The role of latency reversal agents in the cure of HIV: A review of current data

Abstract

The definitive cure for human immunodeficiency virus type-1 (HIV) infection is represented by the eradication of the virus from the patient's body. To reach this result, cells that are infected but do not produce the virus must become recognizable to be killed by the immune system. For this purpose, drugs defined "latency reverting agents" (LRA) that reactivate viral production are under investigation. A few clinical studies have been performed in HIV-infected patients treated with LRA and combined antiretroviral therapy (cART). The strategy is thus to combine cART and LRA to reactivate the virus and unmask latently infected cells that, because of cART, cannot produce a fully competent form of the virus. Unmasked cells can present viral antigens to the immune system, that ultimately recognizes and kills such latently infected cells. This review reports and discusses recent studies that have been published on this topic.

Population Modeling Highlights Drug Disposition Differences Between Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate in the Blood and Semen

“…One strategy with some promise toward a cure is the “kick and kill” approach, in which a latent virus is “kicked” out of latency into viral replication and thus made susceptible to antiretroviral (ARV) therapy. This strategy requires that the virus brought out of latency is presented with adequate concentration of drug for effective “killing.” The success of this strategy hinges on the ability of both latency‐reversing agents and antiretrovirals to adequately penetrate compartments such as the MGT . Thus, it is necessary to understand currently used ARV disposition within these sites.…”

“…The success of this strategy hinges on the ability of both latency-reversing agents and antiretrovirals to adequately penetrate compartments such as the MGT. 4 Thus, it is necessary to understand currently used ARV disposition within these sites.…”

Unveiling the druggable RNA targets and small molecule therapeutics

“…[159][160][161] Referred to as shock-and-kill therapy, this strategy aims to disrupt the viral reservoir to reactivate viral production, followed by antiviral treatment. 162 Currently available latencyreversing agents against herpesvirus infections [163][164][165] manipulate an epigenetic pathway, using histone epigenetic modifications to achieve viral reactivation. It would be interesting to see if specific small molecule could potentially bind to viral RNA and cause a latent-to-lytic switch in viral infection.…”

Targeting reservoirs of HIV replication in lymphoid follicles with cellular therapies to cure HIV

“…For example, one limitation of CAR and T‐cell immunotherapies is that they only recognize and kill cells harboring epitopes of HIV; they do not recognize latently infected cells that do not express HIV epitopes. These strategies could be combined with latency reversal agents as an attempt to completely eradicate HIV. Cell therapies might also be used in combination with broadly neutralizing antibody‐based therapies, which might yield greater suppression of HIV.…”

“…Many innovative and promising HIV functional cure strategies are currently being developed. These include broadly neutralizing antibodies, bi‐ and tri‐specific antibodies, BIKES, and TRIKES; inactivating HIV in latently infected cells; activating latently infected cells for clearance; creating T cells and macrophages that are resistant to infection; and cellular immunotherapies that target HIV‐replicating cells . Whilst detailed discussion of all of these and other exciting current HIV‐cure strategies are beyond the scope of this mini‐review, here I will focus on the three cell therapy approaches and discuss them in the context of targeting lymphoid follicle reservoirs of HIV replication.…”