Human Immunodeficiency Virus (HIV)

Table of Contents

Structure and Special Features of HIV

Human immunodeficiency virus (HIV) is an enveloped virus belonging to the retroviruses. Two main types infect humans: HIV‑1 (worldwide, more aggressive) and HIV‑2 (mainly West Africa, progresses more slowly).

Key structural components:

Lipid envelope

Derived from the host cell membrane when new viruses bud off.
Contains viral glycoproteins:

gp120: binds to host cell receptors.
gp41: anchors gp120 and mediates fusion with the host membrane.

Matrix and capsid

Matrix protein (p17): under the envelope, stabilizes structure.
Capsid protein (p24): forms a cone‑shaped shell around the viral RNA; important for lab diagnostics (p24 antigen tests).

Genetic material

Two copies of single‑stranded, positive‑sense RNA.
Carries its own enzymes:

Reverse transcriptase: copies viral RNA into DNA.
Integrase: incorporates viral DNA into the host genome.
Protease: cuts viral polyproteins into functional proteins.

Genome organization (simplified)

Structural genes:

gag: core and matrix proteins (e.g., p24, p17).
pol: enzymes (reverse transcriptase, integrase, protease).
env: envelope glycoproteins (gp120, gp41).

Regulatory and accessory genes (e.g., tat, rev, nef) fine‑tune virus replication and help the virus evade the immune system.

These features explain why HIV:

Establishes a permanent genetic presence in host cells.
Shows high mutation rates, enabling rapid evolution and drug resistance.
Specifically targets cells of the immune system.

Target Cells and Entry into the Host Cell

HIV primarily infects cells that express the surface molecule CD4:

Main target cells

CD4⁺ T helper cells (central regulators of immune responses).
Certain macrophages and dendritic cells.
Some cells in the central nervous system (via infected macrophages and microglia).

Steps of cell entry (simplified):

Attachment

gp120 on HIV binds to CD4 on the host cell surface.

Coreceptor binding

HIV also needs a chemokine coreceptor, most often:

CCR5 (early in infection; “R5‑tropic” viruses).
CXCR4 (later; “X4‑tropic” viruses).

Individuals with certain mutations in CCR5 can be partly resistant to infection (important in research and therapy concepts).

Membrane fusion

After receptor and coreceptor binding, gp41 mediates fusion of the viral envelope with the host cell membrane.
The viral capsid is released into the cytoplasm.

Replication Cycle and Latency

Once inside the cell, HIV uses its retroviral strategy:

Reverse transcription

Reverse transcriptase converts viral RNA into double‑stranded DNA.
This step is error‑prone → many mutations → high variability and rapid development of resistance.

Integration

Viral DNA enters the nucleus.
Integrase inserts it into the host cell genome → provirus.
The provirus can:

Be actively transcribed → new virus production.
Remain latent → no or minimal expression, the infected cell survives and serves as a reservoir.

Transcription and translation

Host cell machinery makes viral RNAs and proteins from proviral DNA.
Some RNA molecules become new viral genomes.
Others are translated into polyproteins (Gag, Pol, Env).

Assembly and budding

Viral RNA and proteins assemble at the cell membrane.
New virus particles bud off, taking a piece of the host membrane as their envelope.

Maturation

Viral protease cleaves polyproteins into functional proteins.
Only after this cleavage is the virion fully infectious.

Latency and reservoirs

HIV can persist in:

“Resting” memory CD4⁺ T cells.
Macrophages and some tissue cells (e.g., in lymph nodes, brain).

Because the provirus is integrated and can be transcriptionally silent, complete elimination of the virus by the immune system or drugs is extremely difficult.
This is a key reason why HIV infection, once established, is currently considered chronic, not curable with existing standard therapies.

Transmission and Entry into the Body

HIV is transmitted via body fluids that contain infected cells or free virus in sufficient concentration:

High risk fluids

Blood.
Semen, pre‑ejaculate.
Vaginal and rectal secretions.
Breast milk.

Main routes of infection

Sexual contact (vaginal, anal; oral much lower risk, but not zero).
Blood contact

Shared needles/syringes.
Unsafe medical procedures or transfusions (rare where blood is screened).
Needle‑stick injuries in healthcare settings.

Mother‑to‑child transmission

During pregnancy, birth, or breastfeeding.

Not routes of infection

Everyday contact: shaking hands, hugging, using the same toilet or dishes.
Coughing, sneezing, insect bites.
Sweat, tears, and saliva in typical everyday situations (virus concentration too low).

HIV is relatively fragile outside the body and is inactivated by drying, heat, and common disinfectants. The critical factor is direct exposure to infectious fluid entering the bloodstream or mucous membranes.

HIV and the Immune System: Pathogenesis

The hallmark of HIV infection is progressive weakening of the immune system, particularly through loss and dysfunction of CD4⁺ T helper cells.

Key mechanisms:

Direct killing of infected CD4⁺ T cells when:

Virus replicates and buds off → cell damage.
Infected cells are recognized and destroyed by cytotoxic T cells.

Destruction in lymphatic tissues

Lymph nodes and gut‑associated lymphoid tissue are major sites of replication and immune cell depletion.
Early, extensive damage in the intestinal immune system contributes to chronic immune activation.

Chronic immune activation

Continuous viral replication and cell death keep the immune system “switched on.”
Persistent activation leads to “exhaustion” and dysregulation of immune cells.
Increases susceptibility to infections and some cancers.

Decline in CD4⁺ T cell count

Over years, the number of CD4⁺ T cells in blood typically declines.
Below certain thresholds, the risk of opportunistic infections and tumors rises sharply.

Ultimately, this process leads to acquired immunodeficiency syndrome (AIDS) if untreated.

