Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells

McBrien, Julia Bergild; Mavigner, Maud; Franchitti, Lavinia; Smith, S Abigail; White, Erick; Tharp, Gregory K.; Walum, Hasse; Busman‐Sahay, Kathleen; Aguilera-Sandoval, Christian R.; Thayer, William O.; Spagnuolo, Rae Ann; Kovářová, Martina; Wahl, Angela; Cervasi, Barbara; Margolis, David M.; Vanderford, Thomas H.; Carnathan, Diane G.; Paiardini, Mirko; Lifson, Jeffrey D.; Lee, John H.; Safrit, Jeffrey T.; Bosinger, Steven E.; Estes, Jacob D.; Derdeyn, Cynthia A.; García, J. Víctor; Kulpa, Deanna A.; Chahroudi, Ann; Silvestri, Guido

doi:10.1038/s41586-020-1946-0

Cited by 157 publications

(213 citation statements)

References 47 publications

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“…Regardless, none of the results presented here support N-803 as an LRA in vivo. This is in agreement with a report published during the review of this manuscript describing that N-803 alone does not reserve SIV latency in vivo [27].…”

Section: Plos Pathogenssupporting

confidence: 93%

“…We have further established that subcutaneous N-803 delivery drives both NK cells and CD8+ T cells, including SHIV-specific CD8+ T cells to lymph nodes, granting them access to B cell follicles, a primary site of the HIV/SIV reservoir. However, we also demonstrated that subcutaneously administered N-803 does not appear to reverse latency in vivo, further supported by a recent report describing that N-803 alone does not reverse SIV latency in vivo [27]. Nevertheless, the semi-immune privileged cell follicle remains an obstacle to HIV cure [25,33] and N-803 can facilitate immune effector penetration of this barrier.…”

Section: Plos Pathogenssupporting

confidence: 88%

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The human IL-15 superagonist N-803 promotes migration of virus-specific CD8+ T and NK cells to B cell follicles but does not reverse latency in ART-suppressed, SHIV-infected macaques

et al. 2020

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Despite the success of antiretroviral therapy (ART) to halt viral replication and slow disease progression, this treatment is not curative and there remains an urgent need to develop approaches to clear the latent HIV reservoir. The human IL-15 superagonist N-803 (formerly ALT-803) is a promising anti-cancer biologic with potent immunostimulatory properties that has been extended into the field of HIV as a potential "shock and kill" therapeutic for HIV cure. However, the ability of N-803 to reactivate latent virus and modulate anti-viral immunity in vivo under the cover of ART remains undefined. Here, we show that in ART-suppressed, simian-human immunodeficiency virus (SHIV) SF162P3-infected rhesus macaques, subcutaneous administration of N-803 activates and mobilizes both NK cells and SHIV-specific CD8+ T cells from the peripheral blood to lymph node B cell follicles, a sanctuary site for latent virus that normally excludes such effector cells. We observed minimal activation of memory CD4+ T cells and no increase in viral RNA content in lymph node resident CD4+ T cells post N-803 administration. Accordingly, we found no difference in the number or magnitude of plasma viremia timepoints between treated and untreated animals during the N-803 administration period, and no difference in the size of the viral DNA cell-associated reservoir post N-803 treatment. These results substantiate N-803 as a potent immunotherapeutic candidate capable of activating and directing effector CD8+ T and NK cells to the B cell follicle during full ART suppression, and suggest N-803 must be paired with a bona fide latency reversing agent in vivo to facilitate immune-mediated modulation of the latent viral reservoir.

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Section: Plos Pathogenssupporting

confidence: 93%

Section: Plos Pathogenssupporting

confidence: 88%

The human IL-15 superagonist N-803 promotes migration of virus-specific CD8+ T and NK cells to B cell follicles but does not reverse latency in ART-suppressed, SHIV-infected macaques

et al. 2020

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“…An important caveat is that the great majority of proviruses analyzed were defective, and so it is possible that a negative selective effect on intact proviruses went undetected using these methods. An alternative possibility is that CTLs play a role in maintaining latency, as studies of CD8 + T cell depletion in nonhuman primate models of treated HIV-1 infection indicate (66,67).…”

Section: Study Participantsmentioning

confidence: 99%

Longitudinal study reveals HIV-1–infected CD4+ T cell dynamics during long-term antiretroviral therapy

Antar

Jenike

Jang

et al. 2020

Journal of Clinical Investigation

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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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Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells

Cited by 157 publications

References 47 publications

The human IL-15 superagonist N-803 promotes migration of virus-specific CD8+ T and NK cells to B cell follicles but does not reverse latency in ART-suppressed, SHIV-infected macaques

The human IL-15 superagonist N-803 promotes migration of virus-specific CD8+ T and NK cells to B cell follicles but does not reverse latency in ART-suppressed, SHIV-infected macaques

Longitudinal study reveals HIV-1–infected CD4+ T cell dynamics during long-term antiretroviral therapy

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

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