Understanding the mechanism(s) of this pro-latency activity of CD8+ T cells will facilitate the design of novel HIV-1 cure strategies

Understanding the mechanism(s) of this pro-latency activity of CD8+ T cells will facilitate the design of novel HIV-1 cure strategies. kill. The general premise of this strategy is to shut down the pro-latency function(s) of CD8+ T cells, use LRAs to reverse HIV-1 latency, counteract anti-apoptotic molecules, and engage natural killer (NK) cells to mediate the killing of cells harboring reactivated latent HIV-1. strong class=”kwd-title” Keywords: NK cells, HIV-1 latency, HIV-1 cure, CD8+ T cells 1. Introduction Despite major advances in the treatment and management of HIV-1 infection, Rabbit Polyclonal to SLC27A5 curative strategies remain elusive. Treatment of HIV-1 infection with antiretroviral therapy (ART) arrests viral replication and reduces morbidity and mortality [1,2]. Importantly, ART does not cure HIV-1, as the virus persists in latently infected cells in ART-treated people living with HIV (PLWH) [3,4]. Upon ART interruption, latent virus is Lanabecestat responsible for the rapid rebound of virus replication [5,6]. Eliminating cellular sources of latent HIV-1 could cure HIV-1 infection and liberate infected individuals from needing lifelong ART to suppress viral replication. Efforts to design a cure for HIV-1 have primarily focused on the shock and kill approach, which proposes pharmacological intervention to awaken HIV-1 from latency and the elimination of cells carrying reactivated virus via viral cytopathic effect or immune clearance [7,8]. This strategy should be performed in the context of ART to prevent viral spread to new cellular targets. Several pharmacological latency reversing agents (LRAs) have been identified and demonstrated to reverse HIV-1 latency [9]. A subset of these LRAs have been assessed for their ability to reactivate latent HIV-1 in vivo in pre-clinical animal studies and human clinical trials [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24]. In general, the administration of LRAs to ART-treated PLWH has produced only modest reactivation of latent virus and has had little to no impact on the size of the HIV-1 reservoir. These studies Lanabecestat have motivated efforts to identify more potent Lanabecestat LRAs, which reactivate virus more robustly in vivo and facilitate immune recognition and elimination of cellular sources of latent virus. A potential alternative strategy to designing new LRAs is to improve the in vivo activity of currently available LRAs by modulating the capacity for immune cells to sustain latency in their presence. Recent studies have demonstrated that CD8+ lymphocytes play a role in sustaining HIV-1 latency in the context of ART Lanabecestat [25], and even in the presence of LRAs [22,23]. This phenomenon has been observed in vivo in ART-treated SIV- or SHIV-infected rhesus macaques and ART-treated HIV-1-infected humanized mice [22,23,25]. It has also been recapitulated in vitro using human cells [22]. Although the exact identity of the CD8+ lymphocyte population responsible for promoting viral latency remains unresolved, evidence from the rhesus macaque model suggests that CD8+ T cells contribute to the maintenance of viral latency, but CD8+ natural killer (NK) cells are not involved [25]. This is an important observation, as NK cells can kill HIV-1-infected cells via both direct and antibody-dependent mechanisms [26,27,28,29]. Collectively, these observations provide a rationale for designing an improved shock and kill strategy, whereby pro-latency CD8+ T cell function(s) is inhibited, LRAs are administered, anti-apoptotic molecules are counteracted, and NK cells are engaged to eliminate cells harboring reactivated latent HIV-1. Here, we discuss the current LRA landscape and review completed pre-clinical and clinical trials of the shock and kill approach. We recount the evidence that CD8+ T cells contribute to the maintenance of HIV-1 latency in the context of ART and in the presence of LRAs. Finally, we examine a potential multi-pronged HIV-1 cure approach that employs NK cells as cytolytic effector cells. 2. The LRA Landscape Various classes of HIV-1 LRAs have been identified for their ability to induce reactivation of latent HIV-1. These agents have been assessed using in vitro (i.e., latently infected cell lines and main cell models of latency) and ex lover vivo (i.e., reactivation of disease from cells derived from ART-treated PLWH) cell tradition systems. The LRAs examined with this section are summarized in Number 1. Open in a separate windowpane Number 1 HIV-1 latency reversing providers. A major class of LRAs are epigenetic modifiers, such as DNA methyltransferase inhibitors (DNMTi), histone methyltransferase inhibitors (HMTi), and histone deacetylase inhibitors (HDACi). During latency, nucleosomes surrounding the HIV-1 5long terminal repeat (5LTR) are suppressed by epigenetic modifications, such as DNA methylation of the two CpG.