Pathogenesis of HIV infection / AIDS

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

The receptor for HIV is the differentiation antigen CD4, as well as non-specific components that do not depend on the presence of CD4. CD4 is a glycoprotein with a molecular weight of 55,000, similar in structure to certain sections of immunoglobulins. The gp 120 virus protein has a similar structure, which determines the ability of HIV to penetrate the cell. The degree of damage to cells containing CD4 receptors depends on the density of these receptors on the cell membrane. Their density is highest 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 HIV to penetrate the cell. About 40 similar proteins have been isolated in humans, they are divided into alpha and beta chemokines. In 1995, Gallo's laboratory isolated a chemokine from CD8 lymphocytes and two proteins from macrophages. In 1996, Berger discovered a coreceptor for HIV, called CXCR4. In 1996, another coreceptor for HIV 1, CCR5, was discovered. It was found that people who have had long-term contact with HIV-infected people and do not become infected have mutations in the CCR5 receptor.

The human body contains 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 help of glycoprotein gр120, the virus is fixed on the surface of the target cell, and glycolprotein gр41 ensures the fusion of the viral envelope with the membrane of the target cell. Double-stranded RNA of the virus penetrates the cell, where the enzyme reverse transcriptase synthesizes single-stranded proviral DNA. Then double-stranded DNA is formed, which is introduced into the cell DNA with the help of integrase. Viral DNA becomes a matrix from which RNA is copied, assembling a new viral particle.

HIV Infectious Cycle

HIV penetration most often occurs through the mucous membranes of the urogenital system. The virus penetrates into CD4-expressing interstitial dendritic cells located in the cervical-vaginal epithelium, as well as into the lymph nodes of the pharyngeal lymphoid ring in the case of oral sex.

Types of cells affected by HIV

Tchp cells	Tissues and organs
T-lymphocytes, macrophages	Blood
Lagerhans cells	Leather
Follicular dermal cells	Lymph nodes
Alveolar macrophages	Lungs
Epithelial cells	Large intestine, kidneys
Cervical cells	Cervix
Oligodendroglia cells	Brain

However, clinical manifestations of primary HIV infection are mainly due to the subpopulation of the virus penetrating macrophages. HIV tropism to macrophages is determined by the interaction of gр120 with the CCR5 molecule present in the complex of chemokine receptors of macrophages. This subpopulation of the virus is accordingly called R5 in contrast to X4, which interacts with CXCR4 receptors of T-lymphocytes. HIV-infected cells merge with CD4+ T-cells, leading to the spread of the virus to regional lymph nodes, where the virus is detected after 2 days, and through the systemic circulation to distant organs (brain, spleen and lymph nodes) after the next 3 days after infection.

The intestinal mucosa is also a potential portal of entry for infection, as shown in a number of studies demonstrating the destruction of CD4 cells located in the intestinal mucosa, leading to a more disproportionately early loss of T cells in the gastrointestinal tract compared to the peripheral blood.

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

Immunopathogenetically, HIV infection manifests itself primarily by a deficiency of 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 virus-neutralizing antibodies. The number of circulating immune complexes increases, antibodies to lymphocytes appear, which further reduces the number of CD4+ T-lymphocytes. Autoimmune processes occur.

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

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

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

In patients with a deficiency of CD4+ lymphocytes, the functional insufficiency of CD8+ lymphocytes, NK cells, and neutrophils increases in the dynamics of the disease. The disorder of the immune status is clinically manifested by infectious, allergic, autoimmune, and lymphoproliferative syndromes. All this determines the clinical picture of HIV infection as a whole.

In the initial stages of the disease, the body produces virus-neutralizing antibodies that suppress freely circulating viruses, but do not act on viruses that are in cells (proviruses). Over time (usually after 5-6 years), the immune system's protective capabilities are depleted, and the virus accumulates in the blood.

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

Susceptibility to HIV in humans is universal and is determined by the geno- and 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 infection. Interracial differences in the dynamics of infection and progression of HIV infection have been identified. Representatives of the Negroid race are most susceptible to HIV, Europeans are less susceptible, and Mongoloids are the least susceptible.

The incubation period of HIV infection lasts from 2 weeks to 6 months or more, after which in 50-70% of cases the period of primary clinical manifestations occurs in the form of a general viral syndrome: fever (96%), lymphadenopathy (74%), erythematous-maculopapular rash on the face, trunk, limbs (70%), myalgia or arthralgia (54%). Other symptoms such as diarrhea, headache, nausea, vomiting, enlargement of the liver and spleen are less common. Neurological symptoms occur in approximately 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 research, 10 ⁸ copies / ml. Epidemiologically, the period of primary HIV infection is dangerous both due to the high infectivity of biological fluids of the body (blood, sperm, saliva, mucous secretions), and due to the lack of information of the carrier of the infection, who continues to lead a "high-risk" lifestyle. Determination of HIV RNA by the polymerase chain reaction method allows confirming the diagnosis. Antibodies to HIV may not be detected during this period; they appear 1 month after infection in 90-95% of infected people, after 6 months in the remaining 5-9%, and at a later date in 0.5-1%.

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

PGL is characterized by an enlargement of lymph nodes in two or more groups up to 1 cm or more in adults and up to 0.5 cm in children (except for inguinal lymph nodes in adults), persisting for at least 3 months. The cervical, occipital, and axillary lymph nodes are most often enlarged.

Clinically, two variants of the natural course of HIV infection are distinguished: typical progressive and long-term non-progressive. In the first group, with 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 unofficially includes HIV-infected individuals who were infected at least 8 years ago, but have a CD4 count over 500/cm3 and are not receiving 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 results in a 10-20-fold increase in the number of highly activated CD38+ and proliferating Ki-67+ CD4T cells expressing the chemokine receptor CCR5. These cells also actively secrete interferon gamma in response to stimulation by HIV antigens. When therapy is initiated late, HIV manages to destroy 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 resistant to HIV infection despite constant exposure to the virus. Genetic testing has shown that there are 9 genes potentially associated with HIV resistance. Among them, 4 were associated with T-cell function, including the CCR2 gene, CCR5, MIP1A, IL-2. Studies of the CCR5d32 allele, which contains a nucleotide deletion in the main HIV receptor, have shown a decrease in sensitivity to the virus, leading to 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 viral, bacterial, and fungal origin, which are still quite favorable and are relieved by conventional therapeutic agents. Recurrent diseases of the upper respiratory tract occur - otitis, sinusitis, tracheobronchitis; superficial skin lesions - localized mucocutaneous form of recurrent herpes simplex, recurrent herpes zoster, candidiasis of the mucous membranes, dermatomycosis, seborrhea.

Then these changes become more profound, do not respond to standard treatment methods, and become protracted. Patients lose weight, develop fever, night sweats, and diarrhea.

Against the background of increasing immunosuppression, severe progressive diseases develop that do not occur in people with a normally functioning immune system. WHO has defined these diseases as AIDS-indicating or opportunistic infections.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ]