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.
Highlights
Despite major advances in human immunodeficiency virus-1 (HIV-1) treatment and prevention since the discovery of the virus in 1983 [1], the global rate of new infections remains constant at approximately 2 million per year [2,3]
Ex vivo generation and programming of antigen-presenting, monocyte-derived dendritic cells (DCs) (MDCs) was first implemented in cancer immunotherapy to circumvent the dysfunction of endogenous DCs that occurs in cancer patients [41,42,43,44,45,46], capitalizing on the discovery of culture methods that were scalable to quantities required for clinical trials
Class I molecules [261,262] and cytokines [263,264], hijacking of cell signaling pathways [142,263,264,265], and inhibition of apoptosis [266,267]. These findings suggest that CMV coinfection contributes to establishment and maintenance of the HIV-1 reservoir, and that CMV antigen-loaded DCs could offer a means to selectively expose a portion of the HIV-1 reservoir contained within CMV specific CD4+
Summary
Despite major advances in human immunodeficiency virus-1 (HIV-1) treatment and prevention since the discovery of the virus in 1983 [1], the global rate of new infections remains constant at approximately 2 million per year [2,3]. Optimal antiretroviral therapy (ART) suppresses viremia to below the limit of detection of clinical assays, HIV-1 is managed as a chronic disease due to its persistence in a long-lived population of resting memory CD4+ T cells considered to be the major reservoir [4,5]. Based on reservoir decay kinetics following ART initiation, it was initially predicted that 2–3 years of therapy would be sufficient to eliminate all HIV-infected cells [7]. We dissect the potential strengths and limitations of current HIV cure strategies, with a particular emphasis on recent studies employing dendritic cell (DC)-based HIV-1 immunotherapies
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