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Immunology

Acquired

We’ve explored the consequences of an immune system that was never built correctly from the start—the world of hereditary immunodeficiencies. Now, let’s turn to a much more common and equally devastating scenario: what happens when a perfectly healthy, fully functional immune system is attacked and systematically dismantled by an outside force. This is acquired (or secondary) immunodeficiency

Think of the distinction this way: a primary immunodeficiency is like a car factory with a flawed blueprint, so the cars coming off the assembly line are missing an engine. An acquired immunodeficiency is like a perfectly built, high-performance car that is hijacked and driven off a cliff. The initial machine was sound, but an external agent led to its destruction

While many things can cause acquired immunodeficiency—including malnutrition, certain cancers, and immunosuppressive drugs for transplantation—there is one agent that has defined the field and stands as the most infamous saboteur of the human immune system: the Human Immunodeficiency Virus (HIV)

HIV and AIDS: The Quintessential Acquired Immunodeficiency

HIV infection is the cause of Acquired Immunodeficiency Syndrome (AIDS). This is a disease process where a specific virus launches a targeted, relentless assault on the single most important cell in the adaptive immune system, leading to its catastrophic collapse and leaving the body defenseless against a host of other infections

Pathophysiology: A Coordinated Attack on the Command Center

To understand AIDS, you have to understand the virus’s brilliant and sinister strategy

  • The Virus: HIV is a retrovirus. This means its genetic material is RNA, and it carries a special enzyme called reverse transcriptase, which allows it to do something our cells cannot: convert its RNA into DNA. Its outer envelope is studded with glycoproteins, most importantly gp120, which acts as its “key.”

  • The Target: HIV’s primary target is the CD4+ T-helper lymphocyte. This is not a random choice. The CD4+ T-cell is the “general,” the “quarterback,” the master regulator of the entire adaptive immune response. By specifically targeting and eliminating this one cell, HIV can bring the whole system crashing down

  • The Life Cycle of Destruction

    1. Binding and Entry The viral gp120 “key” binds with high affinity to the CD4 molecule on the surface of the T-helper cell. This binding causes a conformational change that allows it to also bind to a co-receptor (either CCR5 or CXCR4). This dual lock-and-key system then allows another viral protein, gp41, to harpoon the cell membrane and fuse the virus with the cell, injecting its contents inside
    2. Reverse Transcription Once inside, the viral reverse transcriptase enzyme gets to work, converting the single-stranded viral RNA into double-stranded viral DNA. This is a sloppy, error-prone process, which is why HIV mutates so rapidly, making it a difficult target for vaccines
    3. Integration The newly made viral DNA is transported into the host cell’s nucleus, where another viral enzyme, integrase, permanently stitches the viral DNA into the host cell’s own genome. At this point, the infection is irreversible. The viral DNA, now called a provirus, will be a part of that cell and all of its descendants for life. It’s a permanent spy within the command center
    4. Replication & Budding The provirus can remain dormant for years. But when the T-cell becomes activated (e.g., during another infection), it begins to transcribe the viral DNA, treating it like one of its own genes. The host cell is hijacked and turned into a virus factory, producing new viral RNA and proteins. These components assemble at the cell membrane and “bud” off, taking a piece of the host membrane with them, ready to infect new CD4+ cells

  • The Outcome: This process is incredibly destructive. Over a period of years, the virus directly kills infected CD4+ cells and indirectly leads to the death of many more. The body tries to keep up, but eventually, the rate of destruction outpaces the rate of production. The CD4+ T-cell count begins a slow, steady decline. When the count drops below a critical level, the entire adaptive immune system collapses. This severe state of immune suppression is AIDS. At this point, the patient becomes susceptible to a wide range of opportunistic infections (like Pneumocystis jirovecii pneumonia, toxoplasmosis, or CMV) and certain cancers that a healthy immune system would easily control

Role of the Clinical Laboratory: Diagnosis and Monitoring

The lab is the central arena for the fight against HIV. Our role is twofold: to accurately diagnose the infection and to provide the critical data needed to monitor the health of the patient and the effectiveness of their treatment

Diagnosis: Finding the Enemy

The key challenge in diagnosis is the serological window period: the time between initial infection and the development of detectable antibodies. Modern testing algorithms are designed to close this window as much as possible

  1. Screening: 4th Generation Combination Immunoassay
    • This is the current gold standard for routine screening. It is a massive improvement over older, antibody-only tests
    • What it Detects: It looks for two things simultaneously:
      1. HIV-1/HIV-2 antibodies The body’s response to the virus
      2. p24 antigen A core viral protein that appears in the blood very early after infection, before antibodies are produced
    • The Advantage: By detecting the p24 antigen, this test can detect an acute/early infection about a week earlier than antibody-only tests, significantly shortening the window period. A non-reactive 4th gen test is considered a true negative
  2. Confirmation: HIV-1/HIV-2 Antibody Differentiation Immunoassay
    • If the screening test is reactive, the current CDC algorithm calls for this follow-up test
    • The Principle: This is a rapid immunoassay that can not only confirm the presence of antibodies but can also distinguish between an HIV-1 infection (most common worldwide) and an HIV-2 infection (primarily in West Africa)
    • If the screen is positive but the differentiation assay is negative, a nucleic acid test (NAT) is performed to look for viral RNA, which would catch a very acute infection where only the p24 antigen was present. The Western Blot, while historically important, is no longer recommended for routine confirmation

Monitoring: Tracking the Battle

Once a patient is diagnosed and starts treatment with Antiretroviral Therapy (ART), the lab’s role shifts to monitoring. We track two key parameters:

  1. CD4 T-Cell Count
    • The Goal: To assess the status of the patient’s immune system. It’s a direct measure of how much damage has been done
    • The Method: Flow Cytometry. We use fluorescently-labeled antibodies to CD3 and CD4 to count the absolute number of CD4+ T-cells per microliter of blood
    • Clinical Significance
      • A normal count is >500 cells/μL
      • < 200 cells/μL: is one of the key laboratory definitions of AIDS and is the threshold at which doctors start prophylactic medication to prevent opportunistic infections
  2. HIV Viral Load
    • The Goal: To measure the amount of active virus circulating in the patient’s blood
    • The Method: Molecular tests, specifically Real-Time Polymerase Chain Reaction (RT-PCR), which directly quantifies the number of copies of HIV RNA per milliliter of plasma
    • Clinical Significance: This is the primary indicator of how well ART is working. A patient’s viral load should plummet after starting effective therapy. The goal of treatment is to achieve an “undetectable” viral load (typically <20 or <50 copies/mL). This does not mean the patient is cured (the provirus is still hiding in their cells), but it means the virus is not replicating, the immune system can recover, and, critically, the patient cannot transmit the virus to others (Undetectable = Untransmittable)