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HIV Virus and the Human Immune System

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Brittannie Probst

on 21 July 2014

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Transcript of HIV Virus and the Human Immune System

In both the second and third lines of defense, leukocytes play a vital role in specific and non-specific defense. It is essential that these cells be able to differentiate between pathogens, infected body cells and non-infected cells.

The body relies on the presence of MHC (Major Histocompatability Complex) markers on the surface of all body cells to distinguish those cells as self cells from non-self cells.

MHC markers are examples of 'self molecules' and are proteins that have a structure similar to immunoglobulins (antibodies).

It is this way that the body mediates which cells should be destroyed by the immune system.

There are two classes of MHC markers: MHC I markers and MHC II markers.

Both are crucial for the efficiency of the immune system.
HIV and the
Human Immune System

HIV
(Human Immunodeficiency Virus)
A virus is a non-cellular pathogen that infects and destroys cells, interfering with their function.
Viruses are 'obligate intracellular pathogens', meaning that they require a host cell to replicate and survive.

This is done by the host cell engulfing the virus via phagocytosis, the virus piercing the cell membrane or the virus attaching to specific sites on the host cell membrane and then injecting nucleic acids, either DNA or RNA.
Once a virus has succeeded in infecting a cell, it will taker over metabolic processes (namely protein synthesis) in order to produce new viruses, which are released when the cell lyses.

A virion [virus, (s)] consists of a core of DNA/RNA surrounded by a protein coat (capsid).


HIV agents
HIV is a retrovirus, meaning it transports RNA into the host cell, which is then reverse transcribed into double stranded DNA, where the enzyme reverse transcriptase is used. This viral DNA integrates itself into the nuclear DNA of the host cell.

T helper cells are preferably infected. Macrophages are also at risk.

It is from this point that the viral DNA produces new viruses and the viral spread continues.

It is an
immunodeficiency disease,
meaning that it causes a defect in the immune system. This makes the body more susceptible to opportunistic diseases and cancers.
In this case, it causes T cell deficiencies.


Transmission of HIV

Bypassing the first line of defense
HIV is not readily transmitted through indirect contact, droplet contact or airborne transmission.

It survives in the bodily fluids of an individual and must bypass the first line of defense of the immune system through transmittal of bodily fluids such as:

Blood
. Sharing of hypodermic needles and blood transfusions bypass barriers such as intact skin and secretions from skin glands such as sebum and salt.
Semen
. Unprotected sex circumvents anal and vaginal secretions and pH and commensal organisms in the vagina. This is a particular problem if broken tissue or blood transmission is involved.
Vaginal fluids.
Breast milk.


In these fluids, HIV is both present as both free virus particles and in cells.

Once HIV is in an individual's bodily fluids, the virus binds to dendritic cells, which are found in mucocutaneous areas such as the mouth, penis, rectum, vagina and the upper gastrointestinal tract.

These cells are involved in the second line of defense and play an important role in the success of HIV.
Dendritic cell
Second Line of Defense
(General Function for all Pathogens, Innate)
Once the first line of defense has failed and the pathogen is inside the body, the body employs the second line of defense. This includes immune responses such as:
Inflammation
Phagocytosis
Interferon
Complement proteins
Similarly to the first line of defense, the second line of defense is
non-specific
, meaning that it acts the same on all pathogens that the body detects, regardless of whether the response is effective against the pathogen.

This is because the second line of defense is unable to distinguish one micro-organism from another.
MHC markers and antigens
play a vital role in this and will be discussed shortly.

This line of defense also does
not retain any memory
of pathogens it encounters and the response will be the same no matter how many times an individual is infected by a pathogen.
Cells Involved in
the Second
Line of
Defense
Inflammation
Inflammation is a process by which histamines are released from mast cells and cause local capillaries to expand.
This expansion has the effect of:

Causing vasodilation and increased blood flow to the area.
Capillaries become more permeable to platelets and leukocytes, increasing phagocytic action at the site of infection.

