Case Study: Human Immunodeficiency Virus

HIV – Human immunodeficiency virus
What is the causative agent of AIDS?
Retrovirus
What type of virus is HIV?
100-120nm
What is the diameter of HIV?
2 single strands of positive sense RNA
What is the genetic material of HIV?
Yes
Does HIV have a lipid envelope?
p24
gp120
gp41
reverse transcriptase
integrase
protease
What are the main proteins of HIV? (6)
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Mucosal surface
Injected by contaminated needles
What are the two most common ways HIV enters the body?
Via sexual intercourse
What is the main way HIV is transmitted?
It is relatively labile
Why is HIV particularly infectious?
Th cells
What are the target cells of HIV in the body?
CD4
What molecule on the surface of Th cells does gp120 on HIV bind to?
gp120
What molecule on HIV binds to the CD4 of Th cells?
Fusion
What mechanism does HIV use to enter a host cell?
Irreversible conformational changes in envelope glycoproteins allowing fusion of the viral envelope with the cell membrane
What does interaction of the virus with CCR5 cause? …What does this allow?
They have a high expression of CCR5
Why are memory CD4+ T cells the primary target of HIV?
They are CD4+ and a surface HIV receptor
Why can dendritic cells also be infected by HIV?
Migrate to local lymph nodes and present processed peptides to Th cells – virus comes into contact with CD4 and CCR5 and infects
What do the dendritic cells do when hey become infected with HIV?
Lymph nodes
Primary lymphoid organs
Mucosal surfaces (especially GALT)
Where does HIV migrate to following initial infection?
Virus in the blood
What is viraemia?
Viraemia
What does infection of large number of Th cells lead to?
Acute
Chronic
AIDS
What are the 3 phases of infection of HIV?
-Production of virus by Th cells leads to detectable viraemia at 7-14 days after infection
-Increase in Tc cells to HIV infected cells
-Antibodies evolve to become against gp41 and gp120
-Levels of circulating Th cells decreases
-Latently infected Th cells and DC cells harbouring the virus remain
-Level of viraemia settles to set point
What events occur in the acute phase of infection with HIV? (6)
7-14 days after infection
When does the production of viruses by Th cells lead to detectable viraemia?
Increased infection of other areas of the body
Increased transmission
What does a higher level of viraemia lead to? (2)
10-100 fold
2-6 months
By how much does the action of Tc cells specific to HIV infected cells reduce the viral load? …Over how long?
p24
What antibodies to HIV originally specific to?
gp41
gp120
What do p24 specific Anti-HIV evolve to become specific to? (2)
Anti-gp41
Anti-gp120
What antibodies persist at high levels throughout life? (2)
Once viraemia has greatly decreased
When do neutralising antibodies appear?
Th cells gradually decrease further
Viraemia gradually increases
What happens in the chronic pause of infection of HIV? (2)
A point of equilibrium that the viral load settles to after the acute phase of infection
What is the set point?
The balance between production of new virions and control by the immune system
What does the set point represent?
The period of infection where there are no symptoms
What is the clinical latency period?
200 cell/mm^3 (or less)
At what CD4 count is a patient considered to be in the AIDS phase of HIV infection?
Acquired Immunodeficiency Syndrome
What does AIDS stand for?
Few months – 10 years
What is the range of times that a patient can take to progress into full-blown AIDS?
Long-term nonprogressors
What are patients that take a long time to progress into full-blown AIDS termed as?
Death of CD4+ T cells
What is the key event that leads to the immunodeficiency associated with AIDS?
-Direct death of infected Th cell as the result of a massive infection
-Apoptosis of Th cell mediated by Tc recognising that the cell is infected
What are the main mechanisms of Th cell death in AIDS? (2)
Together with DCs, it control the development and function of most immunological cell types
Why does the depletion of Th cell from the body lead to such immunodeficiency?
These cells affect the early differentiation of Th0 cells to Th1 and Th2
Disruption of this disrupts all immune responses
How can infected dendritic cells cause some of the immunodeficiency associated with AIDS?
-Infection of thymocytes leading to decreased output of CD4+ T cells
-Changes to thymus stromal cell function
-Loss of tissue architecture in the thymus
-Bone marrow depression
What are the main changes that occur in primary lymphoid tissues the contribute to the immunodeficiency associated with AIDS? (4)
Polyclonal activation of Tc cells and B cells
Reduction in activation of Th cells
What are the main changes that occur in secondary lymphoid tissues the contribute to the immunodeficiency associated with AIDS?
Around 2-8 weeks after exposure
When do symptoms of HIV infection first occur?
(Infectious mononucleosis like illness)
-Fever
-Maculopapular rash
-Sore throat
-Night sweats
-Malaise
-Lymphadenopathy
-Diarrhoea
-Mouth ulcers
-Genital ulcers
What are the common clinical symptoms presented with an HIV infection?
Persistent generalised lymphadenopathy
What clinical symptom do one third of patients in clinical latency develop following the acute infection phase?
Increases
Decreases
What happens to viral load and CD4+ count as the infection progresses into AIDS?
An AIDS defining illness
What may a patient present when their CD4+ count falls below 200 cells/mm^3?
Opportunistic infections
What may a patient present when their CD4+ count falls below 200 x10^6 cells/mm^3?
Bacterial
Viral
Fungal
Cancers
What types of infections are included in the opportunistic infections associated with AIDS?
Opportunistic infections (rather than HIV directly)
What are HIV positive patients most likely to die from?
Kaposi’s sarcoma
What is the most common neoplasm associated with HIV infected individuals?
Skin
Gums of the mouth
What are the common sites of Kaposi’s sarcoma tumours? (2)
HHV-8 (aka KSHV)
What causes Kaposi’s sarcoma in HIV infected patients?
Detecting specific antibodies, antigens, or both
What is the diagnosis of HIV based on?
Western blotting
Anti-HIV assays
ELISA
Real time PCR
What are some of the common techniques used for diagnosing HIV?
Detecting viral RNA
What is real time PCR used for?
Antibody is not present in the earliest stage of infection
Why are tests to diagnose HIV to antibodies and antigens?
Tests to detect viral nucleic acids and proviral DNA
Because mothers IgG to HIV can persist in the newborn for up to 15 months
What test has to be used in order to detect HIV infection in a newborn? …Why?
To determine what stage of the disease the patient is in
Why are levels of CD4+ T cells and viral load measured?
The rate of destruction of the immune system
What does viral load determine?
The degree of immunodeficiency and likelihood of developing opportunistic infections
What does the level of CD4+ cells indicate? (2)
To reduce the replication of a persistently expressed chronic virus infection to a non-detectable level
What is the aim of HIV therapies?
Some HIV genomic information has been integrated into host cells
Why do HIC therapies not lead to the eradication of the virus from the body?
Reverse transcriptase inhibitors
Protease inhibitors
Fusion inhibitors
CCR5 inhibitors
HIV integrase inhibitors
What are the main types of antiretroviral drugs currently in use?
NRTIs – Nucleoside
NNRTIs – Non nucleoside
What are the two classes of reverse transcriptase inhibitors?
High rate of mutation
Ability to recombine
RNA polymerase has no proof reading
What contributes to the massive diversity in HIV viruses? (3)
Highly active antiretroviral treatment
What does HAART stand for?
Sexual health
Drug abuse
Blood plasma products
Antenatal screening
What different types of topics should be targeted for intervention to inhibit the spread of HIV?