HUMAN IMMUNODEFICIENCY VIRUS

HIV
 1. Human Immunodeficiency Virus (HIV)
AIDS - Acquired Immune Deficiency Syndrome - End-stage HIV
Infection
Separate nosological form from 1981-1982.
R. Gallo, L. Montagnier (1983) - independently isolated retrovirus in
AIDS patients, different from the HTLV-I and HTLV-II viruses
A retrospective analysis of sera in the National Center for Infectious
Disease Control (USA) showed that the first cases of the disease
were in the 50s of the 20th century.
For the first time the disease originated in Africa, later spread to
Europe and America
 2. Characteristics of human immunodeficiency virus
Family. Retroviridae; Subfemily: Lentivirinae
Spherical shape 100-120 nm
Lipid sheath with spikes (gp 120 gp41):
                  gp 120 - binds CD4 receptors of T-lymphocytes
                  gp 41 - induces fusion (penetration), especially with CD4
receptor deficiency in some target cells
Matrix protein p17 / 18
Capsid (p24 / 25) cone-shaped
Genome: single-stranded "+" RNA; forms a complex of two identical
subunits connected by p9p7 proteins
Enzymes: reverse transcriptase, protease, endonuclease
 3. Types of Human Immunodeficiency Virus
There are 2 types of virus:
HIV 1 - the main causative agent of HIV infection and
AIDS (America, Europe, Asia);
HIV 2 - less virulent, less common (West Africa)
4. Structure HIV
 5. HIV genome: structural genes
Structural genes (products are part of the virion):
      * gag-genes - encode internal proteins (capsid and matrix)
      * env-genes - encode proteins of the outer membrane
(gp120, gp41)
      * pol-genes - encode enzymes
 6. HIV genome: regulatory genes
Regulatory genes (their products are not part of the virus):
* tat gene - transactivator of viral RNA transcription (high
transcription rate of viral structural and regulatory proteins)
      * rev-gene - transport from the nucleus of viral RNA; enhances
the transcription of structural proteins
      * vif-gene - enhances the budding of the virus and the
introduction into another cell (factor of infectivity of the virus)
      * nef – gene - can reduce the expression of the virus (transition to
the latent state)
 7. HIV variability
High variability!
• "Errors" in the work of reverse transcriptase
• Point mutations; deletions; inserts
• High variability is most characteristic of the env-gene (encode
gp120 and gp41) and the gag-gene (encode proteins of the capsid
and matrix)
•   In a patient, the virus genome changes during the course of the
disease
• Identified recombinant forms of HIV
 8. HIV antigenic properties
Almost all proteins of the virus have antigenic properties (of varying
severity):
• The glycoproteins of the coat - gp120 and gp41 (the most
immunogenic) high variability
                      
  * “Escaping" from antibodies
                        * problem in creating a vaccine

• Core and capsid proteins

• Proteins of some regulatory genes (nef)
 9. HIV resistance
• At room temperature, it retains infectious properties for up to 4-7
days (dried or in a liquid medium)
• T 56°С - inactivated after 30 minutes
• Boiling - inactivated after 1–5 minutes
• Sensitive: 3% solution of hydrogen peroxide, 1% solution of lysol,
0.5% solution of sodium hypochlorite, 70% ethanol
• Relatively resistant to UV rays and ionizing radiation
 10. In HIV infected, the virus is detected:
• Blood - in 0.1 ml to 104 viral particles!
• Although the infectious dose is not determined, there may be from
1 to 100 ID in the blood - I place
• Sperm, vaginal secretion - II place
• Saliva, CSF, tear fluid, urine, mother’s milk - contain a very low
concentration of the virus (saliva requires 400 ml to 4 liters for
infection), but if they have blood, the risk of infection increases
significantly!
 11. Methods and mechanisms of HIV transmission are
divided into natural and artificial.
Natural:
1) sexual - especially anal contact
              a) epithelium of the rectum and macrophages of the mucous
membrane (Langerhans cells) express CD4 receptors - a reservoir
of the virus is created
              b) abundant venous blood supply - with microtraumas the
virus enters the bloodstream immediately
        Risk group: homosexuals, heterosexuals, individuals prone to
promiscuous sexual relations;
 12. Natural Ways of HIV Transmission

2) from mother to fetus (75-90%):

              a) transplacental (main)
              b) during childbirth (during the passage of the birth
canal)
              c) when breastfeeding (extremely rare)
 13. Artificial HIV Transmission
I. Blood: whole (100%), blood products (serum, etc.) - but testing is
obligatory!
                        1. drug addicts (common syringes)
                        2. medical instruments (important - damaged mucous
membranes, skin)
                        3. household tools (blades, manicure tools,
toothbrushes, tattoo needles, etc.)
II. Organs are transplants (but verification is obligatory!)
III. Artificial insemination
 14. Ways of transmission :
Contact-household, transmissive, airborne, food - did not receive
confirmation!

All infected get sick, all sick die!

