Distinct viral reservoirs in individuals with spontaneous control of HIV-1

Jiang, Chenyang; Lian, Xiaodong; Gao, Ce; Sun, Xiaoming; Einkauf, Kevin; Chevalier, Josh; Chen, Samantha M. Y.; Hua, Stéphane; Rhee, Ben; Chang, Kaylee; Blackmer, Jane E.; Osborn, Matthew; Peluso, Michael J.; Hoh, Rebecca; Somsouk, Ma; Milush, Jeffrey M.; Bertagnolli, Lynn N.; Sweet, Sarah E.; Varriale, Joseph; Burbelo, Peter D.; Chun, Tae Wook; Laird, Gregory M.; Serrao, Erik; Engelman, Alan; Carrington, Mary; Siliciano, Robert F.; Siliciano, Janet M.; Deeks, Steven G.; Walker, Bruce D.; Lichterfeld, Mathias; Yu, Xu G.

doi:10.1038/s41586-020-2651-8

Cited by 288 publications

(422 citation statements)

References 60 publications

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“…A single intact proviral clone was detected from 1.02 billion CD4+ T cells in one subject and no detectable intact proviral clones were seen in 1.5 billion PBMCs from the other. Furthermore, they were unable to culture virus from more than 340 million CD4+ T cells and the IPDA did not detect intact DNA in a sample of 14 million CD4+ T cells [27]. These cases raise the question of whether a sterilizing cure has been achieved in some ECs.…”

Section: Exceptional Elite Controllersmentioning

confidence: 99%

“…While one cannot determine whether clonally expanded virus is defective or replication-competent by sequencing individual genes, full genome sequence analysis of multiple viral isolates obtained from a culture assay from an EC with a large reservoir proved that there was clonal expansion of replication-competent virus. Jiang and colleagues also showed that there was clonal expansion of genome-intact viruses in EC and the frequency of these presumed replication-competent clonally expanded viruses was higher in EC than in subjects on ART [27]. It is possible that this enrichment of clonally expanded proviruses in ECs may be due to the fact that while viral replication results in the synthesis of viral proteins that can be identified by the immune system, clonal expansion can take place without antigen expression or virus production [35,36].…”

Section: Characteristics Of Ec Proviruses and Integration Sitesmentioning

confidence: 99%

“…Kwaa et al used the IPDA to compare the size of the viral reservoir in patients on ART and ECs and found that the frequency of both total and intact DNA in EC was approximately 20-fold lower than the frequency seen in patients on ART [26]. Jiang and colleagues sequenced 1,385 and 2,388 full length proviral genomes from 64 ECs and 41 CPs respectively and also found significantly lower levels of intact and total DNA in ECs [27]. Interestingly, the ratio of intact to total DNA was the same or higher in ECs compared to subjects on ART in the 2 cohorts of patients suggesting that ECs do not have a higher portion of defective virus.…”

Section: Characteristics Of Ec Proviruses and Integration Sitesmentioning

confidence: 99%

“…Veenhuis et al showed that in an elite controller with a large reservoir, 15% of proviral clones amplified from 60 peripheral CD4+ T cells were integrated at the same site in WNK1, and 10% were integrated in the same site in ZNF470 [34]. Neither study distinguished between replication-competent and defective proviruses, but Jiang et al used matched integration site and proviral sequencing [39] to analyze both integration sites and the corresponding proviral sequence [27]. They studied 92 integration sites from intact proviruses from 11 ECs and showed that 40% of proviral clones from ECs were integrated into non-genic or pseudogenic regions compared to 13% of intact proviral clones from subjects on ART.…”

Section: Characteristics Of Ec Proviruses and Integration Sitesmentioning

confidence: 99%

“…The authors show that superinfecting CD4+ T cells from elite controllers with a lab strain leads to a normal integration pattern [27] so it is unlikely that the majority of these individuals are infected with virus that happened to integrate at sites with heterochromatin features. It is much more likely that strong immune responses in ECs selectively eliminate CD4+ T cells that harbor transcriptionally competent virus over time due to expression of viral proteins in these cells.…”

Section: Characteristics Of Ec Proviruses and Integration Sitesmentioning

confidence: 99%

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Viral reservoirs in elite controllers of HIV-1 infection: Implications for HIV cure strategies

2020

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Elite controllers are HIV-1 positive subjects who control viral replication without antiretroviral therapy. Many of these subjects have replication-competent virus and thus represent a model of a functional cure. Peripheral CD4+ T cells in these subjects have small reservoirs with a low frequency of intact proviruses. Furthermore, recent studies suggest that many of these intact proviruses are disproportionally integrated at sites that have limited transcriptional activity raising the possibility that replication-competent viruses do not replicate because they are in a “blocked and locked” state. However, this feature is probably a consequence rather than a cause of elite control. Additionally, evolution of plasma virus has been detected in many elites suggesting that there continues to be ongoing viral replication in other compartments. While exceptional elite controllers with very limited viral reservoirs have recently been described, more work is needed to determine whether these patients have achieved a sterilizing cure.

