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Review
. 2022 Jun 26;12(7):894.
doi: 10.3390/biom12070894.

Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity

Harrison Rudd  1 , Michal Toborek  1   2
Affiliations
Review

Pitfalls of Antiretroviral Therapy: Current Status and Long-Term CNS Toxicity

Harrison Rudd et al. Biomolecules. .

Abstract

HIV can traverse the BBB using a Trojan horse-like mechanism. Hidden within infected immune cells, HIV can infiltrate the highly safeguarded CNS and propagate disease. Once integrated within the host genome, HIV becomes a stable provirus, which can remain dormant, evade detection by the immune system or antiretroviral therapy (ART), and result in rebound viraemia. As ART targets actively replicating HIV, has low BBB penetrance, and exposes patients to long-term toxicity, further investigation into novel therapeutic approaches is required. Viral proteins can be produced by latent HIV, which may play a synergistic role alongside ART in promoting neuroinflammatory pathophysiology. It is believed that the ability to specifically target these proviral reservoirs would be a vital driving force towards a cure for HIV infection. A novel drug design platform, using the in-tandem administration of several therapeutic approaches, can be used to precisely target the various components of HIV infection, ultimately leading to the eradication of active and latent HIV and a functional cure for HIV. The aim of this review is to explore the pitfalls of ART and potential novel therapeutic alternatives.

Keywords: HIV; antiretroviral therapy; blood-brain barrier; brain; neuroHIV.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The enigma of persisting latent HIV provirus despite ART. Actively replicating and latent forms of HIV can infiltrate the CNS, resulting in neuroinflammatory pathophysiology. While ART can target active HIV, it is unable to target latent proviral reservoirs. The in-tandem use of ART and novel therapeutic approaches is required to target and eliminate both active and latent HIV within the CNS. Created with BioRender.com. Abbreviations: ART = antiretroviral therapy; HIV = human immunodeficiency virus.
Figure 2
Figure 2
Proposed mechanisms of BBB infiltration of HIV. At the HIV+ BBB, infected CD4+ T cells and monocytes can cross by several proposed mechanisms. The predominate method centers around HIV using infected CD4+ T cells and monocytes as a Trojan horse to paracellularly infiltrate brain parenchyma. HIV+ monocytes can also transcellularly pass through CMECs at the BBB. As HIV infection progresses in the CNS, increased BBB permeability and decreased expression of TJ proteins can provide a pathway for HIV to paracellularly invade the brain parenchyma. Created with BioRender.com. Abbreviations: HIV+ = human immunodeficiency virus-infected; TJs = tight junctions.
Figure 3
Figure 3
Potential endpoints of positive-sense HIV RNA after integration into host genome. Once integrated into the host genome, (+)-sense HIV RNA can persist as either latent provirus, which is capable of being reactivated, or actively replicating HIV, which can be deactivated. Created with BioRender.com. Abbreviations: (+)-sense = positive-sense; HIV = human immunodeficiency virus; RNA = ribonucleic acid.
Figure 4
Figure 4
Proposed forms of HIV proviral reservoir. HIV provirus can persist in three forms: latent, being transcriptionally silent; intact, producing active HIV virions; or defective, containing genetic mutations resulting in viral protein synthesis. Created with BioRender.com. Abbreviations: HIV = human immunodeficiency virus.
Figure 5
Figure 5
HIV infection of CD4+ T cell and points of ARVd intervention in the HIV replication cycle. (1) HIV binds to the CD4 receptor and CCR5/CXCR4 co-receptors. This can be blocked by attachment inhibitors, post-attachment inhibitors, and CCR antagonists. (2) Fusion of the HIV and host cellular membrane occurs. This can be blocked by fusion inhibitors. (3) Entry of viral proteins into the host cell. This can be blocked by fusion inhibitors. (4) Reverse transcription of HIV RNA into proviral HIV DNA. This can be blocked by nucleoside/non-nucleoside reverse transcriptase inhibitors. (5) Integration of HIV DNA into the host genome. This can be blocked by integrase strand transfer inhibitors. (6) Transcription of HIV RNA. (7) Translation of HIV RNA into viral proteins. (8) Assembly of immature HIV. (9) Budding of immature HIV into the host cell membrane. (10) Release and maturation of HIV. This can be blocked by protease inhibitors and maturation inhibitors. Created with BioRender.com. Abbreviations: ARVd = antiretroviral drug; CD4 = cluster of differentiation 4; CCR5 = C-C motif receptor 5; CXCR4 = C-X-C motif receptor 4; DNA = deoxyribonucleic acid; FI = fusion inhibitor; HIV = human immunodeficiency virus; INSTI = integrase strand transfer inhibitor; Tat = transactivator of transcription.
Figure 6
Figure 6
Novel approaches for the eradication of HIV within the CNS. A novel, multimodal drug delivery platform for anti-HIV therapeutics can result in the discovery of a functional HIV cure, allowing for the eradication of actively replicating HIV, latent proviral reservoirs, and specific targeting of the highly safeguarded CNS. Created with BioRender.com. Abbreviations: ART = antiretroviral therapy; bNAbs = broadly neutralizing antibodies; CNS = central nervous system; CRISPR/Cas-9 = clustered regularly interspaced short palindromic repeats-associated protein nuclease-9; HIV = human immunodeficiency virus; TALENs = transcription activator-like effector nucleases.
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