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Case 7: Immunology (HIV Immunopathogenesis), LOM Functions of T Cells…
Case 7: Immunology (HIV Immunopathogenesis)
Central Concepts of HIV Immuno-pathogenesis
Immunity to HIV occurs within hours of infection: with a Cytokines Storm, Cellular Adaptive and Innate immune response
Mobilization of protective immunity that ultimately fails
Overwhelming hyper-activation with microbial translocation
Lecticas: Dissolution of Lymphoid architecture
Lymph Nodes are crucial in the beginning and mounting of an immune response
If there is dissolution of the germinal centre, paracortical region, or micro architecture of the lymph node the patient will be unable to mount an immune response especially to a new pathogen
Bulk of virus is found in the Lymphoid Tissue where most immunity occurs
Tropism of HIV is the Lymphoid Tissue
Epidemiology of the HIV Epidemic in the Eastern and Southern Africa
Describe the Epidemiology of the HIV Epidemic in the Eastern and Southern Africa
An increase in the number of Antiretroviral therapy administered to HIV-positive patients results in a decrease in the number of AIDS-related death
South Africa has a high percentage of HIV/AIDS infections in the Eastern and Southern Africa region
High Prevalence in the general population
Describe the pattern of HIV Prevalence in the general population
When inspecting the HIV prevalence in the general population, the age at which there are peaks of Prevalence in the numbers of people infected with HIV in the population (both males and females) is between 35-39 years
Females and Males who are of child bearing age between the average age of 20-39 years have a 29.3% HIV prevalence in the general population
HIV Infection
Describe how HIV initiates infection in both Females and Males
Females
Female/Vaginal Tract is lined by a Columnar Epithelium
When the Virus comes across the Columnar epithelium, the Virus will trans-migrate across the columnar epithelial cells
After trans-migration across the epithelial cells, the virus will meet with the underlying Dendritic Cells and Langerhans Cells
These Antigen Presenting Cells (APC) also called the Dendritic cells and Langerhans cells will carry the HI virus to the nearest Germinal Centre of Lymph Nodes
And provide the initiation for the immune response by the T-Cells and Macrophages
This is the very beginning of the acute HIV-infection
Males
Male/Penile Genital Tract is lined by a Stratified Epithelium
Physical abrasion resulting in inflammation, causes the Stratified epithelium to become torn thus creating a passage way for the virus
Separation of the stratified epithelial cells allows for the virus to enter the internal environment
The Virus will then come into contact with the Langerhans cells in the actual passage when the Stratified epithelial cells become parted due to physical abrasion
NOTE: Another way in which epithelial cells of the vaginal or penile tract can part is through natural inflammation or an inflammatory response
Thus, causing the cells to naturally part because the Tight Junctions that hold the cells together are loosened
In the Foreskin: Langer Hans Cells
Describe the activity of Langerhans Cells in the Foreskin
Langerhans Cells are HIV targets
When looking at the foreskin tissue in a Keratin Stain, Langerhans cells are patrolling directly beneath the Epidermis
Therefore, when counting the number of Langerhans Cells in the foreskin tissue:
In the presence of a Sexually Transmitted Infection (STI) there is a higher number of Langerhans Cells both in the Outer and Inner Foreskin Tissue
This means that, potentially a STI increases the density of HIV-target cells (Langerhans Cells) in the epithelial tissue, thus creating a hot-bed of infection if there is traversing of HIV beyond the Keratin Layer
This is by way of an example of how important the interplay is between the:
Epithelium
HIV target cells (Langerhans cells)
Epidermal Keratin Layer which protects the epidermis from being infected with pathogens
HIV Transmission per coita act, and 95% confidence intervals, by follow-up interval
Outline the general pattern of HIV Transmission in Incident index partners, and Prevalent index partners
Highest incidence of transmission occurs during acute infection
Incident index partners
The highest number of transmission per 1000 coita acts occurs less than 5 months after index partner seroconversion
It is the highest because the viraemia (presence of virus in the blood) in individuals during early infections is higher than any other times during infections,
Except at the Very Late stage of the infection, where there is dissolution of the Lymph node architecture where the virus is sequestered (concealed)
Thus, causing dissemination/spilling out of the virus
Prevalent Index Partners
The lowest number of transmission per 1000 coital acts occurs between 10-40 months of follow-up during prevalent infection
This is known as the Sub-clinical or Latent Stage, because:
This is where there is the lowest number of transmissions
This is where the virus has already sequestered/concealed itself to the Germinal Centre of the Lymph Nodes, Lymphoid organs, Bone Marrow, Thymus etc.