Course of Infection: From Primary Infection to AIDS

The course of untreated HIV infection can be schematically divided into phases. Individual progression can differ, but the sequence is characteristic.

1. Acute (primary) infection

Occurs 2–6 weeks after infection.
Many, but not all, infected persons develop a flu‑like illness:

Fever, fatigue, sore throat, rash, enlarged lymph nodes, muscle pain.

Very high viral load in blood and secretions → high infectiousness.
The immune system responds:

Production of antibodies against HIV.
Activation of cytotoxic T cells.

Symptoms subside as the virus is partially controlled, but not eliminated.

2. Chronic, often asymptomatic phase

May last several years without treatment.
Virus continues to replicate, mainly in lymphatic tissues.
CD4⁺ T cells are gradually depleted.
Many people feel healthy or only nonspecifically unwell:

Persistent swollen lymph nodes, fatigue, mild recurrent infections.

Despite lack of symptoms, the person is infectious and can transmit the virus.

3. Symptomatic phase and AIDS

When the CD4⁺ T cell count drops below critical values and immune function is severely impaired, characteristic diseases occur:

Opportunistic infections (caused by pathogens that are normally harmless or easily controlled), for example:

Fungal infections of mouth and esophagus.
Pneumocystis pneumonia.
Severe viral infections (e.g., cytomegalovirus).
Certain forms of tuberculosis.

Tumors associated with immunodeficiency, such as:

Kaposi’s sarcoma.
Certain non‑Hodgkin lymphomas.

The term AIDS is used when:

Specific opportunistic infections or tumors are present, and/or
CD4⁺ T cell counts are below a defined threshold (definition details vary by guideline).

Without therapy, AIDS is typically fatal due to life‑threatening infections or cancers.

Diagnosis and Monitoring

HIV infection is diagnosed and followed using specific laboratory tests.

Direct and indirect detection

Antibody tests

Detect antibodies produced by the immune system against HIV.
Often combined in screening tests (e.g., ELISA, rapid tests).
Antibodies become detectable only after a window period (typically a few weeks after infection).

Antigen detection

Detection of viral proteins, especially p24 antigen.
Together with antibody detection, enables early diagnosis.

Nucleic acid detection (PCR)

Detects viral RNA in blood (viral load).
Useful in:

Early infection (before antibodies appear).
Monitoring therapy success.
Diagnosing infection in newborns (maternal antibodies would confuse antibody tests).

Positive screening tests are always followed by confirmatory tests to verify the diagnosis.

Monitoring disease progression and therapy

CD4⁺ T cell count

Indicator of immune status.
Low counts mean high risk for opportunistic infections.

Viral load (HIV RNA)

Amount of virus in blood.
High viral load → higher risk of progression and transmission.
Successful therapy typically reduces viral load to below the detection limit.

Treatment: Antiretroviral Therapy (ART)

HIV infection is currently treatable but not eradicated with standard therapy. The goal is to suppress viral replication as completely and permanently as possible.

Principles of ART

Use of combinations of drugs that attack different steps of the viral life cycle:

Reverse transcriptase inhibitors.
Protease inhibitors.
Integrase inhibitors.
Entry/fusion or coreceptor inhibitors.

Combination therapy:

Reduces viral load to undetectable levels in blood.
Allows recovery or stabilization of CD4⁺ T cells.
Strongly reduces risk of opportunistic infections and AIDS‑defining diseases.
Greatly reduces the risk of transmission to others.

Therapy is usually:

Lifelong.
Needs strict adherence, because:

Irregular intake favors resistance development.
Resistant virus strains can be transmitted to others.

“Undetectable = Untransmittable” (U=U)

If:

Viral load has been below detection limits for a sustained period under consistent ART, and
The person continues to take medication reliably,

then sexual transmission of HIV is effectively prevented according to current evidence. This has major implications for:

Stigma reduction.
Family planning and partnerships involving HIV‑positive individuals.

Prevention and Public Health Aspects

Preventing new HIV infections relies on individual measures and public health strategies.

Individual prevention

Safer sex

Use of condoms during vaginal and anal intercourse.
Knowledge of own and partner(s)’ HIV status.

Pre‑exposure prophylaxis (PrEP)

HIV‑negative people at high risk take antiretroviral drugs preventively.
Substantially reduces risk of infection when taken correctly.

Post‑exposure prophylaxis (PEP)

Short‑term ART after a suspected high‑risk exposure (e.g., needlestick injury, unprotected intercourse with high‑risk partner).
Must be started as soon as possible (ideally within hours, not later than a few days).

Safe handling of blood

Use of sterile needles and instruments.
No sharing of injection equipment.

Prevention of mother‑to‑child transmission

ART for the pregnant person.
Possible adjustments in delivery method and infant feeding depending on context and guidelines.
With appropriate measures, transmission risk can be reduced to very low levels.

Societal and global aspects

Screening and counseling

Anonymous or confidential testing.
Early diagnosis allows timely therapy and prevention of further transmission.

Education and destigmatization

Combatting misinformation and prejudice.
Ensuring affected individuals have access to care without discrimination.

Access to therapy worldwide

In many regions, limited access to ART remains a major challenge.
Global health programs aim to expand testing and treatment.

Why HIV Remains a Major Challenge

Despite great therapeutic progress, HIV remains a significant global pathogen:

No widely available, highly effective vaccine so far.
Lifelong therapy is required for most patients.
Latent reservoirs prevent complete eradication with current standard drugs.
Drug resistance can emerge and spread.
Social factors such as stigma, poverty, and limited healthcare access influence both spread and treatment success.

Understanding HIV as a virus and pathogen is fundamental for appreciating:

How a subviral particle can specifically damage the immune system.
How modern medicine can transform an almost always fatal infection into a chronic, treatable condition.
Why prevention, early diagnosis, and ongoing research remain essential.

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