Novel Nanotechnology-Based Approaches for Targeting HIV Reservoirs

Abstract

Highly active anti-retroviral therapy (HAART) is prescribed for HIV infection and, to a certain extent, limits the infection's spread. However, it cannot completely eradicate the latent virus in remote and cellular reservoir areas, and due to the complex nature of the infection, the total eradication of HIV is difficult to achieve. Furthermore, monotherapy and multiple therapies are not of much help. Hence, there is a dire need for novel drug delivery strategies that may improve efficacy, decrease side effects, reduce dosing frequency, and improve patient adherence to therapy. Such a novel strategy could help to target the reservoir sites and eradicate HIV from different biological sanctuaries. In the current review, we have described HIV pathogenesis, the mechanism of HIV replication, and different biological reservoir sites to better understand the underlying mechanisms of HIV spread. Further, the review deliberates on the challenges faced by the current conventional drug delivery systems and introduces some novel drug delivery strategies that have been explored to overcome conventional drug delivery limitations. In addition, the review also summarizes several nanotechnology-based approaches that are being explored to resolve the challenges of HIV treatment by the virtue of delivering a variety of anti-HIV agents, either as combination therapies or by actively targeting HIV reservoir sites.

Keywords: HIV reservoirs; active targeting; nanomedicine; passive targeting; phagocytosis; viral infection.

Figure 1

HIV virion structure and genome organization. (Created with BioRender.com (accessed on 19 June 2022)).

Figure 2

Infographic illustration of the HIV replication cycle begins with the fusion of HIV with the host cell surface, leading to the entry and release of the virus’s genome and proteins in the form of a capsid. The capsid shell disintegrates, and the HIV reverse transcriptase transcribes the viral RNA into DNA. The viral DNA is transported across the nucleus and integrated into the host’s DNA via the HIV protein integrase. It utilizes the host’s normal transcription machinery to transcribe the HIV DNA into multiple new HIV RNA copies. This RNA can be packaged as a new virus genome or utilized by the cell to make new HIV proteins. The new viral RNA and HIV proteins translocate to the cell surface to form a new, immature HIV virion. Finally, the HIV protease cleaves these newly translocated polyproteins to create a mature infectious virus released from the cell; different stages can be an intervention site for different ARTs. (Created with BioRender.com (accessed on 19 June 2022)).

Figure 3

Summary HIV reservoirs. There are several anatomical compartments (A) that are populated by HIV-infected cells (B). (C) The integrated provirus contained within these cells may be transcriptionally silent (latent), transcriptionally active and capable of producing infectious virions (persistent), or transcriptionally active but replication defective due to mutations or deletions in the HIV genome, leading to translation of specific viral proteins for which an open reading frame remains intact. (Created with BioRender.com (access on 19 June 2022)).

Figure 4

The illustration shows the major side effects of antiretroviral drugs on different body sites in an HIV/AIDS individual. (Created with BioRender.com (access on 19 June 2022)).

Figure 5

HIV sites for therapeutic intervention using nanopharmaceuticals. (Created with Biorender.com (access on 19 June 2022)).

Figure 6

Active and passive uptake of nanoparticles to the HIV-infected tissues/organs. The active targeting strategy can include nanoparticle functionalization directly or indirectly with various molecules; such as drugs, nucleic acids (DNA or RNA), proteins or peptides, antibodies, etc., for ideal biological activities and diverse medical applications. (Created with BioRender.com (access on 19 June 2022)).

Figure 7

Schematic representation of nanocarrier internalization via various endocytosis mechanisms. (Created with BioRender.com (accessed on 19 June 2022)).

Figure 8

Schematic 3D representation of a structural arrangement of a liposome and various loading strategies, which are leading to enhancing the specificity and half-life of the nanocarrier at the targeted HIV-infected sites. (Created with BioRender.com (accessed on 19 June 2022).