Current strategies to induce selective killing of HIV-1-infected cells

Abstract

Although combination antiretroviral therapy (ART) has led to significant HIV‐1 suppression and improvement in immune function, persistent viral reservoirs remain that are refractory to intensified ART. ART poses many challenges such as adherence to drug regimens, the emergence of resistant virus, and cumulative toxicity resulting from long‐term therapy. Moreover, latent HIV‐1 reservoir cells can be stochastically activated to produce viral particles despite effective ART and contribute to the rapid viral rebound that typically occurs within 2 weeks of ART interruption; thus, lifelong ART is required for continued viral suppression. Several strategies have been proposed to address the HIV‐1 reservoir such as reactivation of HIV‐1 transcription using latency reactivating agents with a combination of ART, host immune clearance and HIV‐1‐cytotoxicity to purge the infected cells—a “shock and kill” strategy. However, these approaches do not take into account the multiple transcriptional and translational blocks that contribute to HIV‐1 latency or the complex heterogeneity of the HIV‐1 reservoir, and clinical trials have thus far failed to produce the desired results. Here, we describe alternative strategies being pursued that are designed to kill selectively HIV‐1‐infected cells while sparing uninfected cells in the absence of enhanced humoral or adaptive immune responses.

HIV-1 transcriptional modulation: novel host factors and prospective therapeutic strategies

“…second mitochondrial-derived activator of caspase mimetics) [101–103]. Clinical trials testing this approach have unfortunately been unsuccessful in reducing the proviral reservoir [104]. Reasons for this failure include immune dysfunction in PLWH, and thus limited clearance of reactivated cells, inadequate LRA efficacy and LRA toxicity in immune cells [105–110].…”

“…unsuccessful in reducing the proviral reservoir [104]. Reasons for this failure include immune dysfunction in PLWH, and thus limited clearance of reactivated cells, inadequate LRA efficacy and LRA toxicity in immune cells [105][106][107][108][109][110].…”

The Humanized Mouse Model: What Added Value Does It Offer for HIV Research?

“…The "shock and kill" strategy can also be combined with the use of antibody-drug conjugates (immunotoxins) that target and kill cells that express the HIV envelope protein [17]. The neighboring non-infected cells are protected from infection by the ongoing ART [18,19]. This strategy has been repeatedly explored in clinical trials with a number of repurposed drugs [20,21].…”

HIV associated cell death: Peptide-induced apoptosis restricts viral transmission

“…Targeting cell death as a treatment for HIV is an attractive idea (18,19). However different cell deaths induced may lead to different consequences.…”