Intact HIV-1 proviruses accumulate at distinct chromosomal positions during prolonged antiretroviral therapy

Einkauf, Kevin; Lee, Guinevere Q.; Gao, Ce; Sharaf, Radwa; Sun, Xiaoming; Hua, Stéphane; Chen, Samantha M. Y.; Jiang, Chenyang; Lian, Xiaodong; Chowdhury, Fatema Z.; Rosenberg, Eric S.; Chun, Tae‐Wook; Li, Jonathan Z.; Yu, Xu G.; Lichterfeld, Mathias

doi:10.1172/jci124291

Cited by 233 publications

(388 citation statements)

References 48 publications

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“…Furthermore, in vitro studies showed that cell division and latency are not mutually exclusive (Wang et al, 2018;Hosmane et al, 2017;Pinzone et al, 2019). Finally, isolation of productively infected cells ex vivo (Cohn et al, 2018) and paired full-length viral sequencing and integration site analysis (Einkauf et al, 2019) provided definitive evidence for the existence of expanded clones of CD4 + T cells harboring intact latent proviruses.…”

Section: Discussionmentioning

confidence: 99%

“…However, HIV-1 is preferentially integrated into highly transcribed genes (Schröder et al, 2002) which include many cancerassociated genes. Thus, it has been difficult to definitively determine whether or how integration in the vicinity of cancer related genes contributes to HIV-1 persistence (Cohn et al, 2015;Einkauf et al, 2019). Moreover, unlike transforming retroviruses that integrate into cancer genes and cause unrestricted cell growth, HIV-1 is not known to cause T cell cancers by integration.…”

Section: Discussionmentioning

confidence: 99%

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Antigen responsive CD4⁺T cell clones contribute to the HIV-1 latent reservoir

Mendoza

Jackson

Oliveira

et al. 2020

Preprint

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AbstractAntiretroviral therapy suppresses but does not cure HIV-1 infection due to the existence of a long-lived reservoir of latently infected cells. The reservoir has an estimated half-life of 44 months and is largely composed of clones of infected CD4+ T cells. The long half-life appears to result in part from expansion and contraction of infected CD4+ T cell clones. However, the mechanisms that govern this process are poorly understood. To determine whether the clones might result from, and be maintained by exposure to antigen, we measured responses of reservoir cells to a small subset of antigens from viruses that produce chronic or recurrent infections. Despite the limited panel of test antigens, clones of antigen responsive CD4+ T cells containing defective or intact latent proviruses were found in 7 out of 8 individuals studied. Thus, chronic or repeated exposure to antigen may contribute to the longevity of the HIV-1 reservoir by stimulating the clonal expansion of latently infected CD4+ T cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antigen responsive CD4⁺T cell clones contribute to the HIV-1 latent reservoir

Mendoza

Jackson

Oliveira

et al. 2020

Preprint

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“…Transcriptional interference between the host genes and integrated proviruses is another factor that affects proviral transcription 34, 35 . In line with this notion, a recent study reported that there is a higher proportion of intact proviruses integrated in the opposite orientation relative to the host genes in CD4 + T cells of HIV-1-infected individuals 20 . These findings indicate that susceptibility to LRAs among different HIV-1 clones is variable depending on the genetic and epigenetic environments of integrated proviruses.…”

Section: Discussionmentioning

confidence: 74%

“…Next, we analyzed the effect of PEP005 on the widely distributed HIV-1 proviruses in the host cellular genome 20, 21 . Copy numbers of intracellular HIV-1 DNA was markedly decreased after EFdA- or EFdA + PEP005-treatment ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A widely-distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents in vitro

