Naive infection predicts reservoir diversity and is a formidable hurdle to HIV eradication

Pinzone, Marilia Rita; Weissman, Sam; Pasternak, Alexander; Zurakowski, Ryan; Migueles, Stephen A.; O’Doherty, Una

doi:10.1172/jci.insight.150794

Cited by 16 publications

(3 citation statements)

References 68 publications

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“…Fourth, as our study included a small number of participants, it is possible that larger FIND-seq studies performed in diverse participant populations and incorporating technical improvements to increase the recovery of high-quality data will reveal signatures that were not detected here. Finally, it is important to acknowledge that the barriers to HIV cure under ART may include virus reservoirs outside the memory CD4 T cell pool [60][61][62] .…”

Section: Discussionmentioning

confidence: 99%

HIV silencing and cell survival signatures in infected T cell reservoirs

Clark

Mudvari

Thaploo

et al. 2023

Nature

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Rare CD4 T cells that contain HIV under antiretroviral therapy represent an important barrier to HIV cure1–3, but the infeasibility of isolating and characterizing these cells in their natural state has led to uncertainty about whether they possess distinctive attributes that HIV cure-directed therapies might exploit. Here we address this challenge using a microfluidic technology that isolates the transcriptomes of HIV-infected cells based solely on the detection of HIV DNA. HIV-DNA+ memory CD4 T cells in the blood from people receiving antiretroviral therapy showed inhibition of six transcriptomic pathways, including death receptor signalling, necroptosis signalling and antiproliferative Gα12/13 signalling. Moreover, two groups of genes identified by network co-expression analysis were significantly associated with HIV-DNA+ cells. These genes (n = 145) accounted for just 0.81% of the measured transcriptome and included negative regulators of HIV transcription that were higher in HIV-DNA+ cells, positive regulators of HIV transcription that were lower in HIV-DNA+ cells, and other genes involved in RNA processing, negative regulation of mRNA translation, and regulation of cell state and fate. These findings reveal that HIV-infected memory CD4 T cells under antiretroviral therapy are a distinctive population with host gene expression patterns that favour HIV silencing, cell survival and cell proliferation, with important implications for the development of HIV cure strategies.

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Section: Discussionmentioning

confidence: 99%

HIV silencing and cell survival signatures in infected T cell reservoirs

Clark

Mudvari

Thaploo

et al. 2023

Nature

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“…With the exception of the work of Simonetti et al [60], which was just discussed, relatively little is known that helps us understand the nature of the initial infected cells that can give rise to large clones. It was recently proposed that the infection of naïve T cells is important in generating HIV-infected clones [62]. While it is not possible to rule out this possibility, we do not think it is a major pathway that leads to the generation of clones of infected cells.…”

Section: Infected T Cells That Give Rise To Clones Of Infected T Cellsmentioning

confidence: 69%

Clonal Expansion of Infected CD4+ T Cells in People Living with HIV

Coffin

Hughes

2021

Viruses

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HIV infection is not curable with current antiretroviral therapy (ART) because a small fraction of CD4+ T cells infected prior to ART initiation persists. Understanding the nature of this latent reservoir and how it is created is essential to development of potentially curative strategies. The discovery that a large fraction of the persistently infected cells in individuals on suppressive ART are members of large clones greatly changed our view of the reservoir and how it arises. Rather than being the products of infection of resting cells, as was once thought, HIV persistence is largely or entirely a consequence of infection of cells that are either expanding or are destined to expand, primarily due to antigen-driven activation. Although most of the clones carry defective proviruses, some carry intact infectious proviruses; these clones comprise the majority of the reservoir. A large majority of both the defective and the intact infectious proviruses in clones of infected cells are transcriptionally silent; however, a small fraction expresses a few copies of unspliced HIV RNA. A much smaller fraction is responsible for production of low levels of infectious virus, which can rekindle infection when ART is stopped. Further understanding of the reservoir will be needed to clarify the mechanism(s) by which provirus expression is controlled in the clones of cells that constitute the reservoir.

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“…Infection and establishment of viral latency in the naïve CD4 T cell subset is, perhaps, the most important and unique aspect of our in vitro cell model. Although infected naïve T cells have historically been considered minor contributors to the latent HIV reservoir in vivo , findings from recent published reports have demonstrated that the level of naïve T cell infection is a predictor of viral reservoir size and diversity [ 70 , 71 ]. Therefore, we propose that our primary T cell model of HIV latency represents a valuable asset to the studies of potential mechanisms, which are involved in the establishment and maintenance of viral latency.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 latency is established preferentially in minimally activated and non-dividing cells during productive infection of primary CD4 T cells

et al. 2022

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Latently infected CD4 T cells form a stable reservoir of HIV that leads to life-long viral persistence; the mechanisms involved in establishment of this latency are not well understood. Three scenarios have been proposed: 1) an activated, proliferating cell becomes infected and reverts back to a resting state; 2) an activated cell becomes infected during its return to resting; or 3) infection is established directly in a resting cell. The aim of this study was, therefore, to investigate the relationship between T cell activation and proliferation and the establishment of HIV latency. Isolated primary CD4 cells were infected at different time points before or after TCR-induced stimulation. Cell proliferation within acutely infected cultures was tracked using CFSE viable dye over 14 days; and cell subsets that underwent varying degrees of proliferation were isolated at end of culture by flow cytometric sorting. Recovered cell subpopulations were analyzed for the amount of integrated HIV DNA, and the ability to produce virus, upon a second round of cell stimulation. We show that cell cultures exposed to virus, prior to stimulus addition, contained the highest levels of integrated and replication-competent provirus after returning to quiescence; whereas, cells infected during the height of cell proliferation retained the least. Cells that did not divide or exhibited limited division, following virus exposure and stimulation contained greater amounts of integrated and inducible HIV than did cells that had divided many times. Based on these results, co-culture experiments were conducted to demonstrate that latent infection could be established directly in non-dividing cells via cell-to-cell transmission from autologous productively infected cells. Together, the findings from our studies implicate the likely importance of direct infection of sub-optimally activated T cells in establishment of latently infected reservoirs in vivo, especially in CD4 lymphocytes that surround productive viral foci within immune tissue microenvironments.

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Naive infection predicts reservoir diversity and is a formidable hurdle to HIV eradication

Cited by 16 publications

References 68 publications

HIV silencing and cell survival signatures in infected T cell reservoirs

HIV silencing and cell survival signatures in infected T cell reservoirs

Clonal Expansion of Infected CD4+ T Cells in People Living with HIV

HIV-1 latency is established preferentially in minimally activated and non-dividing cells during productive infection of primary CD4 T cells

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