Pathogenesis of HIV / AIDS

Each type of virus affects a certain type of cells. The ability of the virus to penetrate the cell is determined by the presence of a receptor on the target cell for the given virus, as well as the possibility of the virus genome to integrate into the genome of the cell. It is known that the cell can have receptors for various types of viruses and receptors for a specific virus can be on cells of various types.

The receptor for HIV is the differentiating antigen CD4, as well as nonspecific, independent of the presence of CD4 components. CD4 is a glycoprotein with a molecular weight of 55,000, similar in structure to certain regions of immunoglobulins. A similar structure has the protein of the virus gp 120, which determines the ability of the penetration of HIV into the cell. The degree of damage to cells containing CD4 receptors depends on the density of these receptors on the cell membrane. The highest density is found on the T-helper subpopulation of lymphocytes, which determines the pathogenesis of the disease. In addition to the main receptor for HIV-1 - CD4 - there are a number of co-receptors, in particular, chemokine receptors, necessary for the penetration of HIV into the cell. About 40 such proteins were isolated in humans, they were divided into alpha and beta chemokines. In the Gallo laboratory, in 1995, chemokine from CD8-lymphocytes and two proteins from macrophages were isolated. In 1996, Berger discovered a co-receptor for HIV, called CCCR4. In 1996, another co-receptor for HIV 1-CCR5 was discovered. It was found that long-term contact with HIV-infected and without being infected, have mutations in the CCR5 receptor.

In the human body, there are a number of immunocompetent, somatic and other cells that have receptors for HIV.

The HIV envelope contains human histocompatibility proteins of the first and second class, so the penetration of the virus into the body does not cause a rejection reaction. With the glycoprotein gpl20, the virus is fixed on the surface of the target cell, and glycolrothein gp41 ensures the fusion of the viral envelope with the membrane of the target cell. The double-stranded RNA of the virus penetrates into the cell, where the enzyme reverse transcriptase synthesizes idyne-chain proviral DNA. Then, double-stranded DNA is formed, which is inserted into the DNA of the cell using integrase. Viral DNA becomes a matrix from which RNA is being decommissioned, collecting a new viral particle.

HIV Infection Cycle

The penetration of HIV most often occurs through the mucosa of the genitourinary system. The virus is introduced into CD4 expressing interstitial dendritic cells located in the cervico-vaginal epithelium, as well as the lymph nodes of the pharyngeal lymphoid ring in the case of oral sex.

Types of cells affected by HIV

Tpp cells	Fabrics and organs
T-lymphocytes, macrophages	Blood
Lackergans cells	Leather
Follicular decrystalline cells	Lymphonoduses
Alveolar macrophages	Lungs
Epithelial cells	Large intestine, kidneys
Cervical cells	Cervix
Oligodendroglia cells	Brain

However, the clinical manifestations of primary HIV infection are mainly due to the subpopulation of the virus penetrating into macrophages. Tropism of HIV to macrophages is determined by the interaction of gpl20 with the molecule CCR5 represented in the complex of chemokine receptors of macrophages. This sub-hemolysis of the virus is named R5, in contrast to X4, interacting with CXCR4 receptors of T-lymphocytes. HIV-infected cells fuse with CD4 + T cells, leading to the spread of the virus in the regional lymph nodes, where the virus is detected after 2 days, and through the systemic circulation to the distant organs (the brain of the spleen and lymph nodes) the next 3 days after infection.

The intestinal mucosa is also a possible gateway to infection, which has been shown in a number of studies demonstrating the damage to CD4 cells located in the intestinal mucosa, leading to a more disproportionate early loss of T cells in the digestive tract as compared to peripheral blood.

Viremia in experimental animal models with intravaginal introduction of the virus was observed between 5 and 30 days of infection, reaching a maximum at the time of seroconversion. Recent studies using RT-PCR, sensitive to 4 copies / ml, showed that the period of rapid increase in viral load in 23 of 69 cases was preceded by 9-25 days with low-dose circulation (<100 copies / ml) of the virus.

Immunopathogenetically, HIV infection manifests itself primarily as a deficiency of the T- and B-links of the immune system. Polyclonal activation of B-lymphocytes leads, on the one hand, to hypergammaglobulinemia, and on the other hand to a weakening of their ability to produce a neutralizing antibody virus. The number of circulating immune complexes increases, antibodies to lymphocytes appear, which further reduces the number of CD4 + T-lymphocytes. There are autoimmune processes.

The total concentration of serum immunoglobulins increases, but the disproportion of the levels of subclasses of immunoglobulins is revealed. Thus, the content of IgG1 and IgG3 in patients increases, and the concentration of IgG2 and IgG4 decreases significantly. Obviously, the decrease in IgG2 levels is associated with a high susceptibility of patients to staphylococci, pneumococci, haemophilus influenzae.

Thus, the defeat of the immune system in HIV infection is systemic, manifested by deep suppression of the T- and B-links of cellular immunity. During the development of HIV infection, there are regular changes in immediate and delayed type hypersensitivity, humoral immunity and factors of nonspecific defense, functional activity of lymphocytes and monocytes / macrophages.

The level of serum immunoglobulins, circulating immune complexes, catabolism products of cellular receptors, characteristic changes in the nucleic acids of immunocompetent cells and the activity of the enzymes of the main metabolic cycles occur in them.

Nplndu with deficiency of CD4 + lymphocytes in the dynamics of the disease, the functional insufficiency of CD8 + lymphocytes, NK cells, neutrophils increases. Infringement of the immune status is clinically manifested by infectious, allergic, autoimmune and lymphoproliferative syndromes. All this determines the whole clinic of HIV infection.

