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

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.

Perinatal exposure to atazanavir-based antiretroviral regimens in a mouse model leads to differential long-term motor and cognitive deficits dependent on the NRTI backbone

“…Increased neurodegeneration, including shrinkage of cytoplasm and pyknotic nuclei in CA1 and dentate gyrus, has been reported in Wistar rats exposed to TDF/3TC and efavirenz (Akang, 2019). Multiple in vitro studies report oxidative and mitochondrial stress, neurotoxicity and astrocyte senescence in cultured neurons and astrocytes exposed to monotherapy or combined antiretroviral therapy (Ellis et al, 2007;Liner et al, 2010;Robertson et al, 2012;Akay et al, 2014;Blas-García et al, 2014;Shah et al, 2016;Cohen et al, 2017;Nooka and Ghorpade, 2017;Sanchez and Kaul, 2017;De Benedetto et al, 2020;Bertrand et al, 2021;Lanman et al, 2021;Foster et al, 2022;Rudd and Toborek, 2022). While these studies investigated the direct neurotoxic effects of ARVs, our mice were only exposed to ARVs in utero.…”

Cocaine regulates antiretroviral therapy CNS access through pregnane-x receptor-mediated drug transporter and metabolizing enzyme modulation at the blood brain barrier

“…As a result, cART has revolutionized the HIV epidemic by decreasing the rates of opportunistic infections, acquired immunodeficiency syndrome (AIDS), HIV-related morbidity and mortality, and HIV transmission while increasing the lifespan for people living with the virus [ 1 – 4 ]. However, treating HIV in tissues, including the brain, remains a challenge due to the limited potential of ART to bypass tissue barriers like the blood brain barrier (BBB) [ 5 – 11 ]. This limited tissue access prevents organs from receiving adequate ART concentrations necessary for complete viral suppression and results in the development of sanctuaries that remain a major barrier to HIV eradication efforts [ 12 , 13 ].…”

Adult human brain tissue cultures to study neuroHIV

“…Previous work has highlighted factors that likely contribute to HAND symptoms, including but not limited to chronic low-level inflammation [6,7], continued expression of neurotoxic viral proteins [8,9], defective proviruses [10,11], and possibly long-term exposure to select ART regimens [12][13][14]. Further, HAND symptoms can be aggravated by substance use [15], particularly opioids [16][17][18] and Disclaimer/Publisher's Note: The statements, opinions, and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s).…”