Pilot Study of a Combination of Highly Active Antiretroviral Therapy and Cytokines to Induce HIV-1 Remission

Lafeuillade, Alain; Poggi, Cécile; Chadapaud, Stéphane; Hittinger, Gilles; Chouraqui, Martine; Pisapia, Magali; Delbeke, Emmanuel

doi:10.1097/00042560-200101010-00006

Cited by 19 publications

(14 citation statements)

References 35 publications

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“…One difference between our study and previous reports that may explain this finding is the use of CD8-depleted PBMC rather than MDM to isolate viruses. We used this method because it has been shown to be the most sensitive method for virus isolation from lymphocytes and monocytes (16,59,102). As expected, we found that coculture with CD8-depleted PBMC was more sensitive for isolation of HIV-1 from brain and lymphoid tissue samples than coculture with MDM.…”

Section: Discussionmentioning

confidence: 66%

Macrophage Tropism of Human Immunodeficiency Virus Type 1 Isolates from Brain and Lymphoid Tissues Predicts Neurotropism Independent of Coreceptor Specificity

Gorry

Bristol

Zack

et al. 2001

J Virol

266

324

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The viral determinants that underlie human immunodeficiency virus type 1 (HIV-1) neurotropism are unknown, due in part to limited studies on viruses isolated from brain. Previous studies suggest that brainderived viruses are macrophage tropic (M-tropic) and principally use CCR5 for virus entry. To better understand HIV-1 neurotropism, we isolated primary viruses from autopsy brain, cerebral spinal fluid, blood, spleen, and lymph node samples from AIDS patients with dementia and HIV-1 encephalitis. Isolates were characterized to determine coreceptor usage and replication capacity in peripheral blood mononuclear cells (PBMC), monocyte-derived macrophages (MDM), and microglia. Env V1/V2 and V3 heteroduplex tracking assay and sequence analyses were performed to characterize distinct variants in viral quasispecies. Viruses isolated from brain, which consisted of variants that were distinct from those in lymphoid tissues, used CCR5 (R5), CXCR4 (X4), or both coreceptors (R5X4). Minor usage of CCR2b, CCR3, CCR8, and Apj was also observed. Primary brain and lymphoid isolates that replicated to high levels in MDM showed a similar capacity to replicate in microglia. Six of 11 R5 isolates that replicated efficiently in PBMC could not replicate in MDM or microglia due to a block in virus entry. CD4 overexpression in microglia transduced with retroviral vectors had no effect on the restricted replication of these virus strains. Furthermore, infection of transfected cells expressing different amounts of CD4 or CCR5 with M-tropic and non-M-tropic R5 isolates revealed a similar dependence on CD4 and CCR5 levels for entry, suggesting that the entry block was not due to low levels of either receptor. Studies using TAK-779 and AMD3100 showed that two highly M-tropic isolates entered microglia primarily via CXCR4. These results suggest that HIV-1 tropism for macrophages and microglia is restricted at the entry level by a mechanism independent of coreceptor specificity. These findings provide evidence that M-tropism rather than CCR5 usage predicts HIV-1 neurotropism.

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Section: Discussionmentioning

confidence: 66%

Macrophage Tropism of Human Immunodeficiency Virus Type 1 Isolates from Brain and Lymphoid Tissues Predicts Neurotropism Independent of Coreceptor Specificity

Gorry

Bristol

Zack

et al. 2001

J Virol

266

324

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“…In vitro studies suggest that activation of resting CD4 ϩ T cells with proinflammatory cytokines would also reactivate latent infections (63). However, in vivo activation of resting CD4 ϩ T cells with proinflammatory cytokines interleukin 2 (IL-2) and gamma interferon (IFN-␥) or the anti-CD3 monoclonal antibody OKT3 results in long-term depletion of all CD4 ϩ T cells and fails to measurably purge the latent reservoir (46,87). Moreover, T-cell activation therapies are ineffective against latent infections in actively dividing cells (35) and are unlikely to stimulate latent infections attributed to chromatin silencing or transcriptional interference (reviewed in reference 93).…”

