The human immunodeficiency virus (HIV) has evolved from a death sentence to a manageable chronic condition due to the success of Antiretroviral Therapy (ART). ART regimens suppress the virus to nearly undetectable levels, allowing people with HIV to live long and healthy lives. However, this treatment must be taken daily for life because ART offers control, not a cure. The failure to achieve a sterilizing cure stems from fundamental biological properties of the virus and its interaction with the human body. These roadblocks—specifically how the virus integrates into host DNA, its ability to hide in latent reservoirs, and its high mutation rate—explain why HIV remains permanently embedded.
Integration and Immune Cell Targeting
HIV is a retrovirus, carrying its genetic information as RNA, which must be converted into DNA to infect a host cell. This conversion is performed by the viral enzyme reverse transcriptase. The resulting viral DNA is transported into the host cell’s nucleus.
Inside the nucleus, a second viral enzyme, integrase, splices the viral DNA, known as a provirus, directly into the host cell’s chromosome. Once integrated, the provirus becomes a permanent part of the host cell’s genetic code, replicating every time the cell divides.
The primary targets for this integration are CD4+ T cells, the central command system of the immune response. By targeting these cells, HIV turns the immune system’s defenders into viral factories. The provirus often integrates into transcriptionally active areas of the host genome, positioning the virus for quick expression and replication once the cell is activated.
The Problem of Latent Viral Reservoirs
The most significant barrier to curing HIV is the latent viral reservoir, a pool of infected cells invisible to both ART and the immune system. This reservoir consists primarily of long-lived memory CD4+ T cells that harbor the integrated provirus in a resting, dormant state. In this quiescent state, the provirus is transcriptionally silent and not actively producing new viral particles.
ART works by targeting active steps of the viral life cycle, such as reverse transcription or assembly. Since the virus in a latent cell is not actively replicating, ART cannot eliminate these cells. The integrated provirus persists silently, often for the entire lifespan of the host cell.
If a person stops taking ART, the provirus within these resting cells can reactivate, initiating new virus production and leading to a rapid viral rebound. This confirms the reservoir contains replication-competent virus and necessitates lifelong medication. Furthermore, latently infected cells can undergo clonal expansion, creating large populations of infected cells that maintain the reservoir’s size and ensure the virus’s long-term survival.
High Mutation Rate and Viral Diversity
HIV’s capacity for rapid evolution is a third major obstacle, hindering the development of a lasting vaccine or therapeutic agent. This high rate of change is due to the error-prone nature of the viral enzyme reverse transcriptase. Unlike host cell DNA polymerase, reverse transcriptase lacks a proofreading function, resulting in frequent errors as it converts viral RNA into DNA.
These mistakes generate numerous slightly different viral variants within a single infected individual, known as a viral “quasispecies.” This immense genetic diversity allows the virus to quickly develop resistance to antiretroviral drugs, necessitating combination therapy for successful suppression.
The diversity also allows the virus to evade the host’s immune response, as T cells and antibodies struggle to neutralize all the constantly changing variants. The quasispecies ensures that if one variant is targeted, another resistant or unrecognized variant is readily available to continue the infection, presenting a moving target for cure strategies.
Strategies for Achieving a Cure
Current research efforts focus on two main conceptual approaches designed to overcome the challenge of the latent reservoir.
Shock and Kill
This strategy aims to reactivate the silent provirus within resting CD4+ T cells using latency-reversing agents (LRAs). The “shock” forces the virus to begin replication, making the infected cell visible to the immune system or susceptible to clearance by ART (the “kill”). Challenges include ensuring all latent cells are “shocked” without causing toxicity, and confirming the immune system or drugs can effectively eliminate the reactivated cells.
Block and Lock
This opposing approach seeks to permanently silence the integrated provirus to prevent it from ever reactivating. This strategy uses latency-promoting agents (LPAs) to induce deep, irreversible latency. The goal is to lock the virus in a dormant state so ART can be safely stopped.
Beyond these reservoir-targeting methods, advanced genetic and immune-based strategies are under investigation. Gene editing technologies, such as CRISPR-Cas9, are being explored to physically excise the integrated provirus from the host cell’s DNA. Therapeutic vaccines and broadly neutralizing antibodies (bNAbs) are also being developed to stimulate a robust immune response, potentially enabling the host’s own defenses to control or eliminate the residual virus.