Abstract
Oral administration of a combination of two or three antiretroviral drugs (cART) has transformed HIV from a life-threatening disease to a manageable infection. However, as the discontinuation of therapy leads to virus rebound in plasma within weeks, it is evident that, despite daily pill intake, the treatment is unable to clear the infection from the body. Furthermore, as cART drugs exhibit a much lower concentration in key HIV residual tissues, such as the brain and lymph nodes, there is a rationale for the development of drugs with enhanced tissue penetration. In addition, the treatment, with combinations of multiple different antiviral drugs that display different pharmacokinetic profiles, requires a strict dosing regimen to avoid the emergence of drug-resistant viral strains. An intriguing opportunity lies within the development of long-acting, synthetic scaffolds for delivering cART. These scaffolds can be designed with the goal to reduce the frequency of dosing and furthermore, hold the possibility of potential targeting to key HIV residual sites. Moreover, the synthesis of combinations of therapy as one molecule could unify the pharmacokinetic profiles of different antiviral drugs, thereby eliminating the consequences of sub-therapeutic concentrations. This review discusses the recent progress in the development of long-acting and tissue-targeted therapies against HIV for the delivery of direct antivirals, and examines how such developments fit in the context of exploring HIV cure strategies.
Highlights
Combination antiretroviral therapy has transformed HIV from a life-threatening disease to a manageable infection
These viral reservoirs can be defined on the basis of the cells that are infected e.g., infected T- or myeloid cells, or the anatomical sites such as lymph nodes (LN), central nervous system or gut-associated lymphoid tissues (GALT), where these cells reside [2]
A recent report from studies of simian immunodeficiency virus (SIV)-infected macaques suggests that 98.6% of SIV vRNA+ cells reside in lymphatic tissues (i.e., LNs, spleen, GALT) [3]
Summary
Combination antiretroviral therapy (cART) has transformed HIV from a life-threatening disease to a manageable infection. The formation of latent viral reservoirs that persist despite having none to very limited viral replication prevents a successful cure with suppressive cART These viral reservoirs can be defined on the basis of the cells that are infected e.g., infected T- or myeloid cells, or the anatomical sites such as lymph nodes (LN), central nervous system or gut-associated lymphoid tissues (GALT), where these cells reside [2]. Moving forward, it may be of importance to study and optimize both existing and newly developed ARVs as well as the components of HIV cure treatments for enhanced viral reservoir targeting/penetrance. This review will focus on how features from nanotechnology can aid in overcoming some of the key challenges faced by both cART and HIV cure strategies, including low bioavailability, low tissue penetration in lymphatic tissues and short plasma half-lives
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