Stimulation of HIV-1-Specific Cytolytic T Lymphocytes Facilitates Elimination of Latent Viral Reservoir after Virus Reactivation

Shan, Liang; Deng, Kai; Shroff, Neeta S.; Durand, Christine M.; Rabi, S. Alireza; Yang, Hung‐Chih; Zhang, Hao; Margolick, Joseph B.; Blankson, Joel N.; Siliciano, Robert F.

doi:10.1016/j.immuni.2012.01.014

Cited by 642 publications

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“…Recent in vitro experiments also suggest that cells with virus transcription reactivated by vorinostat and panobinostat may be longer lived than cells that reactivate virus naturally (24,28). Consequently, our model predicted that the potentials of these drugs to reactivate virus in latently infected cells are very different (around 8% above the baseline reservoir HIV reactivation rate for panobinostat and approximately 2.5-fold increase for romidepsin).…”

Section: Figmentioning

confidence: 80%

“…Although all investigated LRAs showed increased virus transcription, no changes in the latent-reservoir size were detected after the use of LRA in vivo (14,(18)(19)(20) or in vitro (24). One reason could be the short time during which LRAs were given to ART patients (ranging from 8 weeks for panobinostat to 3 weeks for romidepsin and 3 days for disulfiram), making the detection of reservoir decay problematic.…”

Section: Resultsmentioning

confidence: 98%

“…2B, in which the fold increase in the number of cells is approximately equal to the fold increase in the HIV reactivation rate, relies on the assumption that all cells with reactivated HIV are short-lived. However, recent studies (24,28) have suggested that cells with HIV reactivated by HDACi may have longer life spans and that virus-specific CD8 ϩ T cells or other immune responses may need to be stimulated in order to facilitate their elimination.…”

Section: Resultsmentioning

confidence: 99%

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Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Petravic

Rasmussen

Lewin

et al. 2017

J Virol

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Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latencyreversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3-to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life Ͼ 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment.IMPORTANCE Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.KEYWORDS latency, reactivation, human immunodeficiency virus C ombination antiretroviral therapy (ART) suppresses plasma HIV RNA below the detection limit of laboratory assays and restores the immune systems of infected patients by preventing new rounds of productive infection. However, ART cannot eradicate the infection, and virus replication starts again within weeks of ART cessation

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Section: Figmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

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Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Petravic

Rasmussen

Lewin

et al. 2017

J Virol

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“…To this end, Siliciano et al recently reported that unstimulated HIV-specific cytotoxic T cell lymphocytes (CTLs) failed to kill www.nature.com/aps Shang HT et al Acta Pharmacologica Sinica npg the latently infected cells reactivated by SAHA. In contrast, antigen-specific stimulation of patients' CTLs led to rapid killing of these SAHA-reactivated cells [79] . Moreover, monocytes, macrophages and myeloid dendritic cells are more resistant to viral cytotoxic effects.…”

Section: Resultsmentioning

confidence: 95%

Progress and challenges in the use of latent HIV-1 reactivating agents

Shang

Ding

et al. 2015

Acta Pharmacol Sin

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Highly active antiretroviral therapy (HAART) can effectively suppress the replication of human immunodeficiency virus-1 (HIV-1) and block disease progression. However, chronic HIV-1 infection remains incurable due to the persistence of a viral reservoir, including the transcriptionally silent provirus in CD4 + memory T cells and the sanctuary sites that are inaccessible to drugs. Reactivation and the subsequent elimination of latent virus through virus-specific cytotoxic effects or host immune responses are critical strategies for combating the disease. Indeed, a number of latency reactivating reagents have been identified through mechanism-directed approaches and large-scale screening, including: (1) histone deacetylase inhibitors (HDACi); (2) cytokines and chemokines; (3) DNA methyltransferase inhibitors (DNMTI); (4) histone methyltransferase inhibitors (HMTI); (5) protein kinase C (PKC) activators; (6) P-TEFb activators; and (7) unclassified agents, such as disulfram. They have proved to be efficacious in latent cell line models and CD4 + T lymphocytes from HIV-1-infected patients. This review comprehensively summarizes the recent progress and relative challenges in this field.

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“…This hypothesis is supported by in vitro experiments in which memory CD8þ T cells from these HICs were able to gain cytotoxic activities within a few days of stimulation with cognate peptides [135]. These experiments are not completely conclusive, because cells from non-controller patients also gain anti-HIV capacities upon stimulation in vitro [136]. Therefore, further studies are necessary to identify clear distinguishable characteristics in memory CD8þ T cells from HICs, which may hold important clues for the development of an efficient T-cell-based vaccine.…”

Section: (B) Adaptive Cellular Responses (I) Cd8þ T Cell Responsesmentioning

confidence: 99%

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

Sáez‐Cirión

Jacquelin

Barré‐Sinoussi

et al. 2014

Phil. Trans. R. Soc. B

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International audienceHIV research has made rapid progress and led to remarkable achievements in recent decades, the most important of which are combination antiretroviral therapies (cART). However, in the absence of a vaccine, the pandemic continues, and additional strategies are needed. The 'towards an HIV cure' initiative aims to eradicate HIV or at least bring about a lasting remission of infection during which the host can control viral replication in the absence of cART. Cases of spontaneous and treatment-induced control of infection offer substantial hope. Here, we describe the scientific knowledge that is lacking, and the priorities that have been established for research into a cure. We discuss in detail the immunological lessons that can be learned by studying natural human and animal models of protection and spontaneous control of viraemia or of disease progression. In particular, we describe the insights we have gained into the immune mechanisms of virus control, the impact of early virus-host interactions and why chronic inflammation, a hallmark of HIV infection, is an obstacle to a cure. Finally, we enumerate current interventions aimed towards improving the host immune response

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Stimulation of HIV-1-Specific Cytolytic T Lymphocytes Facilitates Elimination of Latent Viral Reservoir after Virus Reactivation

Cited by 642 publications

References 60 publications

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

Progress and challenges in the use of latent HIV-1 reactivating agents

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

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