Sunday, November 27, 2016

Latent HIV Clearance: New Drug to Remove Silent HIV Stores

HIV is a serious global health issue with roughly 36.9 million people around the world living with it (CDC 2014).  In the United States, as many as 13% of the HIV+ population has not been diagnosed with HIV because the virus can take on a latent infection (inactive HIV) (CDC 2015)(Figure 1).  Antiretroviral therapy (ART) is currently one of the best secondary prevention methods, however, this only slows the progression of immune system decline and does not actually prevent or cure HIV.  Treatment options have received a good deal of attention, such as latency-reversing agents (LRAs), which induce viral transcription (active HIV) as a “shock and kill” method to remove latent HIV reservoirs from CD4+ T cells.  However, Archin et al. (2013) showed SAHA, a common LRA, was unable to deplete HIV reservoirs following transcription activation.  These results have been further supported by clinical trials with several other histone deacetylase inhibitors, including vorinostat, panobinostat, and romidepsin, which only partially decreased HIV-DNA levels (latent reservoirs) within infected cells (Archin 2014; Rasmussen 2014).

Figure 1: Natural history of HIV showing the decline of infected CD4+ T cells and the rise of HIV RNA.  During clinical latency there are low levels of RNA to avoid immune system detection, until conditions are favorable for HIV reactivation (corresponding to the increase in HIV RNA levels).

Viruses and their hosts coevolve in a battle to dominate the other.  This competition has driven viruses to develop the ability to block host cell recognition and degradation of latent HIV through decreasing the levels of pattern recognition receptors (PRR).  Past research has shown retinoic-acid-inducible gene I (RIG-1), a PRR, is lower in HIV patients, which consequently produces less infected cell death due to the decreased HIV-RNA recognition (Britto et al. 2013).  With less particles to detect HIV, active and latent HIV stores can go largely undetected in infected cells. Li et al. (2016) proposed a novel HIV cure that incorporates both inhibited RIG-1 signaling and ineffective LRA reservoir clearance.  Using acitretin, an FDA approved retinoic acid derivative, HIV reservoir cells could be eliminated from human CD4+ T cells after forced reactivation of HIV RNA production (Li et al. 2016).

 Acitretin, at appropriate doses, was found to induce HIV transcription and RIG-1 expression, leading to increased levels of infected cell death via RIG-1 HIV recognition and signaling (Li et al. 2016).  This drug basically enhances the immune response to HIV by activating latent HIV stores, making the HIV more recognizable to degradation mechanisms, and by increasing the amount of particles that can degrade these recognizable HIV stores.  These effects were amplified when acitretin was taken in combination with the transcriptional activator SAHA, as RIG-1 has a higher recognition of HIV-RNA over latent DNA stores (Li et al. 2016).  This blend of acitretin and LRAs has the ability to target cells with active and inactive HIV stores, a necessary approach to eradicate HIV altogether. 

The recommended dose of acitretin used in experiments by Li et al. (2016) was 5 μM (1650 ng/ml).  This amount of acitretin is currently attainable in commercially produced acitretin pills.  There are side effects reported from acitretin use, however, most do not cause permanent damage.  This treatment is certified as a safe drug for people who follow the recommended use and are not pregnant.  The availability of this FDA approved drug would speed its distribution to people living with HIV, and should limit cost inflation.  Further clinical trials are needed to confirm these positive results and investigate the mechanism behind RIG-1 binding to HIV DNA or RNA and the activation of the RIG-1 signaling pathway.

Li, Peilin, Philipp Kaiser, Harry W. Lampiris, Peggy Kim, Steven A. Yukl, Diane V. Havlir, Warner C. Greene, and Joseph K. Wong. "Stimulating the RIG-I pathway to kill cells in the latent HIV reservoir following viral reactivation." Nature medicine (2016).

Additional Resources:
Archin NM, Bateson R, Tripathy MK, Crooks AM, Yang KH, Dahl NP, et al. “HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat”. Journal Infectious Diseases 210.5 (2014): 728–35.

Britto AM, Amoedo ND, Pezzuto P, Afonso AO, Martínez AM, Silveira J, Sion FS, Machado ES, Soares MA, and Giannini AL. “Expression levels of the innate response gene RIG-I and its regulators RNF125 and TRIM25 in HIV-1-infected adult and pediatric individuals”. AIDS. 27 (2013):1879–1885.

CDC. “HIV Surveillance Report: Diagnoses of HIV Infection in the United States and Dependent Areas”. USDHHS 26(2014).

CDC. “Prevalence of Diagnosed and Undiagnosed HIV Infection — United States, 2008–2012”. MMWR 64(2015): 657-662.

Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, et al. “Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial”. Lancet HIV 1.1 (2014): e13–21.

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