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Section: Exceptional Elite Controllersmentioning

confidence: 99%

Section: Characteristics Of Ec Proviruses and Integration Sitesmentioning

confidence: 99%

Section: Characteristics Of Ec Proviruses and Integration Sitesmentioning

confidence: 99%

Section: Characteristics Of Ec Proviruses and Integration Sitesmentioning

confidence: 99%

Section: Characteristics Of Ec Proviruses and Integration Sitesmentioning

confidence: 99%

See 3 more Smart Citations

Viral reservoirs in elite controllers of HIV-1 infection: Implications for HIV cure strategies

2020

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Advancing basic and translational research to deepen understanding of the molecular immune-mediated mechanisms regulating long-term persistence of HIV-1 in microglia in the adult human brain

Boucher

Liang

Brown

2022

Journal of Leukocyte Biology

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Knowledge about the diversity microglia (MG) type and function in the rodent and human brain has advanced significantly in the last few years. Nevertheless, we have known for 40 years that MG, monocytes, and macrophages in the brain play crucial roles in the pathogenesis of the HIV‐1 in all tissues. HIV enters and spreads in the brain early, long before the initiation of antiviral therapy. As a result, many people with HIV continue to experience neurologic and neuropsychiatric comorbid conditions collectively known as HIV‐associated neurocognitive disorder (HAND). HIV pathogenic sequelae in the CNS pose a challenge for cure strategies. Detailed understanding at a mechanistic level of how low‐level and latent HIV‐1 infection in MG negatively impacts neuroglial function has remained somewhat elusive. Direct rigorous in vivo experimental validation that the virus can integrate into MG and assume a latent but reactivatable state has remained constrained. However, there is much excitement that human in vitro models for MG can now help close the gap. This review will provide a brief background to place the role of MG in the ongoing neurologic complications of HIV infection of the CNS, then focus on the use and refinement of human postmitotic monocyte‐derived MG‐like cells and how they are being applied to advance research on HIV persistence and proinflammatory signaling in the CNS. Critically, an understanding of myeloid plasticity and heterogeneity and rigorous attention to all aspects of cell handling is essential for reproducibility. Summary Sentence: This review focuses on human postmitotic monocyte‐derived microglia‐like cells as tools to advance research on HIV persistence and neuroinflammatory signaling.

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Histone mRNA polyadenylation‐mediated inflammation underlies various virus infections and cancers

Guo

Zhu

et al. 2023

Journal of Medical Virology

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The mechanistic understanding of virus infection and inflammation in many diseases is incomplete. Normally, messenger RNA (mRNA) tails of replication‐dependent histones (RDH) that safeguard naked nuclear DNAs are protected by a specialized stem‐loop instead of polyadenylation. Here, we showed that infection by various RNA viruses (including severe acute respiratory syndrome coronavirus 2) induced aberrant polyadenylation of RDH mRNAs (pARDH) that resulted in inflammation or cellular senescence, based on which we constructed a pARDH inflammation score (pARIS). We further investigated pARIS elevation in various disease conditions, including different types of virus infection, cancer, and cellular senescence. Notably, we found that pARIS was positively correlated with coronavirus disease 2019 severity in specific immune cell types. We also detected a subset of HIV‐1 elite controllers characterized by pARDH “flipping” potentially mediated by HuR. Importantly, pARIS was positively associated with transcription of endogenous retrovirus but negatively associated with most immune cell infiltration in tumors of various cancer types. Finally, we identified and experimentally verified two pARIS regulators, ADAR1 and ZKSCAN1, which was first linked to inflammation. The ZKSCAN1 was known as a transcription factor but instead was shown to regulate pARIS as a novel RNA binding protein. Both regulators were upregulated under most infection and inflammation conditions. In conclusion, we unraveled a potential antiviral mechanism underlying various types of virus infections and cancers.

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Distinct viral reservoirs in individuals with spontaneous control of HIV-1

Cited by 288 publications

References 60 publications

Viral reservoirs in elite controllers of HIV-1 infection: Implications for HIV cure strategies

Viral reservoirs in elite controllers of HIV-1 infection: Implications for HIV cure strategies

Advancing basic and translational research to deepen understanding of the molecular immune-mediated mechanisms regulating long-term persistence of HIV-1 in microglia in the adult human brain

Histone mRNA polyadenylation‐mediated inflammation underlies various virus infections and cancers

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