Pathogen and virion structure
The human immunodeficiency virus belongs to the retrovirus family and the lentivirus (slow virus) subfamily. Of greatest clinical significance is HIV-1 — the culprit of the global pandemic, which originated from the chimpanzee virus. HIV-2, of simian origin, has a milder clinical course and is found predominantly in African countries.
The virion itself is about 100 nm in size. Externally, it is covered by an envelope with specific spikes consisting of glycoproteins:
- gp120 — the outer (surface) part of the spike;
- gp41 — the inner (transmembrane) part.
Beneath the envelope lies the matrix and a cone-shaped capsid. Inside the core are the genome, represented by two RNA strands, and key enzymes for replication: reverse transcriptase (p66/p51), integrase (p31–32), and protease (p10).
Reception mechanism and life cycle
The entry portals of the infection are most often the mucous membranes of the urogenital or digestive tract. The virus is first intercepted by the processes of dendritic cells: they transport it to regional lymph nodes, where they transmit it to the main targets — CD4+ T lymphocytes.
Cellular entry is a complex, multistep cascade:
- Binding: the viral protein gp120 binds to the primary receptor CD4 on the surface of the T lymphocyte.
- Coreceptor binding: following the initial contact, gp120 changes its conformation and binds to coreceptors (chemokine receptors CXCR4 or CCR5).
- Fusion: the gp41 protein ensures the fusion of the viral envelope with the cell membrane.
- Reverse transcription and integration: inside the cell, viral reverse transcriptase synthesizes DNA using RNA as a template. Then, integrase inserts this provirus into the host cell DNA.
Key feature of HIV: for successful genome insertion, the virus does not require the cell to divide. Due to this, latent infection reservoirs are formed in "dormant" macrophages and memory T cells.
Immune response and escape mechanisms
During the acute phase of infection, the body responds quite effectively: virus-specific CD4+ helpers and CD8+ T killers appear. Cytotoxic lymphocytes actively destroy infected targets, interrupting replication and reducing the concentration of the virus in the blood (viremia).
However, the virus possesses colossal variability and rapidly bypasses immune defense. The env gene, which encodes envelope proteins, mutates at an extremely high rate. The hypervariable V3 loop — the main target for neutralizing antibodies — changes especially quickly. The virus constantly alters its surface antigens, avoiding recognition.
In the chronic course, functional exhaustion of the immunity sets in. CD8+ cells lose their aggressiveness due to a deficiency of interleukin-2 (IL-2) produced by helpers. The immune response pathologically shifts from cellular (Th1) to humoral (Th2), which ultimately weakens antiviral defense.
Pathogenesis of AIDS: how immunity is destroyed
The main sign of HIV progression to the terminal stage — AIDS — is a catastrophic drop in the number of CD4+ T lymphocytes. The stage of clinical manifestations is recorded when their count drops below 200 cells per 1 µl of blood. Meanwhile, the immunoregulatory index (CD4/CD8 ratio) decreases from a normal value of 1 to 0.1–0.6.
Paradoxically, no more than 10–15% of lymphocytes in tissues and only about 1% in peripheral blood are actually infected in the body itself. The primary cell loss occurs due to other reasons:
- Apoptosis of uninfected cells. This is the main cause of immunodeficiency. Freely circulating viral proteins (e.g., soluble gp120 or the regulatory protein Vpr) bind to receptors on healthy T lymphocytes and trigger the cellular suicide program within them.
- Cytopathic effect. Direct destruction of the membranes of infected cells during the mass budding of new virions.
- Syncytium formation. The viral protein gp120 glues together the membranes of neighboring T cells, causing them to fuse into massive, non-viable multinucleated structures.
Briefly: answers to topical questions
What enzymes are contained within the core of the HIV virion, and what is the function of each?
- Reverse transcriptase (p66/p51) — uses viral RNA as a template to synthesize a single-stranded DNA copy and double-stranded proviral DNA.
- Integrase (p31–32) — inserts viral cDNA into the host cell DNA, forming a provirus.
- Protease (p10) — cleaves polyproteins into functionally active proteins; participates in the breakdown of capsid and nucleocapsid proteins during virus "uncoating".
- RNase (p15) — an enzyme contained in the nucleocapsid; its function is not specified in the cited sources.
What coreceptors does HIV use, and what is the difference between R5- and X4-tropic strains?
To enter, HIV uses chemokine coreceptors — CCR5 and CXCR4. Differences between the strains lie in their cellular tropism and dynamics:
| Strain | Coreceptor | Targets and features |
|---|---|---|
| R5 strains | CCR5 | Macrophages, dendritic cells, activated T lymphocytes, memory cells. Dominate in early stages. |
| X4 strains | CXCR4 | "Naive" T lymphocytes. Capable of causing syncytium formation, predominate in late stages. |
How are latent reservoirs of HIV infection formed?
A latent reservoir of HIV infection is formed after reverse transcription and integration of the viral cDNA into the host cell genome, resulting in provirus formation. As a result, the virus remains in a hidden, non-expressing state. The main reservoirs of latent infection are memory T cells and "dormant" macrophages. Macrophages and dendritic cells can also become hidden reservoirs of infection. In macrophages, virions can accumulate for a long time inside multivesicular bodies, and HIV can persist as proviral DNA integrated into the chromosome; in the latter case, it is inaccessible to cell-mediated immune mechanisms.
To remember the structure of the HIV spike: "120 outside, 41 inside." Glycoprotein gp120 is the outer cap that hooks onto the receptor, while gp41 is the transmembrane stalk that pierces the cell for fusion.
Class and exam questions
Does HIV require cell division for replication?
No. The viral enzyme integrase is capable of inserting proviral DNA into the genome of even those cells that are in a resting stage (e.g., inactive memory T cells).
How does the antibody profile change over the course of the disease?
Antibodies to envelope proteins (gp120) remain at a high level throughout the disease. However, antibodies to the internal protein p24 (the gag gene) become depleted and disappear in late stages, giving way to a renewed increase in viremia.
Do only infected T-lymphocytes die from HIV?
No, the vast majority of dying cells are uninfected CD4+ lymphocytes. Viral proteins trigger mass apoptosis in them, which leads to profound immunodeficiency.
What else to study on this topic
- Genetic structure of the virus: the role of regulatory genes tat, rev, nef.
- Changes in the cytokine profile and the dynamics of the Th1/Th2 ratio during chronization.
- Features of reception on dendritic cells involving DC-SIGN.
- Impact of the defective nef protein on the emergence of HIV-infected "long-term survivors".
- Spectrum of target cells: from macrophages to astrocytes and microglial cells.
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Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"
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