THE IMMUNE SYSTEM-----------Julius.

20211026
Lecture objectives:
(a) Define immunity
(b) Name the tissues of the immune system
(c) Explain the cells of the immune system
(d) Describe the structural components of the HIV virus

(e) Identify the immune cells that have CD4 receptors

(f) Explain the clinical course of HIV disease

(g) Explain how the infection with HIV leads to a clinical disease
(h) Examine the events accompanying the symptomatic disease
and AIDS

(i) pathogenesis of disease caused by human immunodeficiency

virus (HIV)
Introduction
 What is immunity? Immunity is defined as resistance to disease, specifically
infectious disease.
 The collection of cells, tissues, and molecules
 The immune system is just that: a “system.” It is a network of protective
barriers, organs, cells, and molecules.
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Figure 1 Distribution of tissues of the immune system

Figure 2 Cells of the immune system

CD4+ cells are helper cells that activate B cells, killer cells, and macrophages (large
cell of immune system that engulfs, and digest cellular debris, foreign substances)
when a specific target antigen is present.
NB: CD means cluster of Differentiation
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Innate and adaptive immunity
The human defense system is grouped under:
(a) innate immunity: provides immediate protection against microbial invasion
(b) adaptive immunity: which develops more slowly and provides more
specialized defense against infections

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Structure of the HIV virus
An infectious HIV particle consists of two RNA strands within a protein core,
surrounded by a lipid envelope derived from infected host cells but containing viral
proteins (Fig. 3).
Figure 3 structure of the HIV virus

 The viral RNA encodes structural proteins, various enzymes, and proteins that
regulate transcription of viral genes and the viral life cycle

 HIV virus attaches to the cells of the immune system through special
markers called CD4 receptors
 The following immune cells have CD4 receptors
- T lymphocytes- CD4 cells
- Macrophages
- Monocytes
- Dendritic cells
Therefore, HIV infection of the CD4 cells causes cell dysfunction and death.
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How does the virus infect the body?
The life cycle of HIV consists of the following sequential steps:
a) infection of cells,
b) production of a DNA copy of viral RNA
a) integration viral RNA into the host genome,
b) expression of viral genes,
c) Production of viral particles
Figure 4 Life cycle of human immunodeficiency virus (HIV-1). The sequential steps
in HIV reproduction are shown, from initial infection of a host cell to release of
new virus particles (virions).

o HIV infects cells by virtue of its major envelope glycoprotein

o called gp120 (glycoprotein)

o Binds to CD4 and to particular receptors on human cells (receptors are

called chemokine receptors)
o There are two main receptors : CXCR4 and CCR5

o The major cell types that may be infected by HIV are

(a) CD4+ T lymphocytes,

 (b) macrophages,
(c) and, dendritic cells.
 After binding to cellular receptors, the viral membrane fuses with the host
cell membrane,
 The virus enters the cell’s cytoplasm
 Here the virus is uncoated by viral protease, and its RNA is released.
 A DNA copy of the viral RNA is synthesized by the viral reverse
transcriptase enzyme
 The DNA integrates into the host cell’s DNA by the action of the
integrase enzyme
 The integrated viral DNA is called a provirus
 The virus is then able to form a core structure, which migrates to the
cell membrane, acquires a lipid envelope from the host, and is shed as
an infectious viral particle, ready to infect another cell.
 The integrated HIV provirus may remain latent within infected cells for
months or years, hidden from the patient’s immune system
 Most cases of AIDS are caused by HIV-1 (i.e., HIV type 1)
 A related virus, HIV-2, causes some cases of the disease
Pathogenesis of AIDS
 AIDS develops over many years as latent HIV becomes activated and
destroys cells of the immune system.
 Virus production leads to death of infected cells, as well as to death
of uninfected lymphocytes, subsequent immune deficiencies, and
clinical AIDS
 The number of T cells lost during the progression to AIDS is greater
than the number of infected cells
 The depletion of CD4+ T cells after HIV infection is caused by a
cytopathic effect of the virus, resulting from production of viral
particles in infected cells, as well as death of uninfected cells

 
Figure 5 Pathogenesis of disease caused by human immunodeficiency virus (HIV).
The development of HIV disease is associated with the spread of HIV from the initial
site of infection to lymphoid tissues throughout the body.
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Viral load
  A viral load test measures the number of HIV viral particles
per millilitre of blood.
 A low viral load indicates that treatment is effective.
 A high viral load (≥ 1,000 copies/ml) in a person on
treatment indicates either that the medication is not being
taken properly or that the virus is becoming resistant to the
medication.
What happens on exposure to HIV infection?
There is 2-4 week period of intense viral replication and widespread of virus
characterized by:
a) High blood viral load, often greater than 1 million copies/ml.
b) But within the first 6 months to 1 year after infection, the persons’
immune response brings the viral load down to a steady level which
is sometimes called the viral load set point.
c) In the absence of ART (antiretroviral drugs), the viral load will
increase over the course of several years, and then rises more
rapidly when the patient develops symptoms.
d) The viral load set point can be used to predict HIV disease
progression; the higher the set point, the more quickly the patient
will progress to AIDS.

