Persistent Production of an Integrase-Deleted HIV-1 Variant with No Resistance Mutation and Wild-Type Proviral DNA in a Treated Patient

Trabaud, Mary‐Anne; Cotte, Laurent; Saison, Julien; Ramière, Christophe; Ronfort, Corinne; Venet, Fabienne; Tardy, J.; Monneret, Guillaume; André, Patrice

doi:10.1089/aid.2014.0129

Cited by 6 publications

(4 citation statements)

References 31 publications

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“…We have identified an exception to the rule regarding the necessity of integration for de novo virus production and persistence. Intriguingly a recent study observed persistence of an integrase-defective HIV-1 in a patient [ 70 ], and infectious virus production from uDNA has recently been reported in T cell lines [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

HIV-1 latency and virus production from unintegrated genomes following direct infection of resting CD4 T cells

et al. 2016

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BackgroundHIV-1 integration is prone to a high rate of failure, resulting in the accumulation of unintegrated viral genomes (uDNA) in vivo and in vitro. uDNA can be transcriptionally active, and circularized uDNA genomes are biochemically stable in non-proliferating cells. Resting, non-proliferating CD4 T cells are prime targets of HIV-1 infection and latently infected resting CD4 T cells are the major barrier to HIV cure. Our prior studies demonstrated that uDNA generates infectious virions when T cell activation follows rather than precedes infection.ResultsHere, we characterize in primary resting CD4 T cells the dynamics of integrated and unintegrated virus expression, genome persistence and sensitivity to latency reversing agents. Unintegrated HIV-1 was abundant in directly infected resting CD4 T cells. Maximal gene expression from uDNA was delayed compared with integrated HIV-1 and was less toxic, resulting in uDNA enrichment over time relative to integrated proviruses. Inhibiting integration with raltegravir shunted the generation of durable latency from integrated to unintegrated genomes. Latent uDNA was activated to de novo virus production by latency reversing agents that also activated latent integrated proviruses, including PKC activators, histone deacetylase inhibitors and P-TEFb agonists. However, uDNA responses displayed a wider dynamic range, indicating differential regulation of expression relative to integrated proviruses. Similar to what has recently been demonstrated for latent integrated proviruses, one or two applications of latency reversing agents failed to activate all latent unintegrated genomes. Unlike integrated proviruses, uDNA gene expression did not down modulate expression of HLA Class I on resting CD4 T cells. uDNA did, however, efficiently prime infected cells for killing by HIV-1-specific cytotoxic T cells.ConclusionsThese studies demonstrate that contributions by unintegrated genomes to HIV-1 gene expression, virus production, latency and immune responses are inherent properties of the direct infection of resting CD4 T cells. Experimental models of HIV-1 latency employing directly infected resting CD4 T cells should calibrate the contribution of unintegrated HIV-1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-015-0234-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

HIV-1 latency and virus production from unintegrated genomes following direct infection of resting CD4 T cells

et al. 2016

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“…The accumulation of defective virus in full-length HIV-1 genome level in peripheral blood mononuclear cells (PBMCs) has long been observed in HIV infection [1], [2]. These defective viruses reside in circulating PBMCs and in the viral reservoirs as an integrated provirus and result from the high replication rate of HIV-1 and the low fidelity of reverse transcriptase (RT) [3]. This phenomenon has been confirmed by the detection of large internal deletions (IDs) (45.5%) and hypermutated sequences in gag (32.4%) among 4.4- to 6.4-kb-sized amplicons [4].…”

Section: Introductionmentioning

confidence: 99%

“…To date, only a few reports exist of genetic defects in the pol gene by conventional PCR, even in elite controllers or LTNPs [3], [33], [34].…”

Section: Introductionmentioning

confidence: 99%

Korean Red Ginseng increases defective pol gene in peripheral blood mononuclear cells of HIV-1–infected patients; inhibition of its detection during ginseng-based combination therapy

