The Human Immunodeficiency Virus (HIV) targets and weakens the body’s immune system, specifically attacking CD4 T lymphocytes, which are white blood cells that help coordinate immune responses. When HIV destroys these CD4 cells, it impairs the body’s ability to fight off infections and diseases. While significant advancements in medicine, particularly Antiretroviral Therapy (ART), have transformed HIV into a manageable, chronic condition, it currently remains without a widely available cure. Effective treatment can suppress the virus to undetectable levels in the blood, but it does not eliminate the virus entirely from the body.
The Viral Hiding Strategy
A primary challenge in curing HIV is its ability to establish hidden viral reservoirs. As a retrovirus, HIV integrates its genetic material, proviral DNA, directly into the DNA of infected host cells, making the infection permanent for that cell and its descendants. The integrated provirus can then enter a dormant or “sleeping” state, becoming a latent HIV reservoir.
In this latent state, infected cells do not actively produce new virus particles, making them invisible to the immune system and most antiviral drugs. These long-lived, resting memory CD4+ T cells are the major component of the latent reservoir. They can persist for many years, slowly decaying with a half-life of approximately 44 months. The virus takes advantage of the natural proliferation of these memory cells, allowing the integrated viral DNA to be copied and passed on to new cells, maintaining the reservoir over time.
These viral hiding places are established very early in infection, often within weeks of initial exposure. While the exact distribution is still being mapped, these reservoirs are found throughout the body. Major anatomical sites include lymphoid tissues such as the lymph nodes, spleen, and gut-associated lymphoid tissue (GALT), where concentrations of infected cells are particularly high. HIV-infected cells have also been detected in the brain, bone marrow, lungs, liver, adipose tissue, and genitourinary tract.
A Constantly Changing Target
Another obstacle to an HIV cure is the virus’s rapid mutation ability. HIV’s reverse transcriptase enzyme, which converts its RNA into DNA, is highly error-prone and lacks proofreading activity. This leads to a high rate of genetic variation, generating numerous slightly different versions of the virus within a single individual. It is estimated that HIV-1 reverse transcriptase has an error rate on the order of 10-5 to 10-3 errors per base per replication cycle.
This rapid mutation allows HIV to continuously change its surface proteins, like gp120 and gp41, which are targets for immune system antibodies. By altering these proteins, the virus evades detection and neutralization by the host’s immune response, making it difficult for the body to mount a consistent and effective attack. This constant evolution enables the virus to escape from cytotoxic T lymphocytes (CTLs), specialized immune cells that normally identify and eliminate infected cells.
Furthermore, the high mutation rate contributes to the development of drug resistance if antiretroviral therapy is not strictly adhered to. Even small changes in the viral genetic code can render existing drugs less effective or ineffective, necessitating the development of new drug combinations. This genetic plasticity ensures that HIV remains a moving target, continually adapting to selective pressures from both the host immune system and antiviral medications.
How Current Treatments Work and Their Limits
Current HIV treatment, Antiretroviral Therapy (ART), uses a combination of medications to halt HIV replication. ART interferes with different stages of the HIV life cycle, preventing the virus from making copies and infecting new cells. For instance, some drugs, like nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), block the reverse transcriptase enzyme, stopping the conversion of viral RNA into DNA. Integrase strand transfer inhibitors (INSTIs) prevent the viral DNA from inserting into the host cell’s DNA, and protease inhibitors (PIs) stop the assembly of new infectious virus particles.
When taken consistently as prescribed, ART is highly effective at reducing the amount of HIV in the blood to very low, often undetectable, levels. This viral suppression allows the immune system to recover, improving health and preventing the progression to AIDS. Additionally, achieving an undetectable viral load means the virus cannot be transmitted to others through sexual contact, a concept known as “Undetectable = Untransmittable” (U=U).
However, ART does not eliminate the virus or cure HIV infection. Its fundamental limitation is the inability to target dormant virus in latent reservoirs. As these hidden cells are not actively replicating, current drugs have no effect. If ART is stopped, even after years of undetectable viral load, the latent reservoirs can reactivate and begin producing new virus particles, leading to a rapid rebound of the infection. This re-emergence of the virus necessitates lifelong adherence to ART to maintain viral suppression and overall health.
Scientific Approaches to Finding a Cure
Scientists are actively pursuing several innovative strategies to overcome the challenges posed by HIV’s persistence and achieve a cure. One prominent approach is known as “Shock and Kill” (or “Kick and Kill”). This strategy involves using drugs called latency-reversing agents (LRAs) to “wake up” dormant HIV in latent reservoirs. This forces infected cells to produce viral proteins and new virus particles, making them “visible” for the immune system or ART to clear. While LRAs show promise in activating latent virus, effective clearance of these reactivated cells remains a challenge.
Another area of research is gene editing, particularly using technologies like CRISPR-Cas systems. Researchers are exploring ways to literally cut the integrated HIV DNA out of the host cell’s genome, or to modify host genes to make cells resistant to infection. Early human trials show the ability to target viral DNA and clear it from the blood within months, though viral rebound still occurred in some participants upon ART interruption.
Immune-based therapies aim to enhance the body’s natural defenses against HIV. This includes the development of therapeutic vaccines, designed to boost the immune response in people living with HIV, potentially allowing them to control the virus without lifelong ART. Researchers are also investigating broadly neutralizing antibodies (bNAbs), antibodies capable of recognizing and blocking a wide range of HIV strains. These bNAbs could potentially inhibit viral entry and activate other immune cells to destroy HIV-infected cells, including those in reservoirs.
Rare cases of HIV cure, like the “Berlin Patient” and “London Patient,” have provided valuable insights into potential cure mechanisms. These individuals, who had both HIV and certain blood cancers, received high-risk stem cell transplants from donors with a genetic mutation (CCR5 delta 32) that makes immune cells resistant to most HIV strains. While these cases demonstrated that a cure is possible, the procedure is too risky, complex, and not scalable for the general HIV-positive population due to its high mortality rates and the scarcity of suitable donors. However, these successes continue to inform other, safer cure strategies under investigation.