What is AIDS (Acquired Immune Deficiency Syndrome)?
Acquired Immune Deficiency Syndrome (AIDS, Acquired Immunodeficiency Syndrome, English AIDS) is a condition that develops on the background of HIV infection (eng. Human immunodeficiency virus, HIV) and is characterized by a decrease in the number of CD4 + lymphocytes, multiple opportunistic infections and non-infectious diseases. In fact, is the terminal stage of HIV infection.
Causes of AIDS (Acquired Immune Deficiency Syndrome)
AIDS is caused by a human immunodeficiency virus belonging to the family of retroviruses, the genus of lentiviruses.
Like all retroviruses, HIV has a replication feature called reverse transcription, and the ability to infect human blood cells that have CD4 receptors on their surface (CD4 + T lymphocytes, macrophages).
The virus envelope consists of a bilayer lipid membrane, on the surface of which there are a number of proteins, such as:
gp41 – transmembrane glycoprotein, TM (Transmembrane glycoprotein) and
gp120 is a surface glycoprotein SU (Surface glycoprotein).
Inside the “core” of a virus consisting of the p17 matrix protein and the p24 capsid protein, there are two single-stranded virion RNA molecules and a number of enzymes:
- reverse transcriptase, RT (Reverse transcriptase);
- integrase (IN);
- protease (PR).
Pathogenesis during AIDS (Acquired Immune Deficiency Syndrome)
With the help of gp120 (surface glycoprotein), HIV attaches to the antigen-CD4 receptor and co-receptor located on the surface membrane of cells. For T lymphocytes, the co-receptor is CXCR-4, and for macrophages, CCR-5.
The cell membranes of the cell and the virus fuse, the virus enters the cell, where the viral RNA is released from the capsid and begins using reverse transcriptase, copying two strands of DNA onto the viral RNA (reverse transcription).
The produced DNA penetrates into the nucleus of the host cell and is integrated by the integrase enzyme into the host chromosome. With the help of RNA polymerase, the synthesis of the viral genome and messenger RNA of viral proteins (English RNA messenger) begins. Viral enzymes and structural proteins are read from messenger RNA on the ribosomes of the cell.
The synthesized RNAs leave the cell nucleus into the cytoplasm, where the formation of a new virus begins. The viral genome orders the enzyme – protease, and with the help of gp41 and gp120 a new viral envelope is formed. New viral particles bud off from the cell surface, capturing part of its membrane, and viruses enter the bloodstream, and the host’s CD4 + lymphocyte dies.
During the acute phase of HIV infection, the absence of a specific immune response allows the virus to actively replicate and reach high blood concentrations. The virus colonizes various tissues, primarily the organs of the lymphatic system, and destroys CD4 lymphocytes.
In addition to CD4 lymphocytes (helpers), CD8 lymphocytes and macrophages, the virus can infect other cells as well: alveolar macrophages of the lungs, Langerhans cells, follicular dendritic cells of lymph nodes, oligodendroglial cells and astrocytes of the brain, intestinal epithelial cells.
In lymphoid tissue, HIV multiplies throughout HIV infection, affecting macrophages, activated and resting CD4 lymphocytes, follicular dendritic cells. The number of cells containing proviral DNA in lymphoid tissue is 5-10 times higher than among blood cells, and HIV replication in lymphoid tissue is 1-2 times higher than in blood. Thus, the lymph nodes are the main reservoir of HIV.
In addition, the virus remains in the dendritic cells of the lymph nodes for a long time after a period of acute viremia and is also a reservoir of infection.
For the activation of CD8 lymphocytes and the formation of antigen-specific cytotoxic T-lymphocytes, it is necessary to present the peptide antigen in combination with the human leukocyte antigen of class I (English en: Human leukocyte antigen). Dendritic cells are required for the initiation of primary antigen-specific reactions. They capture antigens, process and transfer them to their surface, where, in combination with additional stimulating molecules, they activate T-lymphocytes. Infected cells often do not secrete additional stimulating molecules and therefore are not able to induce the formation of a sufficient number of response cells (B- and T-lymphocytes), the function of which depends on dendritic cells.
After completion of reverse transcription in the CD4 lymphocyte, the viral genome is represented by non-inserted proviral DNA. For the insertion of proviral DNA into the genome of the host cell, and for the formation of new viruses, activation of T-lymphocytes is required. Contact of CD4 lymphocytes and antigen-presenting cells in lymphoid tissue, the presence of viruses on the surface of follicular dendritic cells, and the presence of pro-inflammatory cytokines (IL-1, IL-6 and TNFα) promotes and supports HIV multiplication in infected cells. Therefore, lymphoid tissue is the most favorable environment for HIV replication.
Several genetic factors can prevent HIV infection. For example: People with mutations in CCR5 (coreceptor of M-tropic virus strains) are little or not at all susceptible to M-tropic strains of HIV-1, but are infected with T-tropic strains.