CD4 cell count

 There is rapid decline in CD4 count since;
a) The HIV virus destroys CD4+ T-cells.
b) There is destruction of mature CD4+ cells, CD4+
progenitor cells (i.e cells which has to differentiate into a
specific type cell) in bone marrow, the thymus, and
peripheral lymphoid organs; as well as CD4+ cells within
the nervous system, such as microglia.
c) The result of this destruction is failure of T-cell production
and eventual immune suppression.
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Immune depletion
a) The CD4+ count in the blood decreases remarkably during
primary infection, resulting to immunodeficiency.
 The CD4 T cell depletion is in twofold:
o Reduction in numbers
o Impairment in function
 The virus targets CD4+ cells in the lymph nodes and
the thymus during this time, making the HIV-infected
person vulnerable to opportunistic infections and
limiting the thymus’s ability to produce T
lymphocytes.
 HIV antibody testing using an enzyme-linked
immunosorbent assay (ELIZA) or enzyme
 immunoassay may yield positive or negative results
depending on the time of seroconversion.
 DNA PCR and RNA PCR will be positive, because
seroconversion can take up to 2–8 weeks to occur.
 The average time to seroconversion is 25 days.

b) During the asymptomatic stage (latent)

 Patients enter a stage of asymptomatic disease
phase lasting 2-10 years.
 Characterised by gradual decline in CD4 count
( rate depends on viral load)
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Long term non progressors
i. rare
ii. ≥ 10-15 years survival
iii. CD4 ≥ 500: low viral load

c) During the symptomatic disease and AIDS

 The viral load continues to rise causing;
(a) Increase demands on immune system as
production of CD4 cells cannot match
destruction
(b)Increased susceptibility to common infections
(URTI, pneumonia, skin etc)
(c) Late-stage diseases is characterised by a CD4
count ≤ 200cells /ul and the development of
opportunistic infections, eg selected tumors,
wasting, and neurological complications
How does the infection lead to a clinical disease?
The clinical course of HIV infection is characterized by several phases,
culminating in immune deficiency
(a)Acute HIV syndrome.
 Early after HIV infection, patients may experience a mild acute
illness
 Characterized by fever and malaise, correlating with the initial
viremia.
 This illness subsides within a few days, and the disease enters a
period of clinical latency.
(b)Latency
  During latency, there may be few clinical problems but usually
there is a progressive loss of CD4+ T cells in lymphoid tissues
and destruction of the architecture of these tissues.
 Eventually, the blood CD4+ T cell count begins to decline, and
when the count falls below 200 cells per mm3 (normal level
about 1500 cells/mm3), patients become susceptible to
infections and are diagnosed as having AIDS.
(c) Clinical AIDS
 The clinicopathologic manifestations of full-blown AIDS are primarily
the result of increased susceptibility to infections and some cancers, as
a consequence of immune deficiency.

Figure 6 Clinical course of HIV disease. A, Blood-borne virus (plasma viremia) is

detected early after infection and may be accompanied by systemic symptoms
typical of acute HIV syndrome. The virus spreads to lymphoid organs, but plasma
viremia falls to very low levels (detectable only by sensitive reverse
transcriptase–polymerase chain reaction assays) and stays this way for many
years. CD4+ T cell counts steadily decline during this clinical latency period
because of active viral replication and T cell destruction in lymphoid tissues. As
the level of CD4+ T cells falls, there is increasing risk of infection and other
clinical components of acquired immunodeficiency syndrome (AIDS)

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  The immune response to HIV is ineffective in controlling spread of the
virus and its pathologic effects
Therapy and Vaccination Strategies
 The current treatment for AIDS is aimed at controlling replication of HIV and
the infectious complications of the disease.
 Combinations of drugs that block the activity of the viral reverse
transcriptase, protease, and integrase enzymes are now being administered
early in the course of the infection.
 This therapeutic approach is called highly active antiretroviral therapy
(HAART) or combination antiretroviral therapy (ART).
 It has changed the clinical course of HIV infection, such that opportunistic
infections (e.g. by Pneumocystis) and some tumors (e.g. Kaposi’s sarcoma,
EBV-induced lymphoma), which were devastating complications in the past,
are now rarely seen.
 In fact, treated patients are living quite long life spans and are dying of
cardiovascular and other diseases that also afflict
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Summary of the lecture
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Learning activities
1. Illustrate the distribution of tissues of the immune system
2. Draw the cells of the immune system

3. Identify the immune cells that have CD4 receptors

4. Draw the structure of the HIV virus

5. Draw the life cycle of human immunodeficiency virus (HIV-1)
6. Summarize how the virus infect the body
7. Explain what happens on exposure to HIV infection?
8. Using an illustration depict the clinical course of HIV disease
9. Explain how the infection with HIV leads to a clinical disease
10.Examine the events accompanying the symptomatic disease and AIDS
11.Explain the reason behind the rapid decline in CD4 count

12.Draw the pathogenesis of disease caused by human immunodeficiency virus

(HIV)