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HIV virus causes AIDS, and it is one of the most challenging public health obstacles in the world. The unavailability of vaccines against this virus, even after its outbreak 30 years ago in 1981, makes it even more lethal. India has the third-highest HIV epidemic globally, with a staggering number of 2.1 million adults living with HIV, in 2017. Current treatment strategies mostly target the replication of the virus within the host and thus exercising some control over the manifestation of the disease.
High mutability, formation of a latent genomic reservoir, and employment of several viral mechanisms to bypass or inhibit cell host factors result in making HIV a very difficult target for drugs and vaccines. A new approach against HIV that is under massive research at the moment is the shock and kill method. This method aims to essentially cure AIDS by inducing latent reservoirs of HIV to go into replication (shock) and then target HIV-producing cells to kill them. This could be a very promising phase of HIV management as it has the potential to eradicate the viral reservoir from HIV-infected individuals completely. This paradigm is not a part of the currently available modes of HIV management.
The first step for the shock-and-kill method of HIV combat is to find a reliable way to induce viral replication in CD4+ cells without any drastic side effects.
Nixon et al. at North Carolina University have been focussing on a drug referred to as AZD5582, originally designed to treat cancer. This drug is known to be able to activate NF-κB, a transcriptional activator. NF-κB is a prime stimulator of gene expression in HIV-1. This study has shown positive results. Treatment with AZD5582 demonstrates a dramatic increase in the viral RNA levels in CD4+ T cells. Both the test species used showed a comparable hike in the HIV-1 RNA levels in the CD4+ cell populations, along with a significant increase in the viral load in the blood, thus indicating, AZD5582 successfully activates the transcription of HIV-1. It can therefore be assumed that activating the NF-κB pathway might be a lucrative method to induce HIV-1-gene expression as the first phase of the shock-and-kill approach
McBrien et al. at Emory University, Atlanta, US, have employed an entirely separate but complementary procedure to induce viral replication by ending the latency period of HIV-1 in their CD4+ reservoirs. They merged two distinct immunological pathways. The first is the depletion of CD8+ T cells using antibodies, and the second is a simultaneous treatment with N-803, a drug that vigorously activates interleukin-15 (IL-15), a signaling molecule. IL-15 has been earlier noted to trigger HIV-1 transcription in in vitro studies. This combination approach used by McBrien et al. looks contradictory at first glance because IL-15 also happens to be one of the greatest activators of CD8+ T cells. However, a complementary effect of the two interventions combined raises the possibility of successfully targeting viral-reservoir cells and simultaneously activating viral replication in these cell populations. The suppression of CD8+ T cells aims to reverse the HIV-1 latency stabilizing activity of these cells while the administration of N-803 drug targets activation of IL-15 signaling, which could activate viral replication. This study also showed a significant increase in blood viral load levels and the concentration of HIV-1 RNA in cells of various tissues.
It would take a while for these studies to be replicated on human subjects. However, these two studies, published early on in the year 2020,, show a ray of hope in the long search for viable drugs that could be used to break the viral latency as a part of the shock-and-kill method of HIV-AIDS treatment. A quest for other possible drugs that could be employed for this role is also underway.
The shock-and-kill method is particularly exciting. Not only can it cure an AIDS patient, but it can also be extrapolated to eradicate HIV reservoirs from infected individuals who haven’t developed AIDS. It could also potentially cure AIDS before it has emerged as a condition in HIV-infected individuals.
