A multidimensional HIV-1 persistence model for clonal expansion and viral rebound in vitro

AbstractDespite antiretroviral therapy (ART) which halts HIV-1 replication and reduces plasma viral load to clinically undetectable levels, viral rebound inevitably occurs once ART is interrupted. HIV-1-infected cells can undergo clonal expansion, and these clonally expanded cells increase over time. Over 50% of latent reservoirs are maintained through clonal expansion. The clonally expanding HIV-1-infected cells, both in the blood and in the lymphoid tissues, contribute to viral rebound. The major drivers of clonal expansion of HIV-1-infected cells include antigen-driven proliferation, homeostatic proliferation and HIV-1 integration site-dependent proliferation. Here, we reviewed how viral, immunologic and genomic factors contribute to clonal expansion of HIV-1-infected cells, and how clonal expansion shapes the HIV-1 latent reservoir. Antigen-specific CD4+ T cells specific for different pathogens have different clonal expansion dynamics, depending on antigen exposure, cytokine profiles and exhaustion phenotypes. Homeostatic proliferation replenishes the HIV-1 latent reservoir without inducing viral expression and immune clearance. Integration site-dependent proliferation, a mechanism also deployed by other retroviruses, leads to slow but steady increase of HIV-1-infected cells harboring HIV-1 proviruses integrated in the same orientation at specific sites of certain cancer-related genes. Targeting clonally expanding HIV-1 latent reservoir without disrupting CD4+ T cell function is a top priority for HIV-1 eradication.

Download Full-text

Faculty Opinions recommendation of Loop-loop interaction of HIV-1 TAR RNA with N3'-->P5' deoxyphosphoramidate aptamers inhibits in vitro Tat-mediated transcription.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1008473.106958 ◽

2002 ◽

Author(s):

Anthony Czarnik

Keyword(s):

Tar Rna ◽

Hiv 1

Download Full-text

Faculty Opinions recommendation of HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726445812.793524772 ◽

2016 ◽

Author(s):

José Alcami

Keyword(s):

Treatment Interruption ◽

Viral Rebound ◽

Hiv 1

Download Full-text

DEVELOPMENT OF APPROACHES FOR DETECTION OF GENOME-INTEGRATED PROVIRAL DNA OF THE HUMAN IMMUNODEFICIENCY VIRUS (HIV-1) IN ULTRA LOW CONCENTRATIONS USING THE CRISPR/CAS SYSTEM

Molecular Diagnostics and Biosafety – 2020. Russian national scientific and practical conference with international participation (October, 6–8, 2020): Conference Proceedings ◽

10.36233/978-5-9900432-9-9-118 ◽

2020 ◽

Author(s):

M.A. Tyumentseva ◽

◽

A.I. Tyumentsev ◽

V.G. Akimkin ◽

◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Health Monitoring ◽

Biological Samples ◽

Proviral Dna ◽

Guide Rnas ◽

Ribonucleoprotein Complexes ◽

Low Concentrations ◽

Immunodeficiency Virus ◽

Hiv 1

For the effective functioning of supervisory and health monitoring services, it is necessary to introduce modern molecular technologies into their practice. Therefore, the task of developing new effective methods for detecting pathogen, for example HIV, based on CRISPR/CAS genome editing systems, remains urgent. In the present work, guide RNAs and specific oligonucleotides were developed for preliminary amplification of highly conserved regions of the HIV-1 genome. The developed guide RNAs make it possible to detect single copies of HIV-1 proviral DNA in vitro as part of CRISPR/CAS ribonucleoprotein complexes in biological samples after preliminary amplification.

Download Full-text

In vitro binding activity between HCK SH3 domain and HIV-1 Nef protein

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2011.00262 ◽

2011 ◽

Vol 31 (3) ◽

pp. 262-265

Author(s):

Xiao-lin QIN ◽

Chao-qi LIU ◽

Dong-ming REN ◽

Yong-qin ZHOU

Keyword(s):

Sh3 Domain ◽

Binding Activity ◽

Hiv 1

Download Full-text

Anti HIV-1 Agents 7. Discovery of 1-Hydroxy-4-chloro-9,10-anthraquinone Derivatives as New HIV-1 Inhibitors in Vitro

Letters in Drug Design & Discovery ◽

10.2174/157018011796235185 ◽

2011 ◽

Vol 8 (7) ◽

pp. 602-605

Author(s):

Ning Huang ◽

Qin Wang ◽

Liu-Meng Yang ◽

Hui Xu ◽

Yong-Tang Zheng

Keyword(s):

Anthraquinone Derivatives ◽

Anti Hiv ◽

Hiv 1

Download Full-text

Mutational analysis of human immunodeficiency virus type 1 (HIV-1) accessory genes: requirement of a site in the nef gene for HIV-1 replication in activated CD4+ T cells in vitro and in vivo.

Journal of Virology ◽

10.1128/jvi.71.11.8456-8466.1997 ◽

1997 ◽

Vol 71 (11) ◽

pp. 8456-8466 ◽

Cited By ~ 36

Author(s):

Y Kawano ◽

Y Tanaka ◽

N Misawa ◽

R Tanaka ◽

J I Kira ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Human Immunodeficiency Virus Type ◽

Mutational Analysis ◽

Immunodeficiency Virus ◽

A Site ◽

Hiv 1

Download Full-text

1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.5.1082 ◽

1997 ◽

Vol 41 (5) ◽

pp. 1082-1093 ◽

Cited By ~ 276

Author(s):

S M Daluge ◽

S S Good ◽

M B Faletto ◽

W H Miller ◽

M H St Clair ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Oral Bioavailability ◽

Human Peripheral Blood ◽

Cross Resistance ◽

Immunodeficiency Virus ◽

Carbocyclic Nucleoside ◽

Hiv 1 ◽

In Cells

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

Download Full-text