Pharmacology of HIV Cure: Site of Action

Abstract

Despite significant advances in HIV treatment over the past 30 years, critical barriers to an HIV cure persist. The HIV reservoir, defined at both the cellular and anatomical level, constitutes the main barrier to cure. While the mechanisms underlying the reservoir are not yet well understood, one theory to explain persistence at the anatomical level is that subtherapeutic exposure to antiretroviral therapy (ART) within certain tissue compartments permits ongoing replication. Characterizing ART pharmacology throughout the body is important in the context of these potential pharmacologic sanctuaries and for maximizing the probability of success with forthcoming cure strategies that rely on latency reversal and require ART to prevent reseeding the reservoir. In this review, we provide a comprehensive overview of ART and latency reversal agent distribution at the site of action for HIV cure (i.e., anatomical sites commonly associated with HIV persistence, such as lymphoid organs and the central nervous system). We also discuss methodologic approaches that provide insight into HIV cure pharmacology, including experimental design and advances within the computational, pharmaceutical, and analytical chemistry fields. The information discussed in this review will assist in streamlining the development of investigational cure strategies by providing a roadmap to ensure therapeutic exposure within the site of action for HIV cure.

Trial registration: ClinicalTrials.gov NCT04003103.

Figure 1.

Investigational Strategies to Impede and/or Eradicate the HIV Reservoir (a) Rapid ART initiation during the hyperacute phase of HIV infection has been proposed to restrict formation of the HIV reservoir; (b) CRISPR-Cas9 gene editing technology has been proposed to excise fragments of integrated proviral DNA rendering latent virus non-infectious; (c) Block & Lock would use xenobiotics to force the HIV reservoir into deep latency that resists reactivation by natural stimulating factors; (d) Kick and Kill would use xenobiotics to reactivate latent virus thereby targeting infected cells for clearance by natural or engineered immune mechanisms. ART: antiretroviral therapy; CRISPR: clustered regularly interspaced short palindromic repeats; Cas9 – CRISPR associated protein 9; LRA: latency reversal agent; HDACi: histone deacetylase inhibitors; PKC: protein kinase C; NF-κb: nuclear factor kappa-light-chain-enhancer of activated B cells; TLR: toll-like receptor.

Figure 2.

Schematic of Anatomic Reservoirs Double asterisks are used to denote tissues for which evidence of HIV compartmentalization in PLWH on suppressive ART has been reported. These tissues may serve as pharmacologic sanctuaries in which HIV replication occurs in isolation due to subtherapeutic ART.