And the Viraemia (presence of virus in the blood) is at it's lowest and therefore transmission is at its lowest
HIV Replication/Latent Reservoirs
Outline the HIV Replication/Latent Reservoirs
Blood has the lowest percentage of HI virus in circulation
The bulk of the HI Virus is in the germinal centres of the Lymph Node
It is important to note that Immunocompetent cells or CD4+ cells, circulating CD4 Cells are only a minority in the circulation
Bulk of CD4 cells are in the Lymph Nodes where the HI virus has sequestered itself and infects the CD4 cells
Therefore, when taking a CD4 count in a patient, and the CD4 count is diminished overtime of the infection
You are only detecting a small percentage of the larger population of the bulk pool of CD4 cells that reside in the Lymph Node tissues
HIV preferentially sequesters to the Germinal Centres where it attaches to the Follicular Dendritic Cells
Passage of CD4 cells is located in the Germinal Centres where the CD4 cells assist the B Cells become Antibodies
AS a result, the CD4 cells become infected with HIV, thus creating a hot-bed of HIV-infection
Central Role of CD4+ Cells
Outline the Central Role of CD4+ Cells
The Central Role of CD4+ Cells is as follows:
When Follicular Dendritic Cells (APC) carrying the HIV come into contact with CD4 Cells
It results in the infection of the CD4 cells, which leads to the natural expansion of the HIV-infected CD4 Cells
After the expansion of the HIV-infected CD4 Cells, the following may occur:
CD4 cells may become CD8 cytotoxic T Lymphocytes to provide protection
CD4 cells can assist the B Cells to produce antibodies
HIV and Immuno-pathogenesis
Describe the structure and characteristics of HIV
HIV is a Retrovirus and is made up of:
Double-stranded RNA enclosed within a Glycosylated Capsule
The target cells for HIV are cells expressing BOTH CD4 and CCR5 or CXCR4 (Chemokine receptors)
HIV has evolved to use these receptors to infect the "central command" of the immune system
And by doing so it ultimately disables the immune response
HIV infection is persistent and chronic
Laboratory Stages of HIV Infection
Describe The Laboratory Stages of HIV Infection
Routes of HIV infection are predominantly through the Mucosal Surfaces such as the:
Male and Female genital tracts
Rectal Surfaces
Gut Surfaces (Perinatal infection)
The acquisition of HIV can also be directly through the bloodstream from injection drug users
Whatever the route of infection, there has been a defined Stage of Infection based on laboratory diagnosis
For example: Fiebig Staging
Fiebig Staging is a 6 stage classification system that was formulated for staging early HIV infection based on the different times viral markers and host antibody responses emerge
Provide an Example of the Stages of HIV Infection
For example: At the acute stage of infection, which is prior to Seroconversion and where there was peak viraemia, it has been shown that there is a Cytokine Storm
This is where a number of pro-inflammatory cytokine levels are high, giving rise to Fever, Pharyngitis, Lymphadenopathy and
And as the Peak Viral Load equilibrates to a set point, the ELISA test shows the presence of anti-p24 antibodies and the production of large amounts of viral proteins.
These are detected in the Western Blots
The Viral Set Point is usually established around 3-6 months after initial infection
The Set Point is where the level of HIV replication in the host is relatively constant over time
It is though that this represent an equilibrium between the Host Immunity to HIV and the Rate of viral turn over
It is important to note that HIV is predominantly found in the Lymphoid Tissue (Germinal Centre) and not in the blood circulation
However, the higher the viral load in the blood plasma, the faster the disease progression occurs
Conversely, the lower the viral load, the slower the disease progression occurs.