Homozygosity for HLA-Bw4 is a protective factor against disease progression. Heterozygotes for HLA class I loci develop immunodeficiency more slowly than homozygotes.
Studies have shown that carriers of HLA-B14, B27, B51, B57, and C8 have a slower infection progression, while carriers of HLA-A23, B37 and B49 develop immunodeficiency rapidly. All HIV-infected with HLA-B35 did not develop AIDS earlier than 8 years after infection.
Studies have also shown that sex partners who are not HLA class I compatible have a lower risk of HIV infection through heterosexual intercourse.
Immunity in AIDS
In the acute phase of HIV infection, at the stage of viremia, there is a sharp decrease in CD4 + T-lymphocytes due to the direct lyzing action of the virus and an increase in the number of copies of viral RNA in the blood.
After that, the stabilization of the process is noted with a slight increase in the number of CD4 cells, which, however, does not reach normal values.
The positive dynamics is due to an increase in the number of cytotoxic CD8 + T-lymphocytes. These lymphocytes are able to destroy HIV-infected cells directly by cytolysis without limitation by the human leukocyte antigen class I (Human leukocyte antigen-HLA).
In addition, they secrete inhibitory factors (chemokines), such as RANTES, MIP-1alpha, MIP-1beta, MDC, which prevent the virus from multiplying by blocking coreceptors.
HIV-specific CD8 + lymphocytes play a major role in the control of the acute phase of HIV infection, however, in the chronic course of infection, it does not correlate with viremia, since:
- The proliferation and activation of CD8 + lymphocytes is dependent on antigen-specific CD4 T-helper cells.
- CD8 + lymphocytes can also become infected with HIV, which can lead to a decrease in their number.
Acquired immunodeficiency syndrome is the terminal stage of HIV infection, which develops, in most patients, when the number of CD4 + T-lymphocytes falls, blood is below 200 cells/ml (the norm of CD4 + T-lymphocytes is 1200 cells/ml).
CD4 + cell depression in HIV infection is explained by the following theories:
- Death of CD4 + T-lymphocytes as a result of the direct cytopathic action of HIV
- HIV primarily affects activated CD4 lymphocytes, and since HIV-specific lymphocytes are among the first cells to be activated during HIV infection, they are among the first to be affected
- Alteration of the cell membrane of CD4 + T-lymphocytes by the virus, which leads them to fusion with each other to form giant syncytia, which is regulated by LFA-1 (Lymphocyte function-associated antigen 1)
- Catastrophe of CD4 cells by antibodies as a result of antibodies-dependent cellular cytotoxicity (ADCC-antibody-dependent cellular cytotoxicity)
- Activation of natural killer cells
- Autoimmune disaster
- Binding of the gp120 virus protein to the CD4 receptor (masking the CD4 receptor) and, as a result, the inability to recognize the antigen, the inability of CD4 to interact with HLA class II
- Programmed cell death
- Anergy of the immune response (Greek – idleness, idleness)
In HIV infection, B-lymphocytes undergo polyclonal activation and secrete a large amount of immunoglobulins, TNF-α, interleukin-6 and DC-SIGN lectin, which promotes the penetration of HIV into T-lymphocytes.
In addition, there is a significant decrease in interleukin-2, produced by type 1 CD4 helper cells, which is critical in the activation of cytotoxic T-lymphocytes (CD8 +, CTL) and the suppression of the secretion of interleukin-12 by macrophages, a key cytokine in the formation and activation of type 1 T-helpers. and NK lymphocytes (Natural killer cells).
Antibodies to HIV
According to some reports, in 99% of those infected, antibodies are detected within the first 12 weeks (6 – 12 weeks) after the initial contact with the virus. According to other data: in 90-95% within 3 months after infection, in 5-9% – after 6 months, 0.5-1% – at a later date).
The period with a false negative antibody result is called the “window period” during which an infected person may already be the source of infection.
The first antibodies to be detected are the “gag” (group antigen) proteins of HIV – p24 and p17, as well as the p55 precursor. The formation of anti-p24 antibodies is combined with a decrease in the levels of free p24 antigen detected in the blood before the appearance of antibodies.
Anti-p24 antibodies are followed by antibodies against the Env (Envelope) proteins – gp160, gp120, p88, gp41 and the “pol” gene (Polymerase) – p31, p51, p66.
Antibodies against genes “vpr”, “vpu”, “vif”, “rev”, “tat”, “nef” can also be detected.
The most studied antibodies are antibodies directed against “Env” proteins – gp120, gp41. They fall into two classes: type-specific and group-specific.
Another group of anti-gp120 antibodies, involved in antibody-dependent cytotoxic action (ADCC) and the destruction of HIV-infected CD4 + cells, can also destroy uninfected cells whose receptors are bound by free gp120 circulating in the blood – an effect named: Innocent bystanders (Bystander killing).