Forcing the Enemy to Come Out and Surrender: A Strategy for an AIDS Cure

Human immunodeficiency virus (HIV), the causative agent for acquired immunodeficiency syndrome (AIDS), has its own strategies to evade immune responses and therefore survive for the lifetime of the patient it infects. ¹ Among these strategies is its ability to hide silently (HIV latency) as a “provirus” inside its target cells for years leading to latent reservoirs of the virus, where the immune response against the virus cannot work. The ability of HIV to live in these strategic reservoirs is one of the main known obstacles for developing a cure to AIDS. Releasing HIV from its safeguard reservoirs will lead to either the immune system eliminating the virus or the designing of drugs to effectively destroy the virus. ²

Infectious diseases are generally cured by the immune system controlling the replication and eradication of the pathogen, with or without the use of antimicrobial agents. Currently combined antiretroviral therapy (cART) has led to a major reduction in HIV-related mortality and morbidity and AIDS is now recognized as a chronic disease. This achievement was a dream more than 20 years ago. The next step in the fight against HIV/AIDS is developing a complete cure.

It is well accepted that cART alone will not cure AIDS because of the existence of these persistent viral reservoirs, which ultimately rekindle viral replication once therapy is stopped. ³ Consequently, any attempts at viral eradication will depend on the implementation of therapeutic strategies to specifically target and clear these reservoirs. The best characterized reservoir to date is the pool of latently infected memory CD4⁺ T cells that need to be eliminated. ²

The hope for a “sterilizing cure,” in which all traces of HIV are eliminated from the body, and/or a “functional cure,” in which HIV is kept in check by the immune system, without using cART, is not a dream anymore. And to achieve a functional or a sterilizing cure, we need to design appropriate and effective strategies against HIV that can counterattack the strategies used by the HIV. An important strategy that can overcome the ability of HIV to evade the immune system is to force HIV to come out of its own safeguard reservoirs and surrender (Fig. 1), as the virus becomes vulnerable to immune attack and susceptible to drug treatment. This can be achieved through the use of compounds that can disrupt and reactivate HIV latency such as activators of protein kinase C (PKC) and/or nuclear factor kappa B (NF-κB) pathways and the discovery of compounds such as prostratin and pryostatin-1, as well as histone deacetylase (HDAC) inhibitors such as vorinostat and romedipsin. ⁴ The hope for a cure for AIDS is on the rise again and scientists now believe that complete eradication of HIV from the human body is no longer impossible. ^1,2,4

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FIG. 1.

A simple cartoon demonstrating that HIVs are forced to surrender and come out of their secured latent safeguard reservoirs (caves=DNA chain), suffocating because of the use of chemical fumes (drugs), and become vulnerable to the army of the immune system. The victory sign as shown by one of the soldiers of the immune system indicates that a cure for AIDS is no longer a dream.