Reversing latency to cure HIV

HIV is a virus that inserts its own DNA into the host DNA upon infection. This “provirus” can remain dormant, or latent, for a long time. Proviruses are the source of new viruses causing viral rebound if antiretroviral therapy (ART) is stopped. This means treatment is a lifelong proposition for people living with HIV (PLWH). The “shock and kill” approach to HIV cure aims to stimulate cells harbouring these proviruses so that they produce new viral particles. This stimulation is known as latency reversal. This reversal allows cells to be targeted by the immune system for elimination. The goal is to remove all or most of the infected cells leading to ART-free remission. There have been many drugs investigated for their ability to reverse latency, however none have been found effective in human clinical trials. There is a need for new drugs, or latency reversal agents (LRAs), that can selectively and potently reverse HIV latency.

HIV latency exists on a spectrum

To effectively reverse HIV latency, we need a greater understanding of the biology behind it. Recent advancements have revealed more about this intricate system.

We previously thought that latently infected cells did not make viral RNA or proteins. However, we now know that HIV latency exists on a spectrum. Latently infected cells often make viral RNA and occasionally make viral proteins. Factors that control whether an infected cell is transcriptionally active (making viral RNA) or translationally active (making viral protein) may involve the maturation state of the infected cell, its location within the body, and a number of other factors such as sex of the infected individual, time and stress.

Do we have to target all HIV proviruses to cure infection? Not necessarily.

Recent evidence shows we may not need to eliminate all proviruses to achieve ART-free remission. It is now understood that the majority of proviruses in latently infected cells contain deletions and mutations in their genome which render them defective. Defective proviruses cannot produce new infectious viruses and they are not thought to be important for HIV cure. What does need targeting is the small fraction (1-10%) of proviruses that contain intact genomes. These are the proviruses that can contribute to viral rebound. We have learnt from studies in elite controllers (PLWH who can naturally control HIV replication without antiretroviral treatment) and PLWH on long-term ART, that many proviruses are integrated in regions of the chromosome that are rarely transcribed. These proviruses may never be stimulated to produce viral RNA or protein, and whether they would contribute to viral rebound when ART is stopped remains unknown. This means that future HIV cure trials will have to include newly developed assays to measure the impact of a drug on intact proviruses and proviruses in transcriptionally active regions.

Current Latency Reversal Agents lack potency

The immune system recognises HIV infected cells by detecting viral proteins. Latently infected cells rarely make viral proteins, so they are often undetected. To be successful, latency reversal agents need to stimulate viral protein production. Unfortunately, most of the investigated latency reversal agents can initiate viral protein production – by stimulating the initiation of RNA production, which is the precursor of protein – but fail to trigger viral protein synthesis. New agents will have to overcome this block. Successful latency reversal agents will also have to overcome the fact that latently cells are difficult to kill. It is now understood that infected cells are programmed to survive primarily through the upregulation of a range of pro-survival proteins.

Latency reversal agents that are more specific, more potent and come with added benefits

To successfully reverse HIV latency, we need new LRAs that are more specific and more potent. Secondary mitochondria-derived activator of caspases mimetics (SMACm) is a new class of LRA that can reactivate latent HIV. They may also influence the latently infected cells to become more susceptible to death. SMACm have been actively investigated in clinical trials for cancer treatment, but their impact on reactivating and eliminating latently infected cells in PLWH is yet to be tested.

Due to the chronic nature of HIV infection, the cells of immune system become ‘exhausted’ which compromises their ability to respond to pathogens. Antibodies that target cell receptors called immune checkpoint molecules may help to reverse this exhausted state in cancer therapy. These antibodies have also been shown to stimulate latent HIV proviruses in the lab. One of these antibodies, pembrolizumab, which targets the immune checkpoint molecule Programmed Cell Death (PD1), was demonstrated to reverse HIV latency in a clinical trial in PLWH on ART with cancer. However, altering the immune system could lead to detrimental side effects since extra inflammatory responses could damage various organs.

Proteins such as toll-like receptors (TLR) detect materials from pathogens and initiate immune responses. Activating TLRs leads to activation of the immune cells, inflammatory responses and reversal of HIV latency. Recently, a clinical trial using vesatolimod (which targets TLR-7) in PLWH on ART showed a decrease in the number of intact proviruses and lead to a modest delay in how long it took for virus rebound to occur when participants stopped ART. Targeting immune checkpoint molecules and toll-like receptors may have the added benefit of stimulating HIV-specific immunity and reversing HIV latency at the same time.

What now?

“Shock and kill” remains a promising approach to elimination of the latent reservoir in PLWH on ART. The approaches used to reverse HIV latency must become more potent, more specific and lead to the death of the infected cells. Recent findings have improved our understanding of HIV latency and the proviruses that persist on ART. These discoveries are guiding us to understand which proviruses must be targeted and the blocks that must be overcome to eliminate latently infected cells and enable people with HIV to live healthily without ongoing ART.