Dual TLR2 and TLR7 agonists as HIV latency-reversing agents

Macedo, Amanda B.; Novis, Camille L.; Assis, C.M.; Sorensen, Eric S.; Moszczynski, Paula; Huang, Szu-Han; Ren, Yanqin; Spivak, Adam M.; Jones, R. Brad; Planelles, Vicente; Bosque, Alberto

doi:10.1172/jci.insight.122673

Cited by 70 publications

(71 citation statements)

References 81 publications

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“…Because of both their adjuvant-like potential to boost immune responses and their ability to induce the expression of HIV-1 in vitro and ex vivo, TLR7 agonists, such as GS-9620 and GS-986, have been viewed as particularly promising agents for HIV reservoir elimination (40,58). Accordingly, GS-9620 is currently being evaluated in clinical trials for safety and residual virus elimination both in HIV-1-infected controllers (NCT03060447) and in those on suppressive cART (NCT02858401).…”

Section: Discussionmentioning

confidence: 99%

TLR7 agonist administration to SIV-infected macaques receiving early initiated cART does not induce plasma viremia

Prete¹,

Alvord²,

Li³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 99%

TLR7 agonist administration to SIV-infected macaques receiving early initiated cART does not induce plasma viremia

Prete¹,

Alvord²,

Li³

et al. 2019

JCI Insight

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“…LRAs tested in vitro or in vivo in clinical trials [14] include HDAC inhibitors (HDACi) such as Vorinostat [15], Romidepsin [16,17] or Panobinostat [18], PKC agonists (PKCa) such as Bryostatin or Ingenol, aldehyde dehydrogenase inhibitor Disulfiram [19,20]. The addition of immunomodulatory components such as TLR agonists [21][22][23][24], PD1 blockade [25], cytokines such as IL-7 or IL-15 [26][27][28], activation of the RIG-I pathway [29], or of non-canonical NF-κB signaling activator [30] may enhance HIV latency reversal in ex vivo or animal studies but have not yet been tested in clinical trials or have not been successful.…”

Section: Introductionmentioning

confidence: 99%

Latency reversal agents modulate HIV antigen processing and presentation to CD8 T cells

et al. 2020

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Latency reversal agents (LRA) variably induce HIV re-expression in CD4 T cells but reservoirs are not cleared. Whether HIV epitope presentation is similar between latency reversal and initial infection of CD4 T cells is unknown yet crucial to define immune responses able to detect HIV-infected CD4 T cells after latency reversal. HIV peptides displayed by MHC comes from the intracellular degradation of proteins by proteasomes and post-proteasomal peptidases but the impact of LRAs on antigen processing is not known. Here we show that HDAC inhibitors (HDCAi) reduced cytosolic proteolytic activities while PKC agonists (PKCa) increased them to a lesser extent than that induced by TCR activation. During the cytosolic degradation of long HIV peptides in LRA-treated CD4 T cells extracts, HDACi and PKCa modulated degradation patterns of peptides and altered the production of HIV epitopes in often opposite ways. Beyond known HIV epitopes, HDACi narrowed the coverage of HIV antigenic fragments by 8-11aa degradation peptides while PKCa broadened it. LRAs altered HIV infection kinetics and modulated CD8 T cell activation in an epitope-and time-dependent manner. Interestingly the efficiency of endogenous epitope processing and presentation to CD8 T cells was increased by PKCa Ingenol at early time points despite low levels of antigens. LRA-induced modulations of antigen processing should be considered and exploited to enhance and broaden HIV peptide presentation by CD4 T cells and to improve immune recognition after latency reversal. This property of LRAs, if confirmed with other antigens, might be exploited to improve immune detection of diseased cells beyond HIV.

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“…MGN1703, a TLR9 agonist, induced HIV plasma RNA in 6 of 15 study participants concomitant with increased activation of NK and CD8 T cells, but no reduction in latent reservoir size was observed [100]. Dual TLR2 and TLR7 agonists such as CL413 have shown potent NF-κB-mediated HIV-1 reactivation that unfortunately is also accompanied by proinflammatory release of TFNα [101]. In rhesus macaques infected with simian immunodeficiency virus (SIV) and in HIV-infected individuals, both on ART, the administration of the TLR7 agonists GS-986 and GS-9620 led to significant increases in plasma SIV and HIV RNA, respectively, consistent with latency reversal [102,103].…”

Section: Toll-like Receptor (Tlr) Agonistsmentioning

confidence: 98%

Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy

Schwarzer

Gramatica

Greene

2020

Viruses

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Human immunodeficiency virus (HIV-1) indefinitely persists, despite effective antiretroviral therapy (ART), within a small pool of latently infected cells. These cells often display markers of immunologic memory and harbor both replication-competent and -incompetent proviruses at approximately a 1:100 ratio. Although complete HIV eradication is a highly desirable goal, this likely represents a bridge too far for our current and foreseeable technologies. A more tractable goal involves engineering a sustained viral remission in the absence of ART--a "functional cure." In this setting, HIV remains detectable during remission, but the size of the reservoir is small and the residual virus is effectively controlled by an engineered immune response or other intervention. Biological precedence for such an approach is found in the post-treatment controllers (PTCs), a rare group of HIV-infected individuals who, following ART withdrawal, do not experience viral rebound. PTCs are characterized by a small reservoir, greatly reduced inflammation, and the presence of a poorly understood immune response that limits viral rebound. Our goal is to devise a safe and effective means for replicating durable post-treatment control on a global scale. This requires devising methods to reduce the size of the reservoir and to control replication of this residual virus. In the following sections, we will review many of the approaches and tools that likely will be important for implementing such a "reduce and control" strategy and for achieving a PTC-like sustained HIV remission in the absence of ART.

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Dual TLR2 and TLR7 agonists as HIV latency-reversing agents

Cited by 70 publications

References 81 publications

TLR7 agonist administration to SIV-infected macaques receiving early initiated cART does not induce plasma viremia

TLR7 agonist administration to SIV-infected macaques receiving early initiated cART does not induce plasma viremia

Latency reversal agents modulate HIV antigen processing and presentation to CD8 T cells

Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy

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