The Human Immunodeficiency Virus (HIV) remains a global health challenge, despite significant medical progress. Antiretroviral Therapy (ART) has been transformative, changing the infection from a death sentence to a manageable, chronic condition. ART successfully suppresses the virus, reducing the viral load to undetectable levels and preventing the onset of Acquired Immunodeficiency Syndrome (AIDS). However, this highly effective treatment must be taken for life because the virus is not truly eliminated from the body.
If ART is stopped, the virus rapidly rebounds and begins actively replicating again, typically within a few weeks. This immediate return shows that a hidden reservoir of infection persists, even when blood tests suggest the virus is gone. The inability to clear the infection is due to two main biological obstacles: the virus’s ability to lie dormant within host cells and its persistence in certain protected anatomical locations.
The Barrier of Latency: How HIV Hides
The most significant hurdle to curing HIV is the establishment of a latent viral reservoir within the body’s immune cells. HIV is a retrovirus that integrates its genetic material, known as a provirus, into the DNA of the host cell. The primary hiding spot for this provirus is within resting CD4+ T-cells, which are long-lived immune cells.
If an infected cell reverts to a dormant state, the provirus becomes transcriptionally silent, meaning the cell is infected but is not actively producing new viral particles. This latent infection is a perfect defense mechanism against current treatments. Antiretroviral drugs target active viral replication, so they have no target and are completely ineffective against the silent provirus hidden in the host cell’s genome.
The immune system also fails to recognize these silent, latently infected cells. Because the cell is not displaying any viral proteins on its surface, killer T-cells cannot identify and destroy it. This state of dormancy allows the provirus to survive for the entire lifespan of the memory T-cell, creating a stable, persistent reservoir.
Anatomical Sanctuaries: Where Drugs Cannot Reach
The effectiveness of ART is limited by the body’s physical structure in certain anatomical sites known as sanctuaries. These are areas where drug concentrations are suboptimal due to biological barriers, creating protected pockets where the virus can persist and potentially replicate at low levels. Drugs may not achieve high enough concentrations in these locations to fully suppress the virus, even with perfect adherence to the ART regimen.
The Central Nervous System (CNS), including the brain and spinal cord, is a primary example. The blood-brain barrier prevents many ART drugs from penetrating effectively, allowing infected macrophages and microglia to serve as a persistent viral reservoir.
Other significant reservoirs include lymphoid tissues, such as lymph nodes and the spleen, which maintain a large pool of latently infected cells. The gut-associated lymphoid tissue (GALT) is another major site of viral persistence, as are the testes and the female genital tract, where drug penetration can be limited.
Current Research Strategies for Eradication
Current research focuses on overcoming the barriers of latency and anatomical persistence by aiming to either flush the virus out of hiding or eliminate the provirus entirely. The goal is to achieve a functional cure, where the virus is permanently suppressed without ART, or a sterilizing cure, where the virus is completely eliminated.
Shock and Kill
The “shock and kill” strategy targets the latent reservoir using latency-reversing agents (LRAs). LRAs “shock” the dormant provirus into an active state, forcing the infected cell to produce viral proteins. Once active, the cell becomes vulnerable to elimination by the immune system or by continued ART drugs, which “kill” the replicating virus.
Block and Lock
The “block and lock” strategy seeks to permanently silence the provirus. This approach uses latency-promoting agents to push the integrated provirus into a deeper, non-inducible state of dormancy. The aim is to lock the viral genome in a permanently silent state, preventing future reactivation and viral rebound.
Gene Editing
Gene editing technologies, such as CRISPR-Cas9, offer the possibility of a sterilizing cure by physically removing the provirus from the host cell’s DNA. This involves using molecular tools to precisely locate and excise the integrated HIV DNA from the human genome. This technique represents a direct attack on the viral blueprint, potentially eliminating the reservoir entirely.
Broadly Neutralizing Antibodies (bNAbs)
Broadly Neutralizing Antibodies (bNAbs) can neutralize a wide range of HIV strains. These antibodies can be used as passive immunization to clear latently infected cells that express viral proteins or to prevent new infections. Combination therapy using multiple bNAbs is being explored to prevent the virus from escaping their effect through mutation.