Cho

Kim

Woo

2019

Journal of Ginseng Research

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BackgroundWe have reported that defective nef and gag genes are induced in HIV-1–infected patients treated with Korean Red Ginseng (KRG).MethodsTo investigate whether KRG treatment and highly active antiretroviral therapy (HAART) affect genetic defects in the pol gene, we amplified and sequenced a partial pol gene (p-pol) containing the integrase portion (1.2 kb) by nested PCR with sequential peripheral blood mononuclear cells over 20 years and compared it with those patients at baseline, in control patients, those taking ginseng-based combination therapy (GCT; KRG plus combinational antiretroviral therapy) and HAART alone. We also compared our findings to look for the full-length pol gene (pol) (3.0-kb)ResultsTwenty-patients infected with subtype B were treated with KRG for 116 ± 58 months in the absence of HAART. Internal deletion in the pol gene (Δpol) was significantly higher in the KRG group (11.9%) than in the control group and at baseline; its detection was significantly inhibited during GCT as much as during HAART. In addition, the Δpol in p-pol significantly depended on the duration of KRG treatment. In pol, the proportion of Δpol was significantly higher in the KRG group (38.7%) than in the control group, and it was significantly inhibited during GCT and HAART. In contrast, the proportion of stop codon appeared not to be affected by KRG treatment. The PCR success rate was significantly decreased with longer GCT.ConclusionThe proportion of Δpol depends on template size as well as KRG treatment. HAART decreases the detection of Δpol.

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“…A consensus sequence was generated using the multiple amplicons sequenced from each pretherapy plasma sample to approximate the sequence of the transmitted/founder virus in each person. The 5′- or 3′-half genome sequences derived from the pretherapy plasma samples, the VOA wells, and the pretherapy consensus sequence were aligned using MAFFT, version 7, and maximum-likelihood (ML) phylogenetic trees were constructed in MEGA 7.0 [ 13 ]. To calculate genetic divergence of the viral populations in each person, pairwise distance between individual sequences and the pretherapy plasma consensus sequence was computed in MEGA 7.0, and the average genetic distance from the pretherapy plasma consensus sequence was calculated for each group of sequences (pretherapy plasma sequences or VOA well sequences).…”

Section: Methodsmentioning

confidence: 99%

Sequence Analysis of Inducible, Replication-Competent Virus Reveals No Evidence of HIV-1 Evolution During Suppressive Antiviral Therapy, Indicating a Lack of Ongoing Viral Replication

Lee,

Sondgeroth,

et al. 2024

Open Forum Infectious Diseases

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Background Persistence of HIV-1 in reservoirs necessitates life-long antiretroviral therapy (ART). There are conflicting data using genetic analysis on whether persistence includes an actively replicating reservoir with strong evidence arguing against replication. Methods We investigated the possibility of ongoing viral evolution during suppressive therapy by comparing near full-length viral genomic sequences using phylogenetic analysis of viral RNA in plasma before therapy initiation early after infection and from virus induced to grow from the latent reservoir after a period of suppressive ART. We also focused our analysis on evidence of selective pressure by drugs in the treatment regimen and at sites of selective pressure by the adaptive immune response. Results Viral genomes induced to grow from the latent reservoir from 10 participants with up to 9 years on suppressive ART were highly similar to the nearly homogeneous sequences in plasma taken early after infection at ART initiation. The finding was consistent across the entire genome and when the analysis focused at sites targeted by the drug regimen and by host selective pressure of antibody and cytotoxic T cells. The lack of viral evolution away from pretherapy sequences in spite of demonstrated selective pressure is most consistent with a lack of viral replication during reservoir persistence. Conclusion These results do not support ongoing viral replication as a mechanism of HIV-1 persistence during suppressive ART.

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Persistent Production of an Integrase-Deleted HIV-1 Variant with No Resistance Mutation and Wild-Type Proviral DNA in a Treated Patient

Cited by 6 publications

References 31 publications

HIV-1 latency and virus production from unintegrated genomes following direct infection of resting CD4 T cells

HIV-1 latency and virus production from unintegrated genomes following direct infection of resting CD4 T cells

Korean Red Ginseng increases defective pol gene in peripheral blood mononuclear cells of HIV-1–infected patients; inhibition of its detection during ginseng-based combination therapy

Sequence Analysis of Inducible, Replication-Competent Virus Reveals No Evidence of HIV-1 Evolution During Suppressive Antiviral Therapy, Indicating a Lack of Ongoing Viral Replication

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