This process occurs in a number of stages:

1
. External barriers are breached.
2
. Mast cells, located under the skin and in blood vessels, are stimulated by damage to tissue.
3.
Mast cells release histamine.
4
. Histamine causes vasodilation and permeability of blood vessels, increasing platelet and phagocyte count at the site of infection.
5
. Phagocytes engulf pathogens and destroy them.
6
. Platelets cause blood clotting and are crucial for preventing blood loss and wound healing.
7
. This can cause swelling (a result of increased platelets and leukocytes), itchiness (caused by histamine), pus (a mixture of dead phagocytes and pathogen) and redness and hotness.
HIV in the Second Line of Defense
Phagocytosis
Phagocytosis is a form of endocytosis, the process by which a cell engulfs a solid. In the immune system, phagocytic cells are white blood cells that include macrophages, monocytes, basophils and neutrophils. These cells engulf a solid, in this case, the invading pathogen.

Phagocytes are chemically attracted to a site of infection (chemotaxis), whether the chemical is released by the body (eg. cytokines or histamine) or the pathogen.

Once in contact with the pathogen, a phagocyte will determine if the foreign particle is 'self' or 'non-self' by the presence of an antigen on the particle's surface.

If the phagocyte determines that a particle does not belong in the body (non-self), it will engulf it to form vesicles called phagosomes, where the particle is digested.

Antigen-presenting cells (such as dendritic cells, which will be seen in more detail in terms of HIV) that engulf a pathogen will display the foreign antigen on its own cell membrane. This is an important part of specific defense.
Phagocytes (green) engulfing yeast cells (red).
Cell - Mediated Response
T-cytotoxic, T-helper, T-suppressor and T-memory Cells
Humoral Response
B Plasma and B Memory Cells
Interferons
Interferons are a group of chemicals secreted by some viral infected cells.

During viral invasion, most cells release interferon into the extracellular environment to reduce the success rate of the virus. This is done by:

Making surrounding cells more resistant to the virus and reducing their chance of infection. These cells produce enzymes that prevent the virus reproducing inside the cell.
Interfering with virus replication inside an already affected cell.
Draws and stimulates macrophages to engulf infected cells.

Interferon is triggered by the presence of double stranded RNA, which is only found in viruses.
Types of Cytokines
Chemical Messengers
Comparison of the Innate and Adaptive Immune Response
The protein interferon
Effects of interferon
Complement Proteins
Proteins that Kill or Hinder Invading Microbes
MHC Markers
The concept of 'self' and 'non-self'
Complement proteins both directly kill and assist phagocytes in combating invading microorganisms.

To fight infection, they must be activated. This can occur by directly coming in contact with a pathogen or in tandem with the humoral response.
They function by:

Lyse cell membranes of bacteria and fungi. Released contents stimulate further leukocyte activity.
Coating and neutralizing viruses and bacteria, blocking antigen binding sites and making them easier to be engulfed.
Attracting leukocytes to the site of infection.
Making the pathogen more easily identifiable by binding to its cell membrane.

There are about 20 different types of complement proteins and they are constantly present in blood plasma.

Antibodies (discussed later) are a vital component of complement protein function.
Complement proteins causing a cell to lyse by puncturing the membrane
A cell being flagged by complement proteins.
An antigen is any foreign particle that initiates an immune response. On the molecular level, an antigen can be a fragment produced by a pathogen (such as toxins produced by bacteria) or found as surface markers on invading pathogens (usually proteins or carbohydrates).

By definition, an antigen is any molecule or molecular fragment that can be recognized by antigen receptors, including:
B-cell receptors
T-cell receptors
Antibodies.

These functions are part of the third line of defense and is how an adaptive immune response is initiated.
On pathogens such as viruses, in this case HIV, antigens are found on their outer coats.



MHC class I molecule
MHC class II molecule
MHC Class I Markers
MHC Class II Markers
All nucleated body cells present MHC class I markers on their cell surface.
If a particle does not have a MHC class I marker present on its cell, the body will attack it.

As well as detecting the patterns of pathogens (such as the presence of double-stranded RNA) This is how the second line of defense detects and attacks pathogens and other particles that the body does not recognize as 'self.'

In a viral infected cell, the cell will extract sections of the virus to display on its own MHC markers. This flags the cell as infected and a target for the immune system. This is called direct presentation.
As well as MHC class I markers, antigen presenting cells have the ability to express the presence of pathogens in the body by placing MHC class II markers on their surface.
This is done by the 'professional antigen presenting cells':

Dendritic cells
Macrophages
B cells

Phagocytes such as dendritic cells and macrophages ingest pathogens and their own surface markers (antigens) via phagocytosis and collect the antigens during digestion of the pathogen to externalise and display on their surface.

