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

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.

The multifaceted nature of HIV latency

“…Disappointingly, none of these studies resulted in a significant decrease in the size of the HIV reservoir in individuals on ART. Several factors may explain these negative results: (a) LRAs may have differential effects between tissues (177); (b) LRAs are not equally efficient in all populations of CD4 + T cells, suggesting that they may be largely ineffective in some cellular reservoirs (107,108); (c) effector cells may be lacking at sites of active viral production such as lymph nodes (14,15,17); (d) the persistent immune exhaustion of CD8 + T cells may not allow the efficient elimination of productively infected cells (182); (e) some LRAs, particularly HDACis, have been shown to impair cytotoxic effector responses (183) and antigen presentation by APCs (184), which could hamper viral reservoir elimination; and (f) productively infected cells may be inherently resistant to immunemediated killing through the expression of prosurvival factors (185).…”

Non-thermal plasma modulates cellular markers associated with immunogenicity in a model of latent HIV-1 infection

“…Furthermore, the molecular mechanism by which NTP modulates the antigen presentation pathway is not known. Other more robust latency reversal agents have been reported to alter antigen processing by affecting the breadth and production of HIV-1 peptides presented on MHC I [ 78 ].…”

Candidate host epigenetic marks predictive for HIV reservoir size, responsiveness to latency reversal, and viral rebound

“…We also observed that late Panobinostat but not early Panobinostat led to a significant loss in DNA methylation at a loci in the gene Fragile Histidine Triad Diadenosine Triphosphtatase (FHIT). Recent work has shown that FHIT gene transfection in mice restores MHC-I expression, and Panobinostat has been shown to augment the expression of MHC genes and HIV antigen processing and presentation [57][58][59][60].…”