Abstract
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.
Highlights
Despite efficient antiretroviral treatments (ART) HIV latently persists in long-lived CD4 T cells [1]
Strategies to flush out HIV reservoirs propose to re-express HIV with latency reversal agents (LRAs), leading to CD4 T cell death or clearance by HIV-specific immune responses
We assessed the effects of 5 LRAs on the antigen processing machinery of primary CD4 T cells
Summary
Despite efficient antiretroviral treatments (ART) HIV latently persists in long-lived CD4 T cells [1]. One of the eradication strategies currently tested in clinical trials proposes to re-activate provirus expression with latency reversal agents (LRAs) to trigger HIV re-expression, leading to cell death or elimination by pre-existing HIV-specific immune responses [2,3]. 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]. 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
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