The role of antigen presenting cells and T-Helper cells in the adaptive immune response is vital.
Cells of the Third Line of Defense
Phagocyte:
Phagocytes are a form of white blood cell that engulf and destroy pathogens. They routinely perform phagocytosis but will move to a site of infection when stimulated by cytokines. Macrophages are antigen presenting cells and can detect microbes by following their chemical trail.
All white blood cells are formed in the bone marrow and differentiate into their separate functions from there.
Dendritic cells:
Dendritic cells are another form of antigen presenting cell that breaks down foreign material to process antigen material and communicate between the second and third line of defense. They are located in tissue in contact with the external environment and blood.
Natural Killer (NK) Cells
NK cells are lymphocytes that re cytotoxic, meaning they release agents that kill cells. In this case, NK cells induce host cell apoptosis. They provide a rapid response to flagged viral infected cells and tumors.
Mast Cells
Mast cells are important during inflammation and allergic responses involving antibodies, releasing histamine to attract phagocytes to sites of infection. They are mostly located under the skin.
Cytokines are chemical messengers released by certain types of leukocytes in order to communicate and coordinate the immune system during an infection. Cells that commonly release cytokines include macrophages, dendritic cells, B cells, T cells and mast cells. Cytokines include:

Interleukin-1
. Activates endolethial cells to release lymphocytes into the bloodstream.
Interleukin-2 and interleukin-4
. Encourages lymphocytes to proliferate and differentiate.
Interleukin-12 and interleukin-gamma.
Associated with inflammation.
Chemokines.
Attracts leukocytes to a site of infection.
Interferons.
Makes nearby cells more resistant to a viral attack.

Cytokines are usually released by cells stimulated by the characteristic surface markers of pathogens or damaged tissue.
Effects of Interleukin-2
Release of cytokine and presentation of an antigen by a stimulated cell
HIV begins its life cycle by infecting the immune system's leukocytes, where their ability to detect the antigens on the virus' surface, the MHC class II markers on the surface of 'self' cells and cytokines are essential to its spread throughout the body.
A 3-D representation of a HIV virus, with antigens in green.
Recognition of HIV
or
Once HIV has been transmitted past the innate physical and chemical barriers of an individual (first line), it comes in contact with second line of defense cells such as dendritic cells and macrophages, which are antigen presenting cells.

The role of these cells is to break down pathogens and externalize the antigen fragments among their membrane MHC makers (MHC class II). These cells then come in contact with T-helper cells, the target cell for HIV.

During the transfer of antigen information, HIV is also transmitted and infects T-helper cells, debilitating the humoral and cell-mediated response. HIV's affects on the third line of defense are crucial for its survival in the human body.

HIV has four stages, three of which will be investigated.
Macrophage
Infection of leukocytes
Third Line of Defense
Specific to an Antigen, Adaptive
When the second line of defense does not prevent infection, as is the case with HIV, the third line of defense is stimulated to fight the pathogen in junction with second line defenses and non-specific leukocytes.

The third line is
specific
, meaning that its response is structurally tailored to seek and destroy the antigens of a specific pathogen.

It also has
memory
, meaning that a second exposure to the same antigen produces a more rapid and larger response than the primary exposure.

The third line involves:

Cell mediated response
T-cells (helper, cytotoxic, memory).
Humoral response
B-cells (memory, plasma and their produced antibodies).

The primary response occurs after the first contact with the pathogen, although unlike the second line, the response is slow to develop. This means that the individual usually shows some symptoms of the disease.
Cell-mediated immunity is the resistance to a pathogen inside cells (namely viruses) as a result of cells.

T-effector cells do not have an impact on free-floating virus particles and only attack 'self' cells that have been flagged with the antigen on their MHC markers.

Communication Between the First and Second Line of Defense
The third line of defense is initiated by communication with the second line. This is done by antigen presenting cells and later T-helper cells. Professional antigen presenting cells (macrophages, dendritic cells) are usually the first leukocytes to come in contact with a pathogen.