In the initial stages of the disease, viral neutralizing antibodies are produced in the body, which suppress freely circulating viruses, but do not affect the viruses in the cells (proviruses). Over time (usually after 5-6 years), the protective capabilities of the immune system are depleted, the virus accumulates in the blood.

The cytopathic effect of HIV leads to the damage of blood cells, nervous, cardiovascular, musculoskeletal, endocrine and other systems, which determines the development of multi-organ failure, characterized by the development of clinical manifestations and the steady progression of HIV infection.

The susceptibility to HIV is universal and is determined by the genotype, phenotypic polymorphism of individuals, which can manifest itself both in limiting the possibility of HIV infection, and in accelerating or reducing the rate of development of clinical symptoms of the infection. Interracial differences in the dynamics of infection and progression of HIV infection have been identified. The most susceptible to HIV are representatives of the Negroid race, less - Europeans and the least - Mongoloids.

The incubation period for HIV infection lasts from 2 weeks to 6 months or more, after which in 50-70% of cases a period of primary clinical manifestations occurs in the form of a common viral syndrome: fever (9%), lymphadenopathy (74%), erythematous-maculopapular rash on the face, trunk, extremities (70%), myalgia or arthralgia (54%). Less common are other symptoms, such as diarrhea, headache, nausea, vomiting, enlarged liver and spleen. Neurological symptoms occur in about 12% of patients and are characterized by the development of meningoencephalitis or aseptic meningitis.

The acute phase of HIV infection lasts from several days to 2 months and often remains unrecognized due to the similarity of its manifestations with the symptoms of influenza and other common infections. In addition, in some patients it is asymptomatic. Microbiologically, this period is characterized by a progressive increase in the viral load in the blood, peripheral tissues and secreted fluids, exceeding, according to the research, 10 ⁸ copies / ml. Epidemiologically, the period of primary HIV infection is dangerous, both because of the high infectivity of body fluids (blood, sperm, saliva, mucous membranes) and due to the lack of awareness of the carrier of the infection, which continues to lead a "high risk" lifestyle. Determination of HIV RNA by polymerase chain reaction allows to confirm the diagnosis Antibodies to HIV during this period may not be detected, they appear 1 month after infection in 90-95% of infected, in 6 months-the remaining 5-9%, and at later dates - 0.5-1%.

The next period of HIV infection is characterized by the persistence of the virus in the body due to integration into the genome of the affected cells. On this. The stage of development of the virus-specific immunity occurs mainly due to CD8 + cytotoxic lymphocytes and is accompanied by a 100-1000 fold decrease in the amount of RNA of the virus in circulation to the equilibrium point and the resolution of acute viral symptoms in the patient up to 6 months. Much more often after acute infection, the stage of persistent generalized lymphadenopathy (PGL) begins, and in exceptional cases the disease immediately progresses to the stage of AIDS.

PGL is characterized by an increase in lymph nodes and two or more groups up to 1 cm or more in adults and up to 0.5 cm in children (with the exception of inguinal lymph nodes in adults) that last for at least 3 months. The most common are cervical, occipital, axillary lymph nodes.

Clinically, there are two variants of the natural course of HIV infection: typical progressive and prolonged non-progressive. In the first group, in the natural course of the disease, a progressive decrease in T-cells is observed, which in turn disrupts the development of the antiviral response.

The second group is unofficially attributed to HIV-infected individuals who were infected at least 8 years ago, but who have a CD4 count of more than 500 / cm3 and who do not receive antiretroviral therapy. A distinctive feature of the cytology of this group of patients is the presence of proliferative responses of HIV-specific T-helpers.

Recent studies of the response to primary infection have shown that early therapy after seroconversion leads to a 10-20-fold increase in the number of highly activated CD38 + and proliferating Ki-67 + cells of CD4T cells expressing the chemokine receptor CCR5. These cells also actively secrete interferon gamma in response to HIV stimulation by antigens. With the late onset of therapy, HIV succeeds in destroying the population of precursors of these cells, leading to a sharp decrease in the antiviral response and the inability to restore it.

A number of studies have also described the presence of a population of people who are not susceptible to HIV infection, despite constant contact with the virus. Genetic tests have shown that there are 9 genes potentially associated with HIV resistance. Among them, 4 were associated with the function of T cells, including the gene CCR2, CCR5, MIP1A, IL-2. Studies of the allele CCR5d32 containing a deletion of nucleotides in the main HIV receptor have shown a decrease in the sensitivity to the virus, leading to a slower progression and, thus, the formation of successful T-cell immunity against the virus.

Following these stages, the total duration of which can vary from 2-3 to 10-15 years, the symptomatic chronic phase of HIV infection begins, which is characterized by various infections of the viral, bacterial, fungal nature, which are still quite favorable and are stopped by conventional therapeutic means. There are repeated diseases of the upper respiratory tract - otitis media, sinusitis, tracheobronchitis; superficial lesions of the skin - localized cutaneous and mucous form of recurrent herpes simplex, recurrent herpes zoster, candidiasis of mucous membranes, dermatomycosis, seborrhea.

Then these changes become deeper, do not react to standard methods of treatment, gaining a protracted character. Patients lose weight, fever, night sweats, diarrhea.

Against the backdrop of increasing immunosuppression, severe progressive diseases develop that do not occur in a person with a normally functioning immune system. This disease is defined by the WHO as AIDS-indicator or opportunistic infections.

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