Nonetheless, Herzig and his colleagues recently proposed a more effective kill of reactivated cells by utilizing chimeric antigen receptors (CAR) coupled with broadly neutralizing antibodies in an ex vivo study [69]

Nonetheless, Herzig and his colleagues recently proposed a more effective kill of reactivated cells by utilizing chimeric antigen receptors (CAR) coupled with broadly neutralizing antibodies in an ex vivo study [69]. Open in a separate window Fig. HIV-infected individuals receiving ART [40, 41], however, the results were not promising. The T cell receptor agonist and PMA (phorbol 12-myristate 13-acetate) were used but resulted in global T cell activation. Therefore, an ideal LRA should be able to cause proviral latency reversal without global T cell activation. Latency-reversing brokers (LRAs) have been categorized based on their mechanism of action as shown in Table ?Table11 [39]. Of the six categories, the histone deacetylase inhibitors (HDACis) have received much attention with several small early clinical trials completed [39, 42C45]. Although the shock and kill approach is the most clinically advanced cure strategy, clinical studies have focused mainly on HDACis which are already approved for cancer therapy. In these trials, some adverse effects have been reported [46]. These include but not limited to nausea, vomiting, anorexia [47C50]; fatigue [51C53]; and skin changes [54]. HDACis have been the focus of many researchers and investigated extensively as a potential LRA [55C57]. However, several groups have shown that one LRA might not be effective in reducing the size of the reservoir either due to an inadequate reactivation or lack of an Ixabepilone effective kill or both [39, 58, 59] and suggested a combination of two or more LRAs to achieve robust viral reactivation and a significant reduction in reservoir size [60C65]. Concerning potential combination LRA treatment, one of the most favored is usually a combination of HDACi and PKC agonists like bryostatin [66, 67]. However, there are fears of severe side effects with bryostatin. Therefore, the idea is to use a lower concentration of bryostatin to synergize with Ixabepilone HDACis to achieve potent reactivation while reducing the chances of adverse events. That said, this combination is yet to be tested in clinical trials. Even though, the combination increases the reactivation potential, several obstacles exist in the killing of the reactivated cells. This includes the resistance of the Ptgfrn cells to apoptosis, exhaustion of CD8?+?cells, and immune escape mutation in chronically infected individuals [68]. Nonetheless, Herzig and his colleagues recently proposed a more effective kill of reactivated cells by utilizing chimeric antigen receptors (CAR) coupled with broadly neutralizing antibodies in an ex vivo study [69]. Open in a separate window Fig. 2 Strategies under development for an HIV cure. A Shock and kill approach using latency-reversing brokers (LRAs) to eradicate the latent reservoir. B Gene therapy utilizing CRISPR to target the latent reservoir. C Block and lock approach using latency-inducing brokers to induce silencing of the latent reservoir. D Immune-based therapies using therapeutic vaccines, CAR-T cells, and broadly neutralizing antibodies. Histone deacetylase, histone methyl transferase, protein kinase C, didehydro-cortistatin A, antiretroviral therapy Table 1 Examples of latency-reversing brokers (LRAs) categorized into six different primary Ixabepilone classes according to their mechanisms of action endonuclease for cleaving Ixabepilone target sequences and the Cys2-His2 zinc-finger proteins (ZFPs) for specific DNA-binding [133, 134]. The initial report utilizing ZFN targeting the CCXCC chemokine receptor type 4 gene (CXCR4) disruption displayed promising results [135, 136]. Given that the mutant CCR5?32 protein confers resistance to HIV Ixabepilone infection and the Berlin patient was cured using a ?32 stem cell transplant, the CCR5 became an ideal target for HIV gene therapy. Following the initial use of the ZFN approach to disrupt the CCR5 in HIV-infected cells [137, 138], several other works have built upon this strategy [138C141]. More so, there is evidence that ZFN could be used to disrupt the CCR5 in human induced pluripotent stem cells and human embryonic stem cells.