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confidence: 99%

Combinatorial Latency Reactivation for HIV-1 Subtypes and Variants

Burnett

Lim

Calafi

et al. 2010

J Virol

115

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The eradication of HIV-1 will likely require novel clinical approaches to purge the reservoir of latently infected cells from a patient. We hypothesize that this therapy should target a wide range of latent integration sites, act effectively against viral variants that have acquired mutations in their promoter regions, and function across multiple HIV-1 subtypes. By using primary CD4؉ and Jurkat cell-based in vitro HIV-1 latency models, we observe that single-agent latency reactivation therapy is ineffective against most HIV-1 subtypes. However, we demonstrate that the combination of two clinically promising drugs-namely, prostratin and suberoylanilide hydroxamic acid (SAHA)-overcomes the limitations of single-agent approaches and can act synergistically for many HIV-1 subtypes, including A, B, C, D, and F. Finally, by identifying the proviral integration position of latent Jurkat cell clones, we demonstrate that this drug combination does not significantly enhance the expression of endogenous genes nearest to the proviral integration site, indicating that its effects may be selective.HIV-1 postintegration latency poses the greatest barrier to complete eradication of the virus from a patient (25). Latent infections have low or no transcriptional activity and fail to generate viral progeny, rendering them untreatable with current antiretroviral treatments that target only actively replicating virus (78). Moreover, latent infections, which persist in resting memory CD4 ϩ T cells with a half-life of up to 44 months (79), provide a permanent reservoir for reactivation and reseeding of the replicating virus (83). Therapeutic reactivation of latent infections, combined with antiretroviral treatments, may accelerate the depletion of latent reservoirs (reviewed in reference 29). However, such latency reactivation strategies have yielded variable results in recent clinical trials (49,80,82), underscoring the difficulties associated with purging latent infections. Therefore, the complexities of latency warrant the further development of in vitro analytical and screening assays that can model the conditions of latency and test potential therapies (9).After viral entry and integration of the viral genome into the host chromosome, the HIV 5Ј long terminal repeat (5Ј LTR) promoter recruits RNA polymerase II (RNAPII) and other host factors to regulate viral gene expression. Initially, low basal transcription generates primarily abortive transcriptsdue to the stalling of RNAPII-and a small fraction of fully elongated viral transcript that is initially spliced to generate mRNA encoding a positive regulator, the transcriptional activator (Tat) (47). Tat protein interacts with cellular positive transcriptional elongation factor B (P-TEFb) (99), and the resulting Tat-P-TEFb complex binds to the trans-activation response (TAR) element at the 5Ј end of nascent viral transcripts (3). Here, P-TEFb phosphorylates the C-terminal domain (CTD) of stalled RNAPII to enhance the efficiency of elongation (98). This Tat-mediated transactivation...

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“…Thus, studying the downstream region, especially in an integrated scenario to focus on DNAse I hypersensitive areas, can provide important cues that can extend our knowledge with respect to transcriptional activation in both active and latent proviral genome pools [59]. The attempts to purge the latent HIV-1 reservoir have included strategies that utilize cytokines like IL-6, IL-2, and TNFα to induce a global cellular activation [60][61][62][63]; HDAC1 inhibitors like valproic acid (VPA) and suberoyl anilide hydroxamic acid (SAHA) to induce transcription [64,65] all of which would have impact on the downstream region of the LTR; and inhibition of DNA methylation using 5-aza-2'deoxycytidine (aza-CdR) [66]. Newer approaches have shown an interest in a novel group of transcriptional regulators that control viral gene expression.…”

Section: Resultsmentioning

confidence: 99%

Role of Downstream Elements in Transcriptional Regulation of the HIV-1 Promoter

Wigdahl¹

2014

JHVRV

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Like the transcription factor binding sites (TFBSs) located upstream of the transcriptional start site, TFBSs Role of Downstream Elements in TranscriptionalRegulation of the HIV-1 Promoter AbstractThe human immunodeficiency virus type1 (HIV-1) promoter, the long terminal repeat (LTR), is central to regulating many aspects of viral life cycle dynamics. After viral integration into the host genome, the interactions of host and viral factors with the regulatory elements in the LTR govern viral gene expression, contributing to formation of either a productive transcriptional state or an inactive one. The molecular architecture of the LTR, especially due to the nucleosomal packaging, presents DNA binding elements to cellular transcription factors not only to sites that are upstream of the transcriptional start site but also to regions of the promoter that are downstream of the start site. The importance of the downstream sites has been appreciated specifically in imposing a fine-tuning on the tightly regulated process of gene expression under the control of HIV-1 LTR. This report provides a comprehensive review of the HIV-1 LTR interactions with the transcription factors in the downstream region and summarizes the functional impact of these events on viral gene expression.

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Pilot Study of a Combination of Highly Active Antiretroviral Therapy and Cytokines to Induce HIV-1 Remission

Cited by 19 publications

References 35 publications

Macrophage Tropism of Human Immunodeficiency Virus Type 1 Isolates from Brain and Lymphoid Tissues Predicts Neurotropism Independent of Coreceptor Specificity

Macrophage Tropism of Human Immunodeficiency Virus Type 1 Isolates from Brain and Lymphoid Tissues Predicts Neurotropism Independent of Coreceptor Specificity

Combinatorial Latency Reactivation for HIV-1 Subtypes and Variants

Role of Downstream Elements in Transcriptional Regulation of the HIV-1 Promoter

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