Human Immunodeficiency Virus (HIV) is a retrovirus that primarily attacks the immune system, leading to its progressive weakening. If untreated, HIV can advance to Acquired Immunodeficiency Syndrome (AIDS), a severe stage where the body’s defenses are compromised. HIV exhibits a remarkable ability to specifically identify and infect certain cell types. Understanding these precise mechanisms is essential for comprehending disease progression.
The Immune System’s Target Cells
HIV primarily targets CD4+ T-cells, also called helper T cells. These white blood cells are crucial components of the adaptive immune system, orchestrating responses against pathogens. CD4+ T-cells secrete chemical signals, known as cytokines, to activate other immune cells, including cytotoxic T cells and B cells, which then mount a direct attack. The CD4 protein on their surface makes them primary targets for HIV.
Macrophages and dendritic cells also serve as target cells for HIV. Macrophages are large white blood cells that engulf cellular debris and pathogens. Dendritic cells are specialized immune cells found in tissues that come into contact with the external environment, presenting antigens to T-cells. Both cell types express the CD4 receptor and co-receptors necessary for viral entry, although macrophages tend to be infected by specific HIV strains.
How HIV Recognizes Its Targets
HIV’s ability to recognize specific cells relies on a molecular “lock and key” system involving viral surface proteins and host cell receptors. The viral envelope is studded with glycoprotein spikes, composed of two main subunits: gp120 (outer surface) and gp41 (transmembrane). The gp120 subunit is responsible for initial binding to the host cell.
The first step involves gp120 binding to the CD4 receptor on target cells like T-cells, macrophages, and dendritic cells. This binding induces a significant conformational change in gp120, exposing a site for subsequent interaction with a co-receptor. The two primary co-receptors exploited by HIV are CCR5 and CXCR4, both of which are chemokine receptors.
Different HIV strains exhibit tropism, meaning they prefer to use either CCR5 or CXCR4. CCR5-tropic (R5) viruses are commonly found in early infection and primarily infect macrophages and T-cells, whereas CXCR4-tropic (X4) viruses tend to emerge later in disease progression and mainly infect T-cells. Binding to the co-receptor is a crucial step that further alters the viral envelope, preparing it for membrane fusion.
The Viral Entry Mechanism
Following gp120 binding to both the CD4 receptor and a co-receptor, viral entry proceeds through structural rearrangements. Co-receptor binding triggers further conformational changes in gp120, leading to the exposure of the gp41 fusion peptide. The gp41 subunit, initially hidden, undergoes substantial changes to mediate the fusion of the viral and cellular membranes.
The newly exposed gp41 fusion peptide inserts into the host cell membrane. This insertion is followed by a dramatic refolding of gp41, which forms a stable six-helix bundle structure. This structural change pulls the viral envelope and the host cell membrane into close proximity. The membranes merge, creating a fusion pore through which the viral core, containing the genetic material, enters the host cell’s cytoplasm.
Impact of Targeted Infection
The specific targeting of CD4+ T-cells by HIV has profound consequences for the immune system. Once inside, HIV integrates its genetic material into the host cell’s DNA, hijacking its machinery to produce new viral copies. This process damages and destroys the infected CD4+ T-cells. The progressive decline in CD4+ T-cell count weakens the immune system’s ability to defend against infections.
As functional CD4+ T-cells diminish, the body becomes increasingly susceptible to opportunistic infections and certain cancers. These illnesses, normally controlled by a healthy immune system, can become severe or life-threatening in an immunocompromised individual. This progressive impairment of the immune system defines the transition to AIDS, the most advanced stage of HIV infection.