Role of Dendritic Cells in Exposing Latent HIV-1 for the Kill

Abstract

The development of effective yet nontoxic strategies to target the latent human immunodeficiency virus-1 (HIV-1) reservoir in antiretroviral therapy (ART)-suppressed individuals poses a critical barrier to a functional cure. The 'kick and kill' approach to HIV eradication entails proviral reactivation during ART, coupled with generation of cytotoxic T lymphocytes (CTLs) or other immune effectors equipped to eliminate exposed infected cells. Pharmacological latency reversal agents (LRAs) that have produced modest reductions in the latent reservoir ex vivo have not impacted levels of proviral DNA in HIV-infected individuals. An optimal cure strategy incorporates methods that facilitate sufficient antigen exposure on reactivated cells following the induction of proviral gene expression, as well as the elimination of infected targets by either polyfunctional HIV-specific CTLs or other immune-based strategies. Although conventional dendritic cells (DCs) have been used extensively for the purpose of inducing antigen-specific CTL responses in HIV-1 clinical trials, their immunotherapeutic potential as cellular LRAs has been largely ignored. In this review, we discuss the challenges associated with current HIV-1 eradication strategies, as well as the unharnessed potential of ex vivo-programmed DCs for both the 'kick and kill' of latent HIV-1.

Keywords: CD40 ligand; HIV-1 latency reversal; T cells; cytomegalovirus; dendritic cells; immunotherapy; ‘kick and kill’.

Figure 1

Monocyte-derived DC (MDC1): the all-in-one ‘kick and kill’ tool. MDC1s induce antigen-specific CD8⁺ and CD4⁺ T cell responses through presentation of antigenic peptides in the context of (1) MHC class-I and (2) MHC class-II molecules, respectively (signal 1), along with costimulatory factors including CD80 and CD86 (not shown, signal 2). Responding CD4⁺ T cells subsequently provide MDC1 with the feedback hyperactivating ‘helper’ signal CD40L (3), necessary for MDC1 release of IL-12p70 (4), which then promotes expansion and differentiation of CD8⁺ human immunodeficiency virus-1 (HIV-1)-specific effector cytotoxic T lymphocytes (CTLs) (5). Activation of CMV and HIV antigen-responsive CD4⁺ T cells harboring latent HIV-1 (6) results in HIV latency reversal (7), with HIV-1 proteins being transcribed and expressed as surface antigen (8). As a result, exposed infected cells harboring replication-competent provirus are targeted for elimination by HIV-specific CTLs (9).