Human Immunodeficiency Virus (HIV) impacts millions globally. While antiretroviral therapy (ART) has revolutionized HIV management, allowing individuals to live longer, healthier lives by suppressing the virus, it does not offer a cure. The ongoing need for daily medication stems from a hidden threat: HIV latency, the primary barrier to eradicating the virus.
The Nature of HIV Latency
HIV latency refers to a state where the virus is present in cells but is not actively replicating or producing new viral particles. These dormant cells become invisible to the immune system, which targets actively infected cells. Current antiretroviral drugs, designed to interfere with viral replication, cannot affect these dormant cells because there is no active replication to inhibit. If ART is stopped, these hidden viruses can reactivate, leading to a rapid rebound in viral load and progression of the disease.
Cellular Reservoirs of Latent HIV
Latent HIV primarily hides within specific long-lived immune cells, forming latent reservoirs. Resting CD4+ T cells are the main cellular “sanctuaries” for the latent virus. These white blood cells are central to the immune system, and their long lifespan makes them ideal hiding spots. While resting CD4+ T cells are the most significant reservoir, other cell types, such as macrophages and dendritic cells, can also harbor latent HIV. The virus can also persist in various anatomical sites, including the central nervous system, lymphatic system, and gut-associated lymphoid tissue.
How HIV Establishes Latency
HIV enters a latent state by integrating its genetic material into the host cell’s DNA. After infecting a CD4+ T cell, its RNA is reverse-transcribed into proviral DNA, which integrates into the host chromosome. In a small fraction of these infected cells, particularly as activated CD4+ T cells return to a resting state, the expression of this integrated viral DNA is suppressed. This suppression prevents the production of new viral components.
Factors contributing to this suppression include the absence of certain host transcription factors, changes in chromatin structure (the tightly packed form of DNA), and a lack of cellular activation signals. Research suggests that this silencing can be initiated by host cell processes, such as the SMC5/6 protein complex, which may silence the provirus even before it fully integrates.
Approaches to Eradicate Latent HIV
Current research strategies to eliminate the latent HIV reservoir focus on several approaches. One strategy is “shock and kill,” which aims to reactivate the dormant virus within latently infected cells, making them visible to the immune system and susceptible to antiretroviral drugs. The “shock” phase uses latency-reversing agents (LRAs) to induce HIV transcription and protein expression. The “kill” phase then clears reactivated cells by the immune system or through virus-induced cell death. A challenge lies in reactivating all latent cells without causing widespread inflammation and ensuring the immune system can effectively eliminate them.
Another approach is “block and lock,” which seeks to permanently silence the latent virus, preventing its reactivation. This strategy uses latency-promoting agents (LPAs) to inhibit HIV transcription and lock the viral promoter into a deeply suppressed state, often through epigenetic modifications that make the viral DNA inaccessible. For instance, didehydro-cortistatin A (dCA), a Tat inhibitor, can block viral transcription and promote a repressive chromatin environment, effectively putting the virus into a “super latency”.
Emerging approaches also include various forms of gene therapy. Gene therapy aims to modify cells to make them resistant to HIV infection, eliminate infected cells, or permanently silence the virus. This can involve modifying genes to prevent viral entry, or introducing genetic elements that inhibit viral replication or promote the death of infected cells. Some research explores using HIV’s own regulatory mechanisms to force it into permanent dormancy by amplifying naturally occurring molecules that suppress its activity. These strategies highlight the complexity of eradicating latent HIV and represent ongoing areas of scientific investigation.