The Human Immunodeficiency Virus (HIV) is a retrovirus that, if left untreated, systematically attacks the body’s immune defenses, eventually leading to Acquired Immunodeficiency Syndrome (AIDS). The AIDS epidemic has tragically claimed millions of lives and continues to affect tens of millions globally. Science has transformed the prognosis for people living with the virus, shifting the focus from a rapid, fatal illness to a manageable chronic condition. This transformation has been driven by deep genetic insights into both the virus and the human host, alongside advancements in therapeutic medicine.
The Role of Host Genetics in Susceptibility
The human genetic code determines an individual’s susceptibility to HIV infection and how quickly the disease advances. This variation is influenced by specific genes coding for proteins on the surface of immune cells. The most widely known example involves the CCR5 gene, which codes for a receptor that HIV exploits to enter host cells.
A specific genetic alteration, the CCR5-delta 32 mutation, results in a non-functional CCR5 receptor that does not reach the cell surface. Individuals inheriting this mutation from both parents are highly resistant to infection with common HIV strains, as the virus lacks an entry point. Those with only one copy of the mutation are susceptible but experience a significantly slower progression to AIDS, often delaying the onset by several years.
Other genetic markers, particularly those in the Human Leukocyte Antigen (HLA) system, influence the immune response. HLA proteins are responsible for presenting viral fragments to the immune system, training it to recognize and attack infected cells. Certain HLA types, such as HLA-B\57, are associated with a better ability to control the virus, leading to a lower viral load and slower disease progression.
How HIV Dismantles the Immune System
HIV primarily targets CD4+ T cells, which are the central coordinators of the adaptive immune response. The virus initiates its attack by binding to the CD4 receptor on the surface of these cells, along with a co-receptor (usually CCR5 or CXCR4). Once fused with the cell membrane, the virus releases its genetic material, which is then converted into viral DNA by an enzyme called reverse transcriptase.
The enzyme integrase then permanently integrates this viral DNA into the host cell’s genome within the nucleus. The infected CD4+ T cell is subsequently hijacked, becoming a viral factory that produces thousands of new HIV particles. The destruction of these immune cells occurs through several mechanisms, including direct viral killing and programmed cell death of both infected and neighboring uninfected cells.
The infection progresses through three stages: acute, chronic (latency), and AIDS. The acute phase involves a dramatic spike in viral load and a sharp drop in CD4+ T cells, often causing flu-like symptoms. In the chronic phase, the immune system mounts a partial defense, achieving a lower but persistent level of viremia, known as the viral set point, which slowly depletes the CD4+ T cell count over many years. Progression to AIDS occurs when the CD4+ T cell count drops below 200 cells per cubic millimeter of blood, severely compromising the immune system and leaving the body vulnerable to opportunistic infections and certain cancers.
Current Landscape of HIV Treatment
The advent of Antiretroviral Therapy (ART) revolutionized HIV management, transforming the infection from a death sentence into a chronic, manageable condition. ART involves a combination of three or more drugs from different classes, each targeting a specific step in the HIV life cycle to prevent viral replication.
These classes include nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), which block the conversion of viral RNA into DNA. Other widely used classes are integrase strand transfer inhibitors (INSTIs), which prevent viral DNA insertion into the host genome, and protease inhibitors, which block the final assembly of new viral particles. Combining drugs that disrupt multiple stages achieves maximum viral suppression and minimizes the chance of the virus developing drug resistance. The primary goal of ART is to reduce the viral load in the blood to an undetectable level.
Sustaining an undetectable viral load preserves immune health and completely prevents the sexual transmission of the virus, summarized by the public health message “Undetectable = Untransmittable” (U=U). Antiretroviral drugs are also highly effective as prevention tools, such as Pre-Exposure Prophylaxis (PrEP) for HIV-negative individuals, and Post-Exposure Prophylaxis (PEP), a short course of medication taken immediately after potential exposure.
Next-Generation Strategies for a Cure
ART suppresses the virus but is not a cure because HIV hides dormant within certain immune cells, forming a persistent viral reservoir. Research efforts are now focused on strategies to eliminate this reservoir, allowing people to stop lifelong medication.
One promising approach is “Shock and Kill,” which uses specific drugs called latency-reversing agents to force the hidden, dormant virus out of its resting state (“shock”). Once the virus is active, it becomes vulnerable to elimination by the immune system or by a highly intensified drug regimen (“kill”).
Another strategy involves gene editing technologies, such as CRISPR-Cas9. This technology could be engineered to physically cut the integrated viral DNA out of the host cell’s genome or to disrupt the CCR5 gene in immune cells, rendering them resistant to infection.
Therapeutic vaccines are also being developed, aiming to train the body’s own immune system to recognize and control the virus without the need for daily medication. These vaccines aim to generate a robust and sustained T cell response capable of suppressing viral replication indefinitely. While these next-generation strategies face significant challenges, they represent the frontier of research toward achieving a true, durable cure for HIV.