HIV attacks CD4 T cells, a type of white blood cell that coordinates your immune system’s response to infections. A healthy person has between 500 and 1,500 CD4 cells per cubic millimeter of blood. Without treatment, HIV steadily destroys these cells until the count drops below 200, the threshold that defines an AIDS diagnosis.
But CD4 T cells aren’t the only targets. HIV also infects other immune cells and can reach the brain, creating damage that extends well beyond a single cell type.
How HIV Gets Inside a CD4 Cell
HIV carries a protein on its surface called gp120 that locks onto the CD4 receptor like a key fitting into a lock. That initial attachment isn’t enough on its own, though. The virus also needs a second receptor, called a co-receptor, to complete entry. The two main co-receptors are CCR5 and CXCR4.
Early in infection, HIV typically uses CCR5 to enter cells. These strains can infect both CD4 T cells and immune cells called macrophages. Later in infection, strains that use CXCR4 can emerge, and these are associated with a faster decline in CD4 counts. Some strains can use either co-receptor. Once gp120 binds to both CD4 and a co-receptor, the virus’s outer envelope fuses with the cell membrane and the viral contents spill inside.
What Happens Once HIV Is Inside
After entering the cell, HIV converts its RNA into DNA using a specialized enzyme. This viral DNA then travels into the cell’s nucleus and stitches itself directly into the cell’s own genetic code. At that point, the cell has essentially been hijacked. Every time the cell activates, it can produce new HIV proteins alongside its normal functions.
Those new proteins assemble into immature virus particles that push their way out of the cell in a process called budding. Once released, another enzyme snips the proteins into their final shape, creating mature, infectious copies of HIV. A single infected cell can produce thousands of new virus particles. Over time, this process destroys the host CD4 cell, and the newly released viruses go on to infect more cells, creating a cycle of escalating damage.
The Gut Takes the Earliest Hit
One of the most striking findings about early HIV infection is how quickly and aggressively it targets CD4 cells in the gut. The lining of the gastrointestinal tract contains a dense concentration of immune cells, and during primary infection, the gut loses CD4 cells far more dramatically than the bloodstream does.
Research published in The Journal of Experimental Medicine found that during early infection, the average percentage of CD4 T cells in the gut mucosa dropped to about 16%, compared to roughly 56% in uninfected individuals. Meanwhile, CD4 levels in the blood remained comparatively higher at around 42%. This means the standard blood test for CD4 count actually underestimates how much immune damage is happening in the body’s largest immune organ. The gut’s immune barrier is compromised early, which allows bacteria to leak into the bloodstream and fuels the chronic inflammation that characterizes HIV infection.
Macrophages and Dendritic Cells
CD4 T cells get most of the attention, but HIV also infects macrophages and dendritic cells, two other types of immune cells found throughout the body. These cells play a particularly troubling role in the infection because, unlike CD4 T cells, they don’t die quickly when infected. Macrophages can harbor the virus for extended periods, essentially acting as long-term storage sites.
Infected macrophages have been found in lymph nodes, the spleen, lungs, digestive tract, urinary tract, and the central nervous system. They often fuse together into large multinucleated giant cells that continue producing virus. They can also transfer HIV directly to uninfected CD4 T cells through close cell-to-cell contact, a method of spreading that is highly efficient. Even macrophages and dendritic cells that don’t become productively infected can capture virus particles on their surface and pass them along to CD4 T cells, amplifying the infection without being infected themselves.
Because infected macrophages survive so long in tissues, they represent one of the biggest obstacles to curing HIV. Even when antiviral treatment suppresses the virus in the blood to undetectable levels, these tissue reservoirs can persist for years.
How HIV Reaches the Brain
HIV can cross the blood-brain barrier, the protective layer that normally keeps pathogens out of the central nervous system. It does this by hitching a ride inside infected immune cells, particularly a subset of monocytes (precursors to macrophages) that express specific adhesion proteins allowing them to slip through the barrier.
Once inside the brain, the virus infects microglia, the brain’s resident immune cells. Microglia carry CCR5 and CCR3 co-receptors on their surface, making them susceptible to HIV entry through the same basic mechanism the virus uses elsewhere. Microglia can also become infected by ingesting HIV-infected CD4 T cells that migrate into brain tissue. Viral DNA, RNA, and proteins have all been detected in microglia from autopsy studies. The resulting inflammation and cell damage can lead to cognitive problems, memory difficulties, and mood changes, a spectrum of symptoms sometimes called HIV-associated neurocognitive disorder.
Chronic Inflammation and Immune Exhaustion
Beyond directly killing CD4 cells, HIV creates a state of persistent immune activation that damages the immune system from the inside out. The body recognizes the ongoing infection and keeps immune cells in a constant state of alert. Over time, this chronic activation leads to what researchers call T cell exhaustion: immune cells that are still alive but no longer function effectively.
This exhaustion is driven by elevated levels of inflammatory signals like TNF-alpha, interleukin-6, and C-reactive protein. The metabolic machinery inside T cells also breaks down, with increased oxidative stress and malfunctioning mitochondria (the energy-producing structures within cells). The result is an immune system that is both depleted in numbers and degraded in function. Even people on effective antiviral treatment continue to show signs of this persistent inflammation, which contributes to higher rates of cardiovascular disease, bone loss, and other conditions compared to the general population.
What Happens as CD4 Counts Drop
The practical consequence of HIV’s attack on the immune system is vulnerability to infections that a healthy immune system would easily control. These opportunistic infections follow a rough pattern based on CD4 count:
- Below 250: Risk increases for certain fungal infections like coccidioidomycosis, and tuberculosis becomes more likely to spread beyond the lungs.
- Below 200: Pneumocystis pneumonia becomes a major threat, with about 90% of cases occurring at this level. This is also the threshold for an AIDS diagnosis.
- Below 100: Toxoplasma encephalitis (a brain infection from a common parasite), severe herpes outbreaks, histoplasmosis, and cryptosporidiosis become significant risks.
- Below 50: The most dangerous infections emerge, including disseminated MAC (a bacterial infection that spreads throughout the body), CMV disease affecting the eyes or organs, and bartonellosis.
Each drop in CD4 count opens the door to progressively more serious infections that define the later stages of untreated HIV.
How Treatment Reverses the Damage
Antiretroviral therapy works by blocking HIV at multiple stages of its life cycle, preventing the virus from making new copies of itself. When viral replication stops, CD4 cells get the chance to recover. The goal is to reach a CD4 count of 500 or above, which is considered immunological recovery.
That recovery takes time, especially for people who start treatment with very low counts. A study of severely immunosuppressed patients in South Africa found that the median time to reach a CD4 count of 500 was about 40 months for women and 59 months for men. People who achieved full viral suppression had a 49% higher rate of CD4 recovery compared to those who didn’t. Starting treatment earlier, before the CD4 count drops significantly, leads to faster and more complete immune recovery, which is why current guidelines recommend beginning treatment as soon as possible after diagnosis regardless of CD4 count.