations journal January 2015
HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects journal March 2010
Defective proviruses rapidly accumulate during acute HIV-1 infection journal August 2016
Antiviral pressure exerted by HIV-l-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus journal February 1997
In vivo fate of HIV-1-infected T cells: Quantitative analysis of the transition to stable latency journal December 1995
Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells journal May 2003
HIV-1 diversity considerations in the application of the Intact Proviral DNA Assay (IPDA) journal January 2021
A quantitative approach for measuring the reservoir of latent HIV-1 proviruses journal January 2019
Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo journal January 2020
Distinct viral reservoirs in individuals with spontaneous control of HIV-1 journal August 2020
Protein expression from unintegrated HIV-1 DNA introduces bias in primary in vitro post-integration latency models journal December 2016
A Controlled Trial of Two Nucleoside Analogues plus Indinavir in Persons with Human Immunodeficiency Virus Infection and CD4 Cell Counts of 200 per Cubic Millimeter or Less journal September 1997
Treatment with Indinavir, Zidovudine, and Lamivudine in Adults with Human Immunodeficiency Virus Infection and Prior Antiretroviral Therapy journal September 1997
Decay dynamics of HIV-1 depend on the inhibited stages of the viral life cycle journal March 2008
Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy journal March 2008
Clonally expanded CD4 + T cells can produce infectious HIV-1 in vivo journal February 2016
Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy journal July 2016
Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART journal April 2017
Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane journal February 2018
A minor population of macrophage-tropic HIV-1 variants is identified in recrudescing viremia following analytic treatment interruption journal April 2020
Intact proviral DNA assay analysis of large cohorts of people with HIV provides a benchmark for the frequency and composition of persistent proviral DNA journal July 2020
Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy journal November 1997
Determinants of Human Immunodeficiency Virus Type 1 Escape from the Primary CD8+ Cytotoxic T Lymphocyte Response journal November 2004
CD4+ T Cell Depletion during all Stages of HIV Disease Occurs Predominantly in the Gastrointestinal Tract journal September 2004
Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract journal September 2004
Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection journal June 2009
Proliferation of latently infected CD4 + T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics journal March 2017
Biphasic Decay of Latently Infected CD4 + T Cells in Acute Human Immunodeficiency Virus Type 1 Infection journal December 2000
HIV-1 DNA Decay Dynamics in Blood During More Than a Decade of Suppressive Antiretroviral Therapy journal July 2014
Selective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy journal August 2020
Similar Frequency and Inducibility of Intact Human Immunodeficiency Virus-1 Proviruses in Blood and Lymph Nodes journal December 2020
Three Distinct Phases of HIV-1 RNA Decay in Treatment-Naive Patients Receiving Raltegravir-Based Antiretroviral Therapy: ACTG A5248 journal June 2013
Increase in 2–Long Terminal Repeat Circles and Decrease in D-dimer After Raltegravir Intensification in Patients With Treated HIV Infection: A Randomized, Placebo-Controlled Trial journal August 2013
Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies journal April 2015
Early HIV RNA decay during raltegravir-containing regimens exhibits two distinct subphases (1a and 1b) journal January 2015
Specific HIV integration sites are linked to clonal expansion and persistence of infected cells journal June 2014
Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection journal July 2014
Quiescent T Lymphocytes as an Inducible Virus Reservoir in HIV-1 Infection journal October 1991
HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time journal March 1996
Recovery of Replication-Competent HIV Despite Prolonged Suppression of Plasma Viremia journal November 1997
Identification of a Reservoir for HIV-1 in Patients on Highly Active Antiretroviral Therapy journal November 1997
Gastrointestinal Tract as a Major Site of CD4+ T Cell Depletion and Viral Replication in SIV Infection journal April 1998
Control of Viremia in Simian Immunodeficiency Virus Infection by CD8+ Lymphocytes journal February 1999
Different human resting memory CD4 + T cell subsets show similar low inducibility of latent HIV-1 proviruses journal January 2020
Residual Human Immunodeficiency Virus Type 1 Viremia in Some Patients on Antiretroviral Therapy Is Dominated by a Small Number of Invariant Clones Rarely Found in Circulating CD4+ T Cells journal June 2006
Dynamics of Simian Immunodeficiency Virus Two-Long-Terminal-Repeat Circles in the Presence and Absence of CD8 + Cells journal April 2018
Gastrointestinal T Lymphocytes Retain High Potential for Cytokine Responses but Have Severe CD4 + T-Cell Depletion at All Stages of Simian Immunodeficiency Virus Infection Compared to Peripheral Lymphocytes journal August 1998
Molecular Characterization of Preintegration Latency in Human Immunodeficiency Virus Type 1 Infection journal September 2002
Human Immunodeficiency Virus cDNA Metabolism: Notable Stability of Two-Long Terminal Repeat Circles journal April 2002
Intrinsic Stability of Episomal Circles Formed during Human Immunodeficiency Virus Type 1 Replication journal April 2002
Evidence that Low-Level Viremias during Effective Highly Active Antiretroviral Therapy Result from Two Processes: Expression of Archival Virus and Replication of Virus journal July 2005
Kinetics of Human Immunodeficiency Virus Type 1 Decay following Entry into Resting CD4+ T Cells journal January 2005
In Vivo Evidence for Instability of Episomal Human Immunodeficiency Virus Type 1 cDNA journal April 2005
Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. journal January 1994
HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy journal September 2019
BCL-2 antagonism sensitizes cytotoxic T cell–resistant HIV reservoirs to elimination ex vivo journal March 2020
Macrophages sustain HIV replication in vivo independently of T cells journal March 2016
Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells journal June 2017
Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells journal January 2018
Differential decay of intact and defective proviral DNA in HIV-1–infected individuals on suppressive antiretroviral therapy journal February 2020
Well-mixed plasma and tissue viral populations in RT-SHIV-infected macaques implies a lack of viral replication in the tissues during antiretroviral therapy journal November 2015
Episomal HIV-1 DNA and its relationship to other markers of HIV-1 persistence journal January 2018
CD8+ Lymphocytes Control Viral Replication in SIVmac239-Infected Rhesus Macaques without Decreasing the Lifespan of Productively Infected Cells journal January 2010
In Vivo CD8+ T-Cell Suppression of SIV Viremia Is Not Mediated by CTL Clearance of Productively Infected Cells journal January 2010
Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies journal February 2013
Proviruses with identical sequences comprise a large fraction of the replication-competent HIV reservoir journal March 2017
Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration journal July 2017
Quantification of Total and 2-LTR (Long terminal repeat) HIV DNA, HIV RNA and Herpesvirus DNA in PBMCs journal January 2015
Life and Death of Activated T Cells: How Are They Different from Naïve T Cells? journal December 2017
Different Dynamics of CD4 + and CD8 + T Cell Responses During and After Acute Lymphocytic Choriomeningitis Virus Infection journal October 2003
The HIV-1 latent reservoir is largely sensitive to circulating T cells journal October 2020

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Related Subjects

2LTR circles
60 APPLIED LIFE SCIENCES
HIV
IPDA
biological science
decay processes
latent reservoir
viral dynamics