In some individuals, HIV infection appears to be under control, and it is these individuals where biomarkers of immune control may be the most informative
The Immune Response to HIV
Explain the Immune Response to HIV which occurs within hours of Infection
The Immune Response to HIV infection occurs within hours of infection
There is an ordered series of events that occur upon the infection of HIV
These are as follows:
Transmission
Dissemination (Distribution widely)
Control
Seroconversion
After the Transmission of HIV to a new Host
There is Dissemination (Distribution) of the virus to the lymphoid tissue
A rapid increase in the viraemia occurs in the acute phase. (Fiebig Stage 1)
The fall in peak viraemia is thought to be due to the initial immune control
As a result, the Viral Load declines to a set point
A decline in CD4+ T cells coincides with the increase in viral load
HIV-specific CD8+ Cytotoxic T cell responses are thought to reduce systemic viral load and an increase in CD4+ T cells is often observed
HIV-specific binding antibodies appear after the reduction of viraemia, but antibodies are detectable by ELISA only later in acute infection (Fiebig Stage 3 onwards)
During chronic infection, CD4+ T cells decline slowly and the viral load remains relatively stable
Neutralising antibodies begin to appear only after about 3-6 months and continued HIV replication
Immune evasion exhausts the immune system leading to opportunistic infections and AIDS
HIV Transmission
Describe the HIV Transmission Step in the Immune Response to HIV Infection
HIV Infection is a "rare" event
In 80% of cases, transmission is thought to be established by a single virus
ALL microorganisms that penetrate the epithelial surfaces are met immediately by cells and molecules that can mount an innate immune response
Epidermal Langerhans cells are a subset of dendritic cells found in the squamous epithelium of the female vagina and male inner foreskin
Epidermal Langerhans cells are the first immune cells to make contact with HIV during heterosexual contact
Epidermal Langerhans cells express surface CD207 ( called Langerin) that captures the virus by binding to the gp120, which induces internalisation and degradation of virus particles
Activated Langerhans cells migrate to draining Lymph Nodes for antigen presentation to CD4+ and CD8+ T cells
In the process, CD4+ T cells can also be infected by the virus bound to Langerhans cell surface, this is called trans-infection
Langerhans cells may also express CD4 and CCR5 and can become infected themselves
Activated Langerhans cells produce pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha that can cause fever
Dilation and increased permeability of the blood vessels during inflammation leads to increased local blood flow
HIV Dissemination
Explain the process of HIV Dissemination during the immune response to HIV Infection
Afferent Lymphatic Vessels drain fluid from the tissues and carry antigen bearing cells from infected tissues to the lymph nodes where they are trapped
Follicles expand as the B lymphocytes proliferate to form germinal centres and the entire lymph node enlarge, this is known as Lymphadenopathy
HIV infected CD4+ T cells, that were activated in the genital draining lymph nodes, migrate to the mucosal tissues such as the gut and skin
Dissemination of the virus results in increased viral replication, mainly in the lymph organs and this leads to high viral loads in the peripheral blood
AS a result, there is also a rapid deletion of CD4+ T cells, particularly in the gut lymphoid tissues
Tissues macrophages express CD4 and CCR5 receptors and also become infected
Dendritic cells are CD4 negative but can capture HIV on surface CD209 molecules and mediate trans-infection of CCR5-bearing CD4+ T cells
Control of Viraemia
Outline the Control of Viraemia during the immune response to HIV Infection
The partial resolution of peak viral load observed during acute stage of HIV Infection is associated with robust T Cells immunity
Tissue Dendritic Cells then engulf virus detected in the extracellular spaces and present viral peptides by both HLA class I and II molecules in the lymph nodes to CD8+ and CD4+ T cells, respectively
Activated CD8+ cytotoxic T lymphocytes impart viral control by killing HIV infected cells and reducing viral replication
