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

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.