Prospects for Treatment of Latent HIV

Barton, Kirston; Burch, Brandon D.; Soriano-Sarabia, Natalia; Margolis, David M.

doi:10.1038/clpt.2012.202

Cited by 82 publications

(68 citation statements)

References 70 publications

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“…Although not completely understood, infection of activated CD4 + T cells as they are transitioning to a resting memory state may be the primary mechanism by which latency is established; direct infection of resting cells has also been demonstrated [10,21]. Several studies have suggested that HIV latency is regulated by the same mechanisms that govern host cell gene expression, including epigenetic transcriptional silencing, availability, and recruitment of host transcription factors and transcriptional interference (reviewed in [22]). There is clear evidence that cells that contain HIV DNA integrants can undergo homeostatic proliferation [23][24][25], and if these genomes are replication competent they will contribute to persistent infection.…”

Section: Discussionmentioning

confidence: 99%

Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies

et al. 2015

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The quantitative viral outgrowth assay (QVOA) provides a precise minimal estimate of the reservoir of resting CD4 + T-cell infection (resting cell infection [RCI]). However, the variability of RCI over time during antiretroviral therapy (ART), relevant to assess potential effects of latency-reversing agents or other interventions, has not been fully described. We performed QVOA on resting CD4 + T cells obtained via leukapheresis from 37 human immunodeficiency virus (HIV)-infected patients receiving stable suppressive ART for a period of 6 years. Patients who started ART during acute (n = 17) or chronic (n = 20) HIV infection were studied once HIV RNA levels were <50 copies/mL for ≥6 months. Using random effects analysis of 160 RCI measurements, we found that RCI declined significantly over time (P < .001), with an estimated mean half-life of 3.6 years (95% confidence interval, 2.3-8.1 years), remarkably consistent with findings of prior studies. There was no evidence of more rapid decay in acute versus chronic HIV infection (P = .99) for patients suppressed ≥6 months. RCI was reliably estimated with longitudinal measurements generally showing <2-fold variation from the previous measure. When QVOA is performed in this format, RCI decreases of >6-fold were rare. We suggest that a 6-fold decline is a relevant threshold to reliably identify effects of antilatency interventions on RCI.

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Section: Discussionmentioning

confidence: 99%

Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies

et al. 2015

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“…For example, HIV-1 expression can be induced in J-lat clones and primary cells from patients by HDAC inhibitors, whereas several primary cell models of latency are resistant to the effects of HDAC inhibitors. Given the complexity and diversity of latency in vivo and the varying responses of these models, information from primary cell models may be expanded by evaluating responses in more than one model 91 .…”

Section: Model Systems Of Hiv-1 Latencymentioning

confidence: 99%

“…Early attempts to reactivate virus production via global T cell activation using OKT3 and IL-2 in combination led to toxic levels of immune activation, and thus current strategies focus on reactivating the virus in the absence of T cell activation 124 . However, most of these approaches have been validated only in cell line models of HIV-1 latency, and only a few have been tested in resting CD4 + T cells that have been isolated from aviraemic patients 51,91,125–128 .…”

Section: Strategies To Disrupt Latent Infectionmentioning

confidence: 99%

Eradicating HIV-1 infection: seeking to clear a persistent pathogen

et al. 2014

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Effective antiretroviral therapy (ART) blunts viraemia, which enables HIV-1-infected individuals to control infection and live long, productive lives. However, HIV-1 infection remains incurable owing to the persistence of a viral reservoir that harbours integrated provirus within host cellular DNA. This latent infection is unaffected by ART and hidden from the immune system. Recent studies have focused on the development of therapies to disrupt latency. These efforts unmasked residual viral genomes and highlighted the need to enable the clearance of latently infected cells, perhaps via old and new strategies that improve the HIV-1-specific immune response. In this Review, we explore new approaches to eradicate established HIV-1 infection and avoid the burden of lifelong ART.

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“…It is worth noting that similar approaches are currently being tested in cell populations latently infected with HIV-1 to promote 'reawakening' of latent HIV gene expression to allow these cells to be recognized and eliminated by HIV-specific T cells. [95][96][97] There is a very clear rational behind reducing the latent load within an individual person to limit viral reactivation; however, this clearly needs to be balanced by the risks that such an intervention may carry with it. In the case of particular clinical settings, such as immunosuppression in transplantation, we would suggest that this balance is in favour of using chemotherapeutic and/or immunological techniques to reduce the latent reservoir.…”

Section: Induction Of Immunogenic Lytic Genes In the Absence Of Immunmentioning

confidence: 99%

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

et al. 2014

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While the host immune response following primary human cytomegalovirus (HCMV) infection is generally effective at stopping virus replication and dissemination, virus is never cleared by the host and like all herpesviruses, persists for life. At least in part, this persistence is known to be facilitated by the ability of HCMV to establish latency in myeloid cells in which infection is essentially silent with, importantly, a total lack of new virus production. However, although the viral transcription programme during latency is much suppressed, a number of viral genes are expressed during latent infection at the protein level and many of these have been shown to have profound effects on the latent cell and its environment. Intriguingly, many of these latency-associated genes are also expressed during lytic infection. Therefore, why the same potent host immune responses generated during lytic infection to these viral gene products are not recognized during latency, thereby allowing clearance of latently infected cells, is far from clear. Reactivation from latency is also a major cause of HCMV-mediated disease, particularly in the immune compromised and immune naive, and is also likely to be a major source of virus in chronic subclinical HCMV infection which has been suggested to be associated with long-term diseases such as atherosclerosis and some neoplasias. Consequently, understanding latency and why latently infected cells appear to be immunoprivileged is crucial for an understanding of the pathogenesis of HCMV and may help to design strategies to eliminate latent virus reservoirs, at least in certain clinical settings.

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Prospects for Treatment of Latent HIV

Cited by 82 publications

References 70 publications

Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies

Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies

Eradicating HIV-1 infection: seeking to clear a persistent pathogen

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

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