Reactivation Kinetics of HIV-1 and Susceptibility of Reactivated Latently Infected CD4<sup>+</sup>T Cells to HIV-1-Specific CD8<sup>+</sup>T Cells

Walker-Sperling, Victoria E.; Cohen, Valerie J.; Tarwater, Patrick M.; Blankson, Joel N.

doi:10.1128/jvi.01454-15

Cited by 17 publications

(21 citation statements)

References 42 publications

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“…LRAs tested so far induced HIV RNA expression to various extents but led to relatively small changes in the size of reservoirs in vivo [9,61]. Beside the efficacy of LRAs, the capacity of pre-existing immune responses to clear reservoirs is uncertain and additional vaccine-induced immune responses are likely needed [10,11,13,62,63].…”

Section: Discussionmentioning

confidence: 99%

“…However, the increased production of 8-11aa long peptides and the enhanced efficiency of peptide presentation at low levels of antigens induced by certain LRAs offer new opportunities to broaden the MHC-peptide repertoire for immune detection and define novel targets for immune clearance after latency reversal. As many HIV-specific preexisting T cell responses may express inhibitory markers [8][9][10]28], additional novel vaccineinduced latency reversal-specific immune responses may be needed to clear reservoirs [67]. Eliciting immune responses against areas of HIV proteome whose processing and presentation…”

Section: Plos Pathogensmentioning

confidence: 99%

“…While HIV RNA re-expression can be induced to variable extents by LRAs in CD4 T cells ex vivo or in vivo, the reservoir is never cleared [4,5]. This failure of LRAs may be explained by limited reactivation of HIV provirus [6,7] and/or of antigen expression, mutations in epitopes impairing immune recognition, ineffective magnitude or functionality of immune effectors [8][9][10][11], or intrinsic resistance of cells to elimination [12,13]. Whether steps leading to HIV MHC-peptide presentation to immune cells are similar during productive infection or latency reversal is not known but play a major role in assessing the capacity of pre-existing immune responses to recognize CD4 T cells after latency reversal and in defining additional vaccineinduced immune responses relevant to latency reversal.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Plos Pathogensmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…These findings indicate that HIV latency reversal must be synergized with killing by vaccine-induced T cells. T cells must also be able to recognize the epitopes generated by reactivated cells during a short window and ideally target regions of vulnerability that are known to lead to loss of viral fitness upon CD8+ T cell attack in vivo [36]. Some of these regions were not included in the HIVconsv immunogen because they were not highly conserved; refinement of the immunogen design may be necessary to ensure boosting of the most potent CD8+ T cell responses [30,[37][38][39][40].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the immunogenicity and impact on the latent HIV‐1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy‐treated subjects

Hancock

Morón-López

Kopycinski

et al. 2017

Journal of the International AIDS Society

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Introduction: Vaccines may be key components of a curative strategy for HIV-1. We investigated whether a novel immunogen, HIVconsv, designed to re-direct T cell responses to conserved viral epitopes, could impact the HIV-1 reservoir in chronic antiretroviral therapy (ART)-treated subjects when delivered by modified vaccinia virus Ankara (MVA).Methods: Nineteen virologically suppressed individuals were randomized to receive vaccinations with MVA.HIVconsv (5.5 × 107 plaque-forming units, pfu, n = 8; 2.2 × 108 pfu, n = 7) or placebo (n = 4) at 0, 4 and 12 weeks. Magnitude, breadth and antiviral function of vaccine-induced T cells, cell-associated HIV-1 DNA in circulating CD4+ T cells and residual viremia in plasma were measured before and after vaccination.Results: 90% of subjects completed the vaccine regimen; there were no serious vaccine-related adverse events. The magnitude of HIVconsv-specific IFN-γ-secreting T cells was not significantly boosted in vaccinees when compared with placebos in ex vivo Elispot assays, due to greater than expected variation in HIV-specific T cell responses in the latter during the observation period. Ex vivo CD8+ T cell viral inhibitory capacity was modest but significantly increased post-vaccination with MVA.HIVconsv at the higher dose (p = 0.004) and was positively correlated with the frequency of HIVconsv-specific CD8+ CD107+ IFN-α± T cells (r = 0.57, p = 0.01). Total HIV-1 DNA and residual viral load did not change significantly from baseline in any group.Conclusions: Homologous prime-boost vaccination with MVA.HIVconsv was safe in HIV-positive ART-treated subjects but showed modest immunogenicity and did not significantly change the size of the viral reservoir. MVA.HIVconsv may be more effective when used in a heterologous prime-boost vaccination regimen and when combined with a latency-reversing agent.Clinical Trials Registration NCT01024842

