Single-Cell Profiling of Latently SIV-Infected CD4
            <sup>+</sup>
            T Cells Directly
            <i>Ex Vivo</i>
            to Reveal Host Factors Supporting Reservoir Persistence

Tokarev, Andrey; Machmach, Kawthar; Creegan, Matthew; Kim, Do-Hoon; Eller, Michael A.; Bolton, Diane L.

doi:10.1128/spectrum.00604-22

Cited by 3 publications

(1 citation statement)

References 81 publications

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“…HIV persisting reservoirs are rapidly established early after infection [5 ▪▪ ,6,7], as well as at the time of ART initiation [8]. Translationally inactive and genetically intact proviruses can be detected in human blood and lymph nodes (LN) even before peak viremia [5 ▪▪ ].…”

Section: Tissue-reservoir Establishmentmentioning

confidence: 99%

Targeting HIV persistence in the tissue

Pieren,

Benítez-Martínez,

Genescà

2024

Current Opinion in HIV and AIDS

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Purpose of review The complex nature and distribution of the HIV reservoir in tissue of people with HIV remains one of the major obstacles to achieve the elimination of HIV persistence. Challenges include the tissue-specific states of latency and viral persistence, which translates into high levels of reservoir heterogeneity. Moreover, the best strategies to reach and eliminate these reservoirs may differ based on the intrinsic characteristics of the cellular and anatomical reservoir to reach. Recent findings While major focus has been undertaken for lymphoid tissues and follicular T helper cells, evidence of viral persistence in HIV and non-HIV antigen-specific CD4+ T cells and macrophages resident in multiple tissues providing long-term protection presents new challenges in the quest for an HIV cure. Considering the microenvironments where these cellular reservoirs persist opens new venues for the delivery of drugs and immunotherapies to target these niches. New tools, such as single-cell RNA sequencing, CRISPR screenings, mRNA technology or tissue organoids are quickly developing and providing detailed information about the complex nature of the tissue reservoirs. Summary Targeting persistence in tissue reservoirs represents a complex but essential step towards achieving HIV cure. Combinatorial strategies, particularly during the early phases of infection to impact initial reservoirs, capable of reaching and reactivating multiple long-lived reservoirs in the body may lead the path.

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Section: Tissue-reservoir Establishmentmentioning

confidence: 99%

Targeting HIV persistence in the tissue

Pieren,

Benítez-Martínez,

Genescà

2024

Current Opinion in HIV and AIDS

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SIV infection and ARV treatment reshape the transcriptional and epigenetic profile of naïve and memory T cells in vivo

Rahmberg,

Markowitz,

Mudd

et al. 2024

J Virol

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Human and simian immunodeficiency viruses (HIV and SIV) are lentiviruses that reverse transcribe their RNA genome with subsequent integration into the genome of the target cell. How progressive infection and administration of antiretrovirals (ARVs) longitudinally influence the transcriptomic and epigenetic landscape of particular T cell subsets, and how these may influence the genetic location of integration are unclear. Here, we use RNAseq and ATACseq to study the transcriptomics and epigenetic landscape of longitudinally sampled naïve and memory CD4+ and CD8+ T cells in two species of non-human primates prior to SIV infection, during chronic SIV infection, and after administration of ARVs. We find that SIV infection leads to significant alteration to the transcriptomic profile of all T cell subsets that are only partially reversed by administration of ARVs. Epigenetic changes were more apparent in animals with longer periods of untreated SIV infection and correlated well with changes in corresponding gene expression. Known SIV integration sites did not vary due to SIV status but did contain more open chromatin in rhesus macaque memory T cells, and the expression of proteasome-related genes at the pre-SIV timepoint correlated with subsequent viremia. IMPORTANCE Chronic inflammation during progressive human and simian immunodeficiency virus (HIV and SIV) infections leads to significant co-morbidities in infected individuals with significant consequences. Antiretroviral (ARV)-treated individuals also manifest increased levels of inflammation which are associated with increased mortalities. These data will help guide rational development of modalities to reduce inflammation observed in people living with HIV and suggest mechanisms underlying lentiviral integration site preferences.

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Isotretinoin promotes elimination of translation-competent HIV latent reservoirs in CD4T cells

Howard,

Levinger,

Deletsu

et al. 2024

PLoS Pathog

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Development of novel therapeutic strategies that reactivate latent HIV and sensitize reactivated cells to apoptosis is crucial towards elimination of the latent viral reservoir. Among the clinically relevant latency reversing agents (LRA) under investigation, the γc-cytokine IL-15 and the superagonist N-803 have been shown to reactivate latent HIV ex vivo and in vivo. However, their clinical benefit can be hindered by IL-15 promoting survival of infected cells. We previously identified a small molecule, HODHBt, that sensitizes latently infected cells to death upon reactivation with γc-cytokines through a STAT-dependent pathway. In here, we aimed to identify and evaluate FDA-approved compounds that could also sensitize HIV-infected cells to apoptosis. Using the Connectivity Map (CMap), we identified the retinol derivative 13-cis-retinoic acid (Isotretinoin) causes similar transcriptional changes as HODHBt. Isotretinoin enhances IL-15-mediated latency reversal without inducing proliferation of memory CD4 T cells. Ex vivo analysis of PBMCs from ACTG A5325, where Isotretinoin was administered to ART-suppressed people with HIV, showed that Isotretinoin treatment enhances IL-15-mediated latency reversal. Furthermore, we showed that a combination of IL-15 with Isotretinoin promotes the reduction of translation-competent reservoirs ex vivo. Mechanistically, combination of IL-15 and Isotretinoin increases caspase-3 activation specifically in HIV-infected cells but not uninfected cells. Our results suggest that Isotretinoin can be a novel approach to target and eliminate translation-competent HIV reservoirs.

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Single-Cell Profiling of Latently SIV-Infected CD4 ⁺ T Cells Directly Ex Vivo to Reveal Host Factors Supporting Reservoir Persistence

Cited by 3 publications

References 81 publications

Targeting HIV persistence in the tissue

Targeting HIV persistence in the tissue

SIV infection and ARV treatment reshape the transcriptional and epigenetic profile of naïve and memory T cells in vivo

Isotretinoin promotes elimination of translation-competent HIV latent reservoirs in CD4T cells

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Single-Cell Profiling of Latently SIV-Infected CD4 + T Cells Directly Ex Vivo to Reveal Host Factors Supporting Reservoir Persistence

Cited by 3 publications

References 81 publications

Targeting HIV persistence in the tissue

Targeting HIV persistence in the tissue

SIV infection and ARV treatment reshape the transcriptional and epigenetic profile of naïve and memory T cells in vivo

Isotretinoin promotes elimination of translation-competent HIV latent reservoirs in CD4T cells

Contact Info

Product

Resources

About

Single-Cell Profiling of Latently SIV-Infected CD4 ⁺ T Cells Directly Ex Vivo to Reveal Host Factors Supporting Reservoir Persistence