Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells

Lee, Guinevere Q.; Orlova-Fink, Nina; Einkauf, Kevin; Chowdhury, Fatema Z.; Sun, Xiaoming; Harrington, Sean; Kuo, Hsiao-Hsuan; Hua, Stéphane; Chen, Hsiao-Rong; Ouyang, Zhengyu; Reddy, Kavidha; Dong, Krista; Ndung’u, Thumbi; Walker, Bruce D.; Rosenberg, Eric S.; Yu, Xu G.; Lichterfeld, Mathias

doi:10.1172/jci93289

Cited by 261 publications

(396 citation statements)

References 37 publications

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“…The stability and longevity of the HIV-1 reservoir is thought to be maintained via proliferation of cells containing HIV-1 proviruses (Maldarelli et al, 2014, Wagner et al, 2014, Cohn et al, 2015, Lee et al, 2017), with antigen-driven and/or homeostatic proliferation of CD4 + T cells containing an integrated HIV-1 provirus the likely mechanism (von Stockenstrom et al, 2015, Chomont et al, 2009). Phylogenetic trees of proviral contigs were prepared for each participant (Figure 3 and Data S1A–E).…”

Section: Resultsmentioning

confidence: 99%

“…It is important to note that the proportion of intact proviruses and the different types of defective proviruses obtained in this study were similar to those obtained by Bruner et al (2016), indicating the reproducibility of obtaining the genetic sequence of HIV-1 proviruses from participants on long-term ART. Recent studies also utilized NGS for sequencing near full-length HIV-1 proviruses (Lee et al, 2017, Imamichi et al, 2016), however the advantages of this approach over SPS and existing sanger-based assays were not presented or discussed.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, it is possible these methods may not capture the entire population of proviruses present in an individual as, due to the number and complexity of primers used, these methods may be influenced by primer mismatches. In response to these limitations, we and others have developed Next Generation Sequencing (NGS) based assays to sequence near full-length HIV-1 proviruses (Lee et al, 2017, Imamichi et al, 2016). Here, we present the Full-Length Individual Proviral Sequencing (FLIPS) assay: a high-throughput assay utilizing NGS to sequence single, full-length HIV-1 proviruses and predict their potential replication-competency by comparative genomics.…”

Section: Introductionmentioning

confidence: 99%

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Identification of Genetically Intact HIV-1 Proviruses in Specific CD4 + T Cells from Effectively Treated Participants

et al. 2017

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Summary Latent replication-competent HIV-1 persists in individuals on long-term antiretroviral therapy (ART). We developed the Full-Length Individual Proviral Sequencing (FLIPS) assay to determine the distribution of latent replication-competent HIV-1 within memory CD4+ T cell subsets in six individuals on long-term ART. FLIPS is an efficient, high-throughput assay that amplifies and sequences near full-length (~9 kb) HIV-1 proviral genomes and determines potential replication-competency through genetic characterization. FLIPS provides a genome-scale perspective which addresses the limitations of other methods that also genetically characterize the latent reservoir. Using FLIPS, we identified 5% proviruses as intact and potentially replication-competent. Intact proviruses were unequally distributed between T cell subsets, with effector memory cells containing the largest proportion of genetically intact HIV-1 proviruses. We identified multiple identical intact proviruses suggesting a role for cellular proliferation in the maintenance of the latent HIV-1 reservoir.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Genetically Intact HIV-1 Proviruses in Specific CD4 + T Cells from Effectively Treated Participants

et al. 2017

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“…While it was originally believed by many that latently infected cells must be intrinsically long-lived, since cell division was expected to reactivate viral expression and lead to eventual cell death, a series of studies over the past few years have convincingly demonstrated that cells in the reservoir can proliferate while remaining latently infected (Reference 110,112). These studies have identified multiple latently infected cells -even in small samples -with virus integrated into identical sites [113][114][115] in the genome or with sequence-identical virus [116][117][118][119] -two findings that would be exceedingly unlikely to occur in two independent infection events and likely reflect division of infected cells.…”

Section: What Maintains the Latent Reservoir And How Can We Reducementioning

confidence: 99%

Insight into treatment ofHIVinfection from viral dynamics models

Hill

Rosenbloom

Nowak

et al. 2018

Immunological Reviews

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SUMMARY The odds of living a long and healthy life with HIV infection have dramatically improved with the advent of combination antiretroviral therapy. Along with the early development and clinical trials of these drugs, and new field of research emerged called viral dynamics, which uses mathematical models to interpret and predict the time course of viral levels during infection and how they are altered by treatment. In this review, we summarize the contributions that virus dynamics models have made to understanding the pathophysiology of infection and to designing effective therapies. This includes studies of the multi-phasic decay of viral load when antiretroviral therapy is given, the evolution of drug resistance, the long-term persistence latently infected cells, and the rebound of viremia when drugs are stopped. We additionally discuss new work applying viral dynamics models to new classes of investigational treatment for HIV, including latency-reversing agents and immunotherapy.

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“…Several recent studies have revealed important features of persistent HIV-1 that directly impact our understanding of the latent reservoir. Full viral genome sequencing studies have shown that over 93% of proviruses in resting CD4 + T cells in HIV + individuals on cART are defective (Ho et al 2013; Bruner et al 2016; Imamichi et al 2016; Hiener et al 2017; Lee et al 2017). These defective proviruses contain large internal deletions and/or hypermutation mediated by APOBEC3G, a host enzyme that deaminates dC to dU on the minus strand of HIV-1 cDNA during reverse transcription (resulting in a G to A hypermutation).…”

Section: A Historical Perspectivementioning

confidence: 99%

Targeting the Latent Reservoir for HIV-1

2018

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Antiretroviral therapy can effectively block HIV-1 viral replication and prevent or reverse immunodeficiency in HIV-1-infected individuals. However, viral replication resumes within weeks of treatment interruption. The major barrier to cure is a small pool of resting memory CD4+ T cells that harbor latent HIV-1 proviruses. This latent reservoir is now the focus of an intense international research effort. We describe how the reservoir is established, challenges involved in eliminating it, and pharmacologic and immunologic strategies for targeting this reservoir. The development of a successful cure strategy will likely require understanding the mechanisms that maintain HIV-1 proviruses in a latent state and pathways that drive the proliferation of infected cells, which slows reservoir decay. In addition, cure will require the development of effective immunologic approaches to eliminating infected cells. There is renewed optimism about the prospect of a cure, and the interventions discussed here may pave the way.

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Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells

Cited by 261 publications

References 37 publications

Identification of Genetically Intact HIV-1 Proviruses in Specific CD4 + T Cells from Effectively Treated Participants

Identification of Genetically Intact HIV-1 Proviruses in Specific CD4 + T Cells from Effectively Treated Participants

Insight into treatment ofHIVinfection from viral dynamics models

Targeting the Latent Reservoir for HIV-1

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