Matsuda

Islam²,

Takada

et al. 2019

Preprint

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22Persistence of HIV-1 latent reservoir cells during antiretroviral therapy (ART) is a major 23 obstacle for curing HIV-1. Latency-reversing agents (LRAs) are under intensive development to 24 reactivate and eradicate latently infected cells; however, there are a few useful models for 25 evaluating LRA activity in vitro. Here, we established a chronically HIV-1-infected culture 26 system harboring thousands of different HIV-1-infected cell clones with a wide distribution of 27 HIV-1 provirus similar to that observed in vivo. A combination of an LRA and an anti-HIV-1 28 drug successfully inhibited viral re-emergence after drug discontinuation, demonstrating 29 "experimental cure" in the in vitro model. We demonstrated that the epigenetic environment of 30 the integrated provirus plays a role in determining drug susceptibility. Our widely distributed 31 intact provirus elimination (WIPE) assay will be useful for optimizing therapeutics against 32HIV-1 latency and provides mechanistic insights into the selection of heterogeneous Advances in antiviral therapy have dramatically improved the therapeutic options available for 36 treating human immunodeficiency virus type 1 (HIV-1) infection. However, even with the most 37 potent combined antiretroviral therapy (cART), HIV-1-infected patients remain on medication 38 throughout their lifetime because HIV-1 persists in viral reservoirs in vivo regardless of 39 treatment 1-3 . In this regard, the "shock and kill" approach, which first activates cells latently 40 infected with HIV-1 2,3 using small molecule agents called HIV-1 latency-reversing agents 41 (LRAs), is a possible strategy for curing HIV-1 4-9 . LRAs reverse HIV-1 latency and induce viral 42 production in cells latently infected with the virus. In theory, infected cells that express viral 43 antigens are then killed by the human immune system, such as cytotoxic T lymphocytes, or viral 44 cytopathic effects 10-12 . However, LRAs that appear potent in in vitro assays are not necessarily 45 effective in vivo because the viral reservoir situation is quite different in vitro and in vivo [13][14][15][16] . 46The host factors shaping the HIV-1 reservoir in vivo include the immunological status with 47 respect to the virus, anatomical location, and a variety of host cells. From the viral perspective, 48wide heterogeneity is noted in vivo, such as the viral sequence, presence of defective proviruses, 49integration sites (ISs) in the host cellular genomic DNA, and expansion of some infected 50 clones 17-21 . These factors potentially affect the efficacy of LRA in vivo. 51As the "shock" step may trigger the production of infectious virus and thereby induce 52 de novo infection, it is essential to combine LRAs with the existing anti-HIV-1 drugs. However, 53no suitable in vitro model system to evaluate the efficacy of such combination therapies exists. 54Currently available in vitro models for HIV-1 latency, such as ACH2, J1.1, and U1 cells, carry 55 only one or two integrated proviruses with a specific genetic and epigenetic...

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“…To extend our studies to more physiologically relevant models and provide clinical relevance, we first assembled open source, publicly available HIV integration datasets from 11 patients studies (Mack et al 2003;Han et al 2004;Ikeda et al 2007;Maldarelli et al 2014;Wagner et al 2014;Kok et al 2016;Sharaf et al 2018;Coffin et al 2019;Einkauf et al 2019;Garcia-Broncano et al 2019;McManus et al 2019) and 4 studies with primary CD4 + T cells infected ex vivo (Sherrill-Mix et al 2013;Sunshine et al 2016;Ferris et al 2019;Lucic et al 2019) ( Supplemental Table S4). We used these datasets to interrogate the epigenomic landscape of intact vs defective proviruses to provide fundamental principles of differential positioning and regulation of these two proviral classes and to compare their epigenomic landscapes to proviruses in the immortalized (Jurkat T cell) models of latency ( Fig.…”

Section: Combination Of In Vitro Hiv Integration/expression Data Withmentioning

confidence: 99%

An integrated genomics approach towards deciphering human genome codes shaping HIV-1 proviral transcription and fate

Ruess

Guzmán

et al. 2020

Preprint

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A large body of work has revealed fundamental principles of HIV-1 integration into the human genome.However, the effect of the integration site to proviral transcription activity has so far remained elusive.Here we combine open-source, large-scale datasets including epigenetics, transcriptome, and 3D genome architecture to interrogate the chromatin states, transcription activity landscape, and nuclear sub-compartments around HIV-1 integration sites in CD4 + T cells to decipher human genome codes shaping the transcription of proviral classes defined based on their position and orientation in the genome. Using a Hidden Markov Model, we describe the importance of specific chromatin states and genome architecture in the control of HIV-1 transcription activity. Additionally, implementation of a machine-learning logistic regression model reveals upstream chromatin accessibility, transcription activity, and categorical nuclear sub-compartments as optimal features predicting HIV-1 transcriptional outcomes. We finally demonstrate clinical relevance by interrogating the positions of intact proviruses persisting in patients under suppressive therapy and provide a compass compatible with clinical decision-making.

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Intact HIV-1 proviruses accumulate at distinct chromosomal positions during prolonged antiretroviral therapy

Cited by 233 publications

References 48 publications

Antigen responsive CD4⁺T cell clones contribute to the HIV-1 latent reservoir

Antigen responsive CD4⁺T cell clones contribute to the HIV-1 latent reservoir

A widely-distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents in vitro

An integrated genomics approach towards deciphering human genome codes shaping HIV-1 proviral transcription and fate

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Intact HIV-1 proviruses accumulate at distinct chromosomal positions during prolonged antiretroviral therapy

Cited by 233 publications

References 48 publications

Antigen responsive CD4+T cell clones contribute to the HIV-1 latent reservoir

Antigen responsive CD4+T cell clones contribute to the HIV-1 latent reservoir

A widely-distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents in vitro

An integrated genomics approach towards deciphering human genome codes shaping HIV-1 proviral transcription and fate

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Product

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Antigen responsive CD4⁺T cell clones contribute to the HIV-1 latent reservoir

Antigen responsive CD4⁺T cell clones contribute to the HIV-1 latent reservoir