Induction of HIV-1 latency and reactivation in primary memory CD4+ T cells

Bosque, Alberto; Planelles, Vicente

doi:10.1182/blood-2008-07-168393

Cited by 306 publications

(468 citation statements)

References 53 publications

Supporting

Mentioning

454

Contrasting

Unclassified

Order By: Relevance

“…Our group and others are exploring single-cell methods to resolve the frequency and amplitude of latency reversal, but with in vivo frequencies on the order of 1 per million, the quantitation of infected cells by such methods is extremely challenging. Flow cytometrybased methods are readily applied to primary cell models of HIV-1 latency in which the frequency of latently infected cells is several orders of magnitude higher, and in those models, latency-reversing agents clearly increase the number of cells expressing HIV-1 genes (13,19,57). Further studies of the fraction of cells induced ex vivo as well as the life span of newly induced cells may address these questions.…”

Section: Discussionmentioning

confidence: 99%

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Laird¹,

Bullen²,

et al. 2015

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Ex vivo analysis identifies effective HIV-1 latency–reversing drug combinations

Laird¹,

Bullen²,

et al. 2015

View full text Add to dashboard Cite

“…Alternatively, preactivation latency has also been described, where HIV-1 DNA can be integrated into quiescent rCD4 cells via interactions of chemokines with CCR7, CXCR3, and CCR6 in the absence of productive infection (21). Independently of whether productive infection has occurred, the G 0 resting state in rCD4 cells contributes to the inhibition of HIV-1 transcription and translation through a variety of mechanisms, including the sequestration of transcription factors NF-κB and NFAT (22,23); association of P-TEFb with the inhibitory 7SK snRNA complex (24,25); and association of the BAF complex and histone deacetylases with the HIV long terminal repeat (26,27). In addition to transcriptional blocks, posttranscriptional nuclear sequestration of the spliced tat and rev HIV-1 mRNAs in latently infected rCD4 cells prevent productive infection (28).…”

Section: Discussionmentioning

confidence: 99%

Quantification of HIV-1 latency reversal in resting CD4 ⁺ T cells from patients on suppressive antiretroviral therapy

Cillo

Sobolewski

Bosch

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

215

218

View full text Add to dashboard Cite

Reversal of proviral latency is being pursued as a curative strategy for HIV-1 infection. Recent clinical studies of in vivo administration of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat) show increases in unspliced cellular HIV-1 RNA levels in resting CD4 + T cells. A critical unknown, however, is the proportion of latent proviruses that can be transcriptionally reactivated by SAHA or T-cell activation. In this study, we quantified the fraction of HIV-1 proviruses in resting CD4 + T cells from patients on suppressive antiretroviral therapy that were reactivated ex vivo with SAHA or antibodies to CD3/CD28. At concentrations of SAHA achieved clinically, only 0.079% of proviruses in resting CD4 + T cells were reactivated to produce virions, compared with 1.5% of proviruses in cells treated with anti-CD3/CD28 antibodies after correcting for spontaneous virion production in the medium control. A significant positive correlation (ρ = 0.67, P < 0.001) was found between levels of virions in the supernatant and unspliced cellular HIV-1 RNA following anti-CD3/CD28 treatment, but not following SAHA treatment (ρ = 0.21, P = 0.99). These results reveal that the majority of HIV-1 proviruses are not reactivated by current therapeutic approaches and that more effective means of reversing proviral latency will likely be required to deplete HIV-1 reservoirs.HIV-1 persistence | HIV-1 eradication | HIV-1 cure | fractional provirus expression A ntiretroviral therapy (ART) for HIV-1 infection suppresses viral replication but is not curative. Assays of infectious virus recovery from quiescent CD4 + T cells isolated from patients on ART have revealed the existence of a reservoir of latent, replication competent HIV-1 with a half-life of 44 mo (1-4). In addition, low-level plasma viremia persists indefinitely on ART (5, 6), and the level of virus in plasma rebounds following cessation of ART (7,8). New therapeutic approaches are required to eliminate both persistent low-level viremia and the latent proviral reservoir. A "kick and kill" approach has been proposed in which latency reversing agents, administered in conjunction with ART, will "kick" proviruses out of latency, followed by a "kill" of the infected cells through viral cytopathic effects or immune-mediated cytotoxicity.Histone deacetylase inhibitors (HDACi) have been proposed as latency reversing agents, and single-dose or multidose administration of suberoylanilide hydroxamic acid (SAHA; vorinostat) in vivo was shown to increase expression of unspliced cellular HIV-1 RNA in resting CD4 + T (rCD4) cells in patients on suppressive ART (9, 10). Although three-to fivefold increases in cellular HIV-1 RNA were observed (9), the fraction of latent HIV-1 proviruses that were reactivated by SAHA was not quantified. It is possible that SAHA transcriptionally reactivated many latent proviruses, or alternatively reactivated only a minority of latent proviruses. These two alternatives have very different implications in terms of the impact SAHA coul...

show abstract

“…However this process is challenging to reconstruct in vitro and only recently Alberto Bosque and Vicente Planelles described an ex vivo experimental system that generates high levels of HIV-1 latently infected memory cells using primary CD4 + T cells. 33 Using a simplified model of a lymphoblastoid cell line carrying a single HIV-1 latent vector we were able to demonstrate that in the silenced state the provirus was associated in trans with a pericentromeric region of another chromosome at the periphery of the nucleus. 13 Interestingly, this association was lost upon transcriptional activation, although the provirus remained peripheral also during active transcription.…”

Section: Nucleusmentioning

confidence: 91%