 15. Immune target cells for HIV
1. T-helpers (CD4-receptors) - the virus multiplies in them!
             * activated! (even the infectious process of another etiology)
             * can "catch" from macrophages during the presentation of
HIV antigens
  2. Monocytes and macrophages incl. rectal macrophages
(Langerhans cells) (they can “become infected” by phagocytosis
of Ag-HIV-Ab complexes) - they are not accompanied by a
cytopathic effect, the virus persists in them!
3. Immunocompetent cells of the spleen, Kupffer cells of the liver
(can be "infected" by phagocytosis of the Ag-HIV-Ab complexes)
 16. Non-immune HIV Target Cells
With the penetration of the virus plays an important role gp41!
       1. Glial cells of the CNS
       2. Neurons of the central and peripheral NS
       3. Vascular endothelium
       4. Epithelium of the mucous membrane of the rectum
       5. Platelets
Target cells must be activated: insolation, radiation, stress, etc.
17. HIV reproduction scheme
 18. HIV reproduction
The main reservoir of the virus is lymphoid tissue:
      it constantly reproduces the virus, even in its early stages
• Reproduction mainly in T-helpers:
     sporadically and not in all cells!
• In monocytes / macrophages, the virus multiplies with moderate
intensity, does not cause CPE when exiting - cells become a
reservoir of HIV
 19. HIV reproduction
• Activation of the provirus: * synthesis of viral RNA
                                                 * expression of viral Ag (proteins)
                                                 * exit of virus particles
• Activation can occur under the action of:
                                                 * toxic substances
                                                 * radiation, insolation
                                                 * immunomodulators
                                                 * virus transactivators (hepatitis
B, adeno-, herpes viruses, etc.)
 20. Pathogenesis of HIV
Stage I - incubation period: until the onset of an acute clinic or the
appearance of antibodies
• Duration - from 3 weeks to 3 months or up to 1 year
• Corresponds to the period of introduction of HIV into target cells
• The virus is in a state of provirus or is very limitedly replicated
(Ag-p24 and virus particles circulate) - primary viremia
• Antibodies may appear by the end of the period
   *** The period of HIV integration may be accompanied by fever,
Flu-like symptoms, etc.
 21. Pathogenesis of HIV (continued)
Stage II - accompanied by a steady decline in T-helper
immunosuppression!
                     2 forms: asymptomatic and acute
I. Asymptomatic - a virus in a state of provirus or limited replication
                * detected Ab or Ag (p24) of virus
                * Duration up to 10-15 years
 22. Pathogenesis of HIV (continued)
II. Acute clinic - intensive reproduction of the virus
      * Ab not detected!
      * detected: virus RNA (PCR), Ag (p24)
      * Clinical manifestations: SARS, nephropathy, diarrhea,
encephalopathy, an increase in lymph nodes, etc.
      * Duration: from several days to 2-4 weeks
      * Infected person can die!
 23. Pathogenesis of HIV (continued)
• Stage III: * the addition of a secondary infection on the
background of immunosuppression
                           * CNS lesions (dementia)
                           * tumor processes

• Stages I - III: HIV Infection

 24. Pathogenesis of HIV (continued)
• Stage IV (terminal) - AIDS:
                          * opportunistic infections
                          * progressive exhaustion
                          * specific oncology (Kaposi's sarcoma)
*** In children, this may look like unusual, frequent infections that
are not considered opportunistic: recurrent pneumonia, tuberculosis,
etc.
*** In adolescents - developmental delay
 25. Causes of immunosuppression in HIV :
1. Reducing the number of T-helper cells:
    * destruction during virus replication
    * Antibody-dependent cytolysis (K-cells)
    * cellular immune response (T-killers)
                                              gp120 is expressed on the membrane
or binds to CD4 during circulation
     * damage to progenitor cells by a virus
  2. Disturbance of the regulatory functions of T-helper cells -
cytokine production
 26. Causes of immunosuppression in HIV :
3. Infection of macrophages abnormality of their
functions:
                     * antigen presentations
                     * regulatory function - impaired production of
interleukins and other mediators
                     * phagocytosis
  4. Polyclonal activation of B-lymphocytes - spontaneous
production of nonspecific immunoglobulins
 27. Causes of damage to organs and systems in HIV
• Dysregulation of immune surveillance (tumor processes)
• CPE connected with the HIV virus (central and peripheral
nervous system, etc.)
• Destruction under the action of circulating immune complexes
(central and peripheral nervous system, etc.)
• Autoimmune processes (central and peripheral nervous system,
etc.)
 28. HIV immunity
• Immunosuppression
• The virus “escape" the immune system:
•                   * genome integration with minimal expression
•                   * high variability
• Antibodies are produced, but do not have protective
properties (they have only diagnostic value)
• The main factor inhibiting the infection is cellular immune
responses (T-cells)
 29. Laboratory diagnosis of HIV
1.Virological method (virus isolation) - cultivation on T-cell
lymphoblastic lines with subsequent identification (CPE, virus
RNA, reverse transcriptase activity, Ag-p24)
2. Genetic method - detection of viral DNA (hybridization; PCR);
and RNA (reverse PCR)
3. Immunological method - detection of Ag p24 (ELISA)
4. Detection of antibodies to viral Ag: gp120, gp24, gp41 - ELISA,
IF, immunoblotting
                                  *** antibodies in 95% of cases appear 5-8
months after infection; extremely rare - after 2 months
 30. Laboratory diagnosis of HIV in children
Maternal antibodies (IgG) circulate in a child up to 1 year!

It is advisable to isolate the virus or its nucleic acids.

         * up to 1 week - positive result 30-35%
         * 3-6 month old children - positive result 90-100%
Detection of Ag-p24 - 85-95% positive results in 4-6 months old
babies
Detection of IgA in serum and urine (formed in the body of the fetus)
- a significant increase in Ab titers detected in children older than 3
months
 31. HIV etiotropic therapy
Reverse transcriptase inhibitors:
     * nucleotide analogues - competition with nucleotides
     * inhibitors directly binding the enzyme
HIV protease inhibitors - blocking proteins cutting into functional
proteins
Perspectives:
      * interaction with regulatory proteins of HIV
      * blocking the assembly and maturation of daughter populations
 32. HIV immunization
Vaccination problem associated with:
                * feature of pathogenesis - immunosuppression, variability
of the virus, DNA integration, the need to induce a killer T-
response, etc.
                * lack of adequate laboratory models
Perspective directions:
            * recombinant vaccines (based on other viruses)
* live vector vaccines (bird pox virus)
* subunit vaccines (gp120 - VaxGen)