The Paradox of HIV Blood-Brain Barrier Penetrance and Antiretroviral Drug Delivery Deficiencies

Abstract

HIV attacks the body's immune cells, frequently compromises the integrity of the blood-brain barrier (BBB), and infects the CNS in the early stages of infection. Dysfunction of the BBB further potentiates viral replication within the CNS, which can lead to HIV-associated neuropathology. Antiretroviral therapy (ART) significantly improves HIV patient outcomes and reduces mortality rates. However, there has been limited progress in targeting latent viral reservoirs within the CNS, which may eventually lead to rebound viremia. While ART drugs are shown to be effective in attenuating HIV replication in the periphery, the protection of the brain by the BBB offers an isolated sanctuary to harbor HIV and maintains chronic and persistent replication within the CNS. In this review, we elucidate the pathology of the BBB, its ability to potentiate viral replication, as well as current therapies and insufficiencies in treating HIV-infected individuals.

Keywords: HIV; antiretroviral therapy; blood–brain barrier; drug delivery; nanomedicine.

Figure 1.. The Central Paradox of HIV Infection in the Brain

HIV has the innate ability to bind to receptors that are expressed on circulating leukocytes in the blood. Once bound, recruitment of these leukocytes into the brain across the blood-brain barrier (BBB) is possible via different hypothesized mechanisms. The ease at which these infected host cells migrate into the brain surpasses the ability for therapeutic drugs to complete the same task. ART circulates in peripheral blood and has been shown to adequately suppress HIV replication levels; however, the inability for ART to penetrate the BBB leads to a safe haven for HIV to accumulate and lie dormant. This is a major challenge with treating HIV and preventing disease recurrence.

Figure 2.. Invasion of HIV into CNS via CD4⁺ T Cells and Monocytes.

Schematic of the hypothesized infiltration of HIV-infected immune cells. Receptors on CD4⁺ T cells (green) and monocytes (red) can bind to HIV, allowing for its replication and viral injection into a healthy host cell. The blood-brain barrier (BBB) expresses chemokines with chemokine-specific receptors for recruitment of immune cells, including T cell and monocytes depicted here. As a result, HIV can covertly cross the otherwise impermeable BBB, leading to invasion into the CNS.

Figure 3.. Comparison of Blood-Brain Barrier (BBB) Before and After Dysregulation and Subsequent HIV Infection.

In healthy individuals (left), the BBB functions as an impermeable structure to separate the CNS parenchyma from peripheral blood circulation and other pathogens. A main component of the BBB is endothelial cells, which are bridged by a tight junction protein complex. Illustrated are three critical tight junction proteins that make up the BBB: claudin (claudin-5 is the main claudin constituent of the BBB), zonula occludens (ZO-1, ZO-2, and ZO-3), and occludin. Right: HIV infection and long-term ART regimens can induce tight junction protein dysregulation, thereby potentiating further CNS HIV infection. Abbreviation: TJ, tight junction.

Figure I.. The Structure of HIV.

The structure of HIV is depicted in this schematic. The viral RNA genome is enclosed within a protein capsid that is surrounded by a lipoprotein-rich membrane. The important structural proteins glycoprotein-120 (gp120) and glycoprotein-41 (gp41) are embedded within the lipid membrane and assist HIV in binding to receptors for viral transfection and fusion into the host cell. HIV contains an RNA genome consisting of two single strands at the core of the viral capsid. Reverse transcriptase is an enzyme responsible for catalyzing the transcription of viral RNA into complementary DNA (cDNA). HIV integrase is a crucial enzyme that can integrate HIV DNA into the host cell’s genome once it is transcribed. Once this viral DNA is inserted into a host cell, it is commonly referred to as proviral DNA.