Development of HIV reservoir targeted long acting nanoformulated antiretroviral therapies

Abstract

Human immunodeficiency virus (HIV) infection commonly results in a myriad of comorbid conditions secondary to immune deficiency. Infection also affects broad organ system function. Although current antiretroviral therapy (ART) reduces disease morbidity and mortality through effective control of peripheral viral load, restricted infection in HIV reservoirs including gut, lymphoid and central nervous system tissues, is not eliminated. What underlies these events is, in part, poor ART penetrance into each organ across tissue barriers, viral mutation and the longevity of infected cells. We posit that one means to improve these disease outcomes is through nanotechnology. To this end, this review discusses a broad range of cutting-edge nanomedicines and nanomedicine platforms that are or can be used to improve ART delivery. Discussion points include how polymer-drug conjugates, dendrimers, micelles, liposomes, solid lipid nanoparticles and polymeric nanoparticles can be harnessed to best yield cell-based delivery systems. When completely developed, such nanomedicine platforms have the potential to clear reservoirs of viral infection.

Figure 1. Schematic model illustrating the cell-mediated drug delivery for nanoformulated antiretroviral therapy (nanoART)

This schematic reflects the potential of long-acting antiretrovirals to reduce viral load and protect both CD4⁺ T cells and viral sanctuaries against HIV-1-associated injuries. Human HIV exposure through sexual transmission, blood transfusions, or maternal/fetal transfer results in chronic HIV infection (red virions). Infected patients are treated with nanoART (green particles), which can gain entry into monocyte-macrophages (center of picture), captured by blood-filtrating liver/splenic tissue macrophages and serve as a long-term drug depot leading to the suppression of viral replication and protection of CD4⁺ T cell numbers. The nanoformulations may also facilitate ART delivery to the CNS, spleen, lymph nodes and gut associated lymphoid tissue to reduce viral replication (green organs).

Scheme 1

Synthetic scheme for chitosan-O-isopropyl-5′-O-d4T monophosphate conjugate.

Scheme 2

Synthetic route for mPEG-succinyl-AZT conjugates.

Scheme 3

Chemical structure of poloxamer block copolymer.

Scheme 4

Chemical structures of liposomal components.

Scheme 5

Representative solid lipids (fatty acids, glycerides, and waxes) for the preparation of SLNs.