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“…We minimized our IFN-␣ preincubation exposure for two reasons. The first was to determine the feasibility of efficiently enhancing NK cell effector function within the narrow time frame that effector cells have for the elimination of infected CD4 ϩ T cells prior to the release of virions after latency reversal (48). We show here that 6 h of preincubation with IFN-␣ was as effective as 24 h. Our finding that this short window of exposure was sufficient to efficiently and significantly enhance the suppressive, cytotoxic, and polyfunctional responses of NK cells in CP is exciting and suggests that it may be possible to optimize NK cell activity while avoiding IFN-␣-mediated immune exhaustion in both NK cells and CD8 ϩ T cells (25,26).…”

Section: Fig 6 Ifn-␣ Enhances the Suppressive Capacity Of Vp And Es Cd8mentioning

confidence: 99%

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8⁺T Cells

Kwaa

Talana

Blankson

2019

J Virol

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Current shock-and-kill strategies for the eradication of the HIV-1 reservoir have resulted in blips of viremia but not in a decrease in the size of the latent reservoir in patients on suppressive antiretroviral therapy (ART). This discrepancy could potentially be explained by an inability of the immune system to kill HIV-1-infected cells following the reversal of latency. Furthermore, some studies have suggested that certain latency-reversing agents (LRAs) may inhibit CD8+T cell and natural killer (NK) cell responses. In this study, we tested the hypothesis that alpha interferon (IFN-α) could improve the function of NK cells from chronic progressors (CP) on ART. We show here that IFN-α treatment enhanced cytokine secretion, polyfunctionality, degranulation, and the cytotoxic potential of NK cells from healthy donors (HD) and CP. We also show that this cytokine enhanced the viral suppressive capacity of NK cells from HD and elite controllers or suppressors. Furthermore, IFN-α enhanced global CP CD8+T cell cytokine responses and the suppressive capacity of ES CD8+T cells. Our data suggest that IFN-α treatment may potentially be used as an immunomodulatory agent in HIV-1 cure strategies.IMPORTANCEData suggest that HIV+individuals unable to control infection fail to do so due to impaired cytokine production and/cytotoxic effector cell function. Consequently, the success of cure agendas such as the shock-and-kill strategy will probably depend on enhancing patient effector cell function. In this regard, NK cells are of particular interest since they complement the function of CD8+T cells. Here, we demonstrate the ability of short-course alpha interferon (IFN-α) treatments to effectively enhance such effector functions in chronic progressor NK cells without inhibiting their general CD8+T cell function. These results point to the possibility of exploring such short-course IFN-α treatments for the enhancement of effector cell function in HIV+patients in future cure strategies.

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Reactivation Kinetics of HIV-1 and Susceptibility of Reactivated Latently Infected CD4⁺T Cells to HIV-1-Specific CD8⁺T Cells

Cited by 17 publications

References 42 publications

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

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

Evaluation of the immunogenicity and impact on the latent HIV‐1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy‐treated subjects

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8⁺T Cells

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Reactivation Kinetics of HIV-1 and Susceptibility of Reactivated Latently Infected CD4+T Cells to HIV-1-Specific CD8+T Cells

Cited by 17 publications

References 42 publications

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

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

Evaluation of the immunogenicity and impact on the latent HIV‐1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy‐treated subjects

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8+T Cells

Contact Info

Product

Resources

About

Reactivation Kinetics of HIV-1 and Susceptibility of Reactivated Latently Infected CD4⁺T Cells to HIV-1-Specific CD8⁺T Cells

Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8⁺T Cells