1
. The pathogen is destroyed by an antigen presenting cell and its antigens are displayed on this cell's surface (on MHC class II markers).
2
. Cytokines are released by this cell to attract T-helper cells.
3
. This cell comes in contact with a T-helper cell, which recognizes the foreign antigen and binds to the cell's surface.
4
. The T-helper cell then releases interleukin-2 to stimulate other T-helper cells, T-cytotoxic cells and B cells to activate against the pathogen.
5.
This involves proliferation and differentiation of B and T lymphocytes in the lymph nodes.

Without notification from T-helper cells, T-cytotoxic cells and a majority of B cells will remain inactive against the pathogen they are programmed to attack.

This is why the effects of HIV on the adaptive immune system is such a problem.
T-helper Cells are the Link
T-cells and B-cells, like most leukocytes, are produced in the bone marrow.

T-cells are produced in the bone marrow but migrate to the thymus.
B-cells are produced and mature in the bone marrow but also move to the thymus for the duration of their adult life.
T-helper cell:
Act as messengers between innate immunity and adaptive immunity. They aid antigen presenting cells in signaling an adaptive immune response by releasing cytokines (interleukin-2) that stimulate the division of B cells into plasma or memory. They activate other T-helper cells and T-cytotoxic cells.
T-cytotoxic cell:
Are able to recognize specific antigen markers on infected 'self' cells (MHC class I) and binds to the surface, releasing a cytotoxic protein called
perforin
that destroys the membrane of the infected cell.
T-memory cell:
Remains long after the immune response. During a secondary exposure to a specific antigen, they proliferate into T-effector cells for a faster, larger immune response.
T-suppressor cell:
Comes into action once a pathogen has been destroyed and the adaptive immune response needs to be suppressed.
B-plasma cell:
Once stimulated by the antigen, produces antibodies that are specific against the antigen. These antibodies are released into the bloodstream
B-memory cell
: During differentiation and proliferation of B cells, a section of B cells do not differentiate into effector B cells but remain long after the infection to provide a larger and faster antibody response with each successive infection.
Cell-Mediated Immunity Flowchart
Invasion of a pathogen (eg. virus/bacteria). Presents an antigen to the immune system.
Antigen presenting cells (eg. dendritic cells) break down the pathogen and present its antigens on their cell surface. Releases interleukin-1 to attract T-helper cells.
T-helper cells receive antigen information from the antigen presenting cell by binding to its markers. They then release interleukin-2 to activate adaptive immunity involving other T and B cells.
Memory T cells are formed and remain in lymph nodes.
Effector T cells specific to the antigen are rapidly produced during a successive exposure.
A majority of T cells differentiate in the lymph nodes to form:
T-cytotoxic cells
T-helper cells
T-suppressor cells

T-cytotoxic cells leave the lymph nodes to fight infection. Releases interleukins and lymphokines that:
Destroy pathogens
Activates more T cells
Attracts and stimulates more macrophages
Increases inflammation
Antibodies
The humoral response is called so because the cells involved (B plasma and B memory cells) do not actually leave the lymph nodes but fight the pathogen by producing
antibodies,
protein molecules that leave the lymph nodes to circulate throughout the bloodstream (humor).

In humoral immunity, stimulated B-plasma cells produce antibodies (immunoglobulins) that are specific to the antigen infecting the body.

There are several different types of antibodies, such as IgM, IgG, IgA, IgD and IgE.

Unlike cell-mediated immunity, antibodies are ab to act on free pathogen particles.

Stimulation of B cells relies on the activity of T cells.


One of the reasons why adaptive immunity is considered specific is the structure of antibody variable regions (antigen-binding sites) to their antigen.
During differentiation and proliferation of B cells after they are activated, some turn into B-memory cells. B memory cells are essential for long-term immunity and during a seconday exposure to the same antigen will divide to produce plasma cells, specialised to make antibodies for the antigen at hand.
Antibodies are protein molecules produced by plasma cells and are designed to act on a specific antigen.

This specificity lies in the antigen binding site of an
antibody, where its receptors are structurally
tailored to bind to and inactivate an antigen.

Once this is done, the antigen can be easily
engulfed by innate leukocytes such as
macrophages.
Specificity, Similarities and Differences
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