The Human Immunodeficiency Virus (HIV) is a retrovirus that targets and destroys the immune system’s CD4+ T-cells. While modern Antiretroviral Therapy (ART) has transformed HIV infection into a manageable chronic condition, it is not a cure. ART suppresses the virus to undetectable levels in the bloodstream, halting disease progression. However, a cure requires the complete eradication of all replication-competent virus, and the fundamental obstacle is the virus’s ability to hide its genetic material within host cells.
The Mechanism of Viral Integration and Latency
HIV is a retrovirus that uses reverse transcriptase to convert its RNA genome into double-stranded DNA. This viral DNA is then transported into the nucleus of the host CD4+ T-cell. There, the enzyme integrase splices the viral DNA directly into the host cell’s own genetic material.
Once integrated, the viral DNA is known as the provirus, which can remain dormant for long periods. This provirus state forms the viral reservoir, a population of infected cells, primarily resting memory CD4+ T-cells, where the virus is transcriptionally silent and not actively producing new virus particles.
Antiretroviral drugs work by interfering with the active stages of the viral life cycle, such as reverse transcription or assembly of new virions. Because the provirus in a latent cell is not actively transcribing or replicating, it becomes invisible to the effects of ART. The infected cell carries the instruction manual for HIV production within its own genome.
The viral reservoir is stable and decays at an extremely slow rate, estimated to have a half-life of approximately 44 months. This slow decay means a lifelong treatment regimen is necessary, as natural clearance would take decades. If a patient stops taking ART, the provirus can reactivate, begin producing new infectious virions, and rapidly lead to a viral rebound in the bloodstream.
Genetic Instability and Immune Evasion
A second major challenge is the virus’s remarkable ability to mutate and evade the body’s defenses. This high rate of genetic change stems from the inherent inaccuracy of the reverse transcriptase enzyme, which lacks the proofreading function of human DNA polymerases. Errors occur at a rate of about 0.1 mutations for every new viral genome produced.
This constant introduction of errors results in a highly diverse population of viral variants within a single infected individual, known as viral quasispecies. Since the virus is not genetically uniform, a vaccine targeting one specific protein sequence may be ineffective against the entire cloud of quasispecies. This genetic diversity allows the virus to adapt rapidly to both antiretroviral drugs and immune responses.
The chronic nature of HIV infection leads to immune exhaustion in the body’s primary virus-fighting cells, particularly cytotoxic CD8+ T-cells. Prolonged exposure to high levels of viral antigens causes these T-cells to become dysfunctional, losing their ability to proliferate and effectively kill infected cells. Exhausted T-cells exhibit high expression of inhibitory receptors, such as PD-1, which suppress their activity.
This exhaustion means that even when the latent reservoir is shocked into activity, the compromised immune system is often unable to clear the newly activated, virus-producing cells. This failure ensures the virus’s long-term persistence even in the presence of suppressive medication.
Current Strategies for HIV Eradication
Current research focuses on two main strategies to overcome the latent reservoir: reactivating the virus to eliminate it, and directly removing the provirus. The “Shock and Kill” approach aims to flush the virus out of hiding using latency-reversing agents (LRAs). These agents awaken the dormant provirus, forcing the infected cell to produce viral proteins and making it visible to the immune system or vulnerable to ART.
The “kill” part of this strategy relies on the patient’s immune system or drug therapy to eliminate the newly activated cells before they can re-establish the reservoir. An alternative is the “Block and Lock” strategy, which seeks to permanently silence the provirus by inducing a deep, irreversible state of latency, preventing the virus from ever reactivating.
Gene Editing
Gene editing technologies, most notably CRISPR-Cas9, represent a radical attempt to directly address the integrated provirus. Researchers are exploring two main approaches. The first is to physically cut the viral DNA out of the host cell’s genome or introduce mutations that render the provirus permanently non-functional. The second application is to disrupt the CCR5 co-receptor on the surface of T-cells, making the cells resistant to new infection.
The ultimate proof that a cure is possible comes from a handful of patients, such as the Berlin and London Patients, who were cured of HIV following a highly invasive allogeneic hematopoietic stem cell transplant. These patients received bone marrow from donors who possessed a rare genetic mutation (CCR5-delta32) that naturally blocks HIV entry into cells. While this procedure is too dangerous and complex for general use, its success confirms that replacing the entire susceptible immune system can eliminate the virus.