This response is not sufficient to eradicate the virus, but it reduces the viral load and allows CD4+ T helper lymphocytes number to increase
The absolute CD4+ count does not however return to baseline levels BUT it remains reduced
Seroconversion
Outline the Seroconversion during the immune response to HIV Infection
A multitude of immunological events have occurred prior to seroconversion, many resulting in the clinical symptoms of acute retroviral syndrome
Antibodies to HIV (Seroconversion) only begin to appear in the peripheral blood 4-6 weeks after transmission, but in rare instances they can take up to 3 months to appear
In order for HIV specific antibodies to be generated there must be sufficient presentation of HIV antigens to B Lymphocytes
This is achieved by capture of viral particles and proteins on the surface of follicular dendritic cells located in the lymphoid follicle
In addition, HIV-specific CD4+ helper T Cells are required to provide activation signals for B cells to differentiation into plasma cells
HIV Pathogenesis
Outline the pathological features of the HIV Infection
The main feature of HIV is that is a persistent viral infection
This means that the viral RNA genome after being Reverse-Transcribed to pro-viral DNA is integrated into the host CD4+ T target cells
Once the virus has become integrated, there is no ability of the infected individual to clear the infection
This persistent infection is the hallmark of the pathology that develops
The main lymphoid site of Viral Integration is the Lymph Node, especially the thousands that surround the gut, making up the Gut-Associated Lymphoid Tissue (GALT)
Mucosal Surfaces and Mucosal-Associated Lymphoid Tissue
Mucosal surfaces and the MALT are the tissue iterface with the environment
They are the frontline defence against many environmental antigens: Food antigens, Commensals, Viral, Bacterial and parasitic organisms
The Gut Lumen
Describe the structures of the Gut Lumen
The structures of the Gut Lumen is as follows:
Most of the breakdown and absorption of nutrients takes place in the small intestine
Numerous finger-like Villi project into the lumen of the gut
Villi are mostly made up of specialised absorptive epithelial cells called Enterocytes
There are also Goblet Cells that produce mucous to protect and lubricate the epithelial cell layer
The Crypts of Lieberkühn contain epithelial stem cells that generate new Enterocytes and other cell types
The stem cells are protected by the Paneth Cells that secrete antimicrobial defense molecules
Outline the function of the each of the structures found in the Gut Lumen
Enterocytes
Absorption of nutrients is done by the Enterocytes that have specialised microvilli on the luminal surface this is also known as the brush border
Goblet Cells
Goblet cells secrete mucous that protects and lubricates the epithelial cell layer
Crypts of Lieberkühn
Crypts of Lieberkühn contain epithelial stem cells that generate new Enterocytes and other cell types
Paneth Cells
Paneth cells secrete antimicrobial defense molecules to protect the epithelial stem cells
Lamina Propria
Lamina Propria contains immune cells that monitor the invasion of the epithelial lining by microorganisms
Describe the hallmark effects of HIV infection on the Lymphoid Tissue throughout the body
In the small intestine, luminal antigen sampling is carried out in the Secondary Lymphoid Tissue known as the Peyer's Patch
The surface is composed of specialised epithelial cells known as M Cells (microfold cells)
M Cells are capable of delivering intact antigens by transcytosis to antigen presenting cells
Antigen presentation and activation of the T and B cells occurs in the Lymphoid follicles in close proximity to the epithelial cell layer
Reduced Villous height
HIV Infection and the outgrowth of opportunistic organisms in the gut can lead to malabsorption of nutrients due to the disruption in the normal development of the intestinal villi
The absorptive surface area is reduced due to villous atrophy
This is thought to be a consequence of mucosal immune activation caused by HIV replication in the lamina propria CD4+ T Lymphocytes
Pro-inflammatory cytokines affect the growth of the epithelial cell layer
And there is an increase in the gut permeability to microbial organisms and antigens that can further stimulate the immune system and enhance HIV Replication
Reduced Cell Proliferation in Peyer's Patch
Antigen presentation in the Peyer's Patch is greatly reduced in HIV infection
This is due to the failure in maintaining the homeostasis of immune cells in the lymphoid follicles and the structure and function of the tissue
Depletion of CD4+ Helper T cells in the lamina propria reduces the recruitment of new T and b Lymphocytes into the lymphoid tissues
In the absence of immune cell proliferation in the lymphoid follicle the physical size of the Peyer's Patch is greatly reduced giving the gut a smooth appearance
Translocation
Activation of the Mucosal immune system due to HIV replication in CD4+ T helper lymphocytes in the Lamina Propria leads to a production of pro-inflammatory cytokines
This can cause a disruption of the gut epithelial cell development, leading to:
Villous Atrophy
Increased gut permeability to microbes and microbial antigens
Consequences of this are malabsorption of nutrients due to reduced absorptive surface area and the further stimulation of mucosal immune cells that can enhance HIV Replication
Describe the Hallmark effects of HIV infection on Lymphoid Tissue throughout the body
The Hallmark Effects of HIV Infection on Lymphoid Tissue throughout is as follows:
Within the Crypts of Lieberkühn are Peyer's Patches, which consist of M cells, that sample the contents of the lumen
This is a natural process that provides immunological protection to food and antigens
However, during HIV infection and persistence of the virus, there is a continual inactivation of infected cells leading to cell death
Dead cells are engulfed and phagocytosed resulting in further immune responses and inflammation
Another hallmark is the destruction of Lymph Node architecture, where Germinal Centres involute and disintegrate
Therefore, the disappearance of the germinal centres remove the immunological structures that enable B and T Cell responses to be formed
Along with Lymphoid architecture disintegration is the destruction of surrounding non-lymphoid Tissue such as Micro-villi, Villi, and Payer's Patches
As a result, the mucosal barrier will be unable to prevent the movement of microbial products and antigens into the systemic circulation
This results in systemic immune activation and a generalised chronic inflammatory condition of the host
This cause:
Lymph Node fibrosis
T Cells exhaustion
Monocyte Activation
Therefore, Activated Monocytes may then become HIV-infected
HIV infection of activated monocytes is the one possible link between Microbial Translocation and AIDS dementia
Where monocytes break through the blood brain barrier and serve to pass HIV into the brain where they can infect astrocytes
Consequences of Immune activation in HIV Infection
List the Consequences of Immune Activation in HIV Infection
Persistent HIV
Microbial Translocation
Co-infections (CMV and HCV)
Activation of pDC (Dendritic Cells)
Altered Treg/TH17
ALL of the above mentioned consequences result in Immune Activation
Immune activation causes:
Lymph Node Fibrosis
T Cell Exhaustion
Local inflammation driven by Monocyte activation
Lymph Node fibrosis and T Cell exhaustion results in impaired CD4 T cell recovery
This then may result in End organ disease such as CVD, Liver, and Dementia
T Cell exhaustion and Local inflammation driven by Monocyte Activation results in End-organ disease such as CVD, Liver Failure, and Dementia
NOTE: Microbial Translocation an directly give rise to impaired CD4+ T cell recovery
Outline the benefits of HIV Prevention in relation to the consequences of immune activation in HIV Infection
If an individual can prevent HIV Infection, they can prevent:
Persistent HIV infection
Microbial Translocation
Co-infections (CMV, and HCV)
Activation of pDC
Altered Treg/Th17
Thus, resulting in the prevention of Immune Activation
This then prevent:
Lymph Node activation
T Cell Exhaustion
Local Inflammation driven by Monocyte activation
As a result, this can all prevent: Impaired CD4 T cell recover and End-organ disease such as CVD, Liver failure and Dementia
HIV-induced Immune Action
HIV-induced Immune Action also results in:
Increased T-cell turnover and death
Monocyte/macrophage dysfunction
Polyclonal B cell activation - Hypergammaglobulinaemia
NK cell and T Cell dysfunction (Direct or bystander effect)
LOM
Functions of T Cells
Types and Functions of Antibodies
