FMS Week 10: HIV Flashcards
HIV is what type of virus
Retrovirus
Gag genes
Viral structural proteins
Pol genes encode
Viral Enzymes
Env genes encode
Surface glycoproteins
HIV regulatory proteins
- tat
- rev
HIV accessory proteins
4 Listed
- vif
- vpr
- vpu
- nef
HIV Virion Structure
- viral glycoproteins
- Viral Matrix
- 2 copies of viral single stranded (+) sense RNA Genome
- assoicated nucleocapsid protein
- Viral enzymes (protease, integrase, reverse transcriptase, accessory proteins)
The HIV Life Cycle
6 Listed
- Binding and Fusion
- Reverse transcription
- Integration
- Transcription and Translation
- Assembly
- Budding
The HIV Life Cycle: Binding and Fusion
The virus binds to CD4 receptor and a coreceptor (CCR5 and CXCR4) and initiated fusion with the cellular membrane
HIV Tropism is largely defined by?
Receptor expression
CD4 is expressed on?
6 Listed
- T helper cells
- macrophages
- monocytes
- DCs
- Eosinophils
- microglial cells
CCR5 is ____________ tropic
Macrophage R5-tropic
CCR5 is expressed on
3 listed
- many immune cells
in particular
- Memory T cells and Macrophages
50% of HIV infected individuals only have …
R5-Tropic HIV
CCR5Δ32 mutation
confers resistance to HIV infection
HIV type that predominates early after transmission
R5-tropic HIV
CXCR4 HIV AKA
T-cell (X4)-tropic HIV
CXCR4 is expressed on
Naive T cells and DCs
X4-tropic HIV is associated with
immunodeficiency
X4-isolates are typically highly?
Cytotoxic
The HIV Life Cycle: Reverse Transcription
The viral enzyme reverse transcriptase converts the viral RNA genome into dsDNA
HIV Reverse Transcriptase proofreading activity Consequences
2 Listed
- Replication of the viral genome is an error-prone process
- ~1 base/genome is mutated per replication cycle
The HIV Life Cycle: Integration
The viral enzyme integrase transports the viral DNA into the nucleus and inserts the viral genome into the host chromosomal DNA (this is referred to as proviral DNA)
Proviral DNA AKA
when the viral genome is inserted into the host chromosomal DNA
Integration into the host genome allows the virus to establish a…
Latent State
The HIV Life Cycle: Transcription and Translation
3 Listed
- Viral mRNA is transcribed and translated using host cell machinery
- Viral proteins are synthesized as polyproteins
- Viral transcription only occurs in actively replicating cells
The HIV Life Cycle: Assembly
2 Listed
- Polyproteins are cleaved by the viral enzyme protease
- Viral RNA and enzymes are encapsidated by gag proteins (CA and NC)
The HIV Life Cycle: Budding
2 Listed
- The viral glycoprotein is expressed on the membrane of the host cell
- Immature viral capsid structures traffic to the cell membrane and bud from this surface
The HIV Life Cycle Figures
Anti-retroviral drug classes that interfere with essential steps in the viral life cycle
4 Listed
- Entry inhbitors
- RT inhibitors
- Integrase inhibitors
- Protease Inhibitors
Anti-retroviral drugs: Entry Inhibitors Drug Name and Target
2 Listed
- Maraviroc (CCR5)
- Enfuvirtide (viral gp41)
Anti-retroviral drugs: RT Inhibitors Drug Name and Target
2 Listed
- Nucleotide/nucleoside analogs
- Non-nucleotide inhibitors
Anti-retroviral drugs: Integrase inhibitors Drug Name and Target
1 Listed
- Raltegravir (Isentress)
Anti-retroviral drugs: Protease Inhibitors Drug Name and Target
~10 clinically approved
Clinical Course Stages of HIV Infection
3 Listed
- Acute Phase
- Clinical Latency
- AIDS
Clinical Course of HIV Infection: Acute Phase Description
3 Listed
- Marked by a mild acute flu-like illness and an acute viremia
- These high viral loads then rapidly decrease
- Wide dissemination of the virus throughout lymphoid tissues
Clinical Course of HIV Infection: Clinical Latency Phase Description
5 Listed
- Typically absent clinical symptoms
- Low viral loads, strong debatable immunity
- Massive viral replication and turnover of infected T cells
- Disruption of lymphoid architecture
- A slow decline in CD4+ T cell numbers
Clinical Course of HIV Infection: AIDS Phase Description
3 Listed
- CD4+ T cell count <200
- Dramatic Increase in plasma viral loads
- Increased susceptibility to opportunistic infection due to compromised B and T cell function
Routes of Transmission for HIV
3 Listed
HIV Trojan Horse
4 Listed
Productive HIV Viral infection is dependent on
Cellular Activation
HIV can only establish a productive infection in?
Activated T cells
HIV can infect
Activated and memory T cells by can only establish a productive infection in activated T cells
How do T cells become activated for HIV to establish a productive infection
The initial immune response to HIV infection provides a source of activated T cells allowing enhanced infection
HIV can infect activated and memory T cells that are positive for?
CCR5-positive cells
Infection of activated cells produces virions and causes…
More T cell activation
HIV can remain in a latent form in
long-lived memory T cells
Memory T cells found at high levels in
lymphoid tissues (especially the mucosal lymphoid tissues)
Mucosal T cells are typically…
activated and owing their stimulation to gut flora
CCR5-positive cells CD4+ location percentiles
- 20% of peripheral blood CD4+ T cells
- 80% of gut CD4+ T cells
- 10% of LN CD4+ T cells
________ Lymphoid tissue is a site of HIV Replicaiton early in infection
Summary of early events upon HIV infection
3 Listed
- Depletion of T cells in gut-associated lymphoid tissue
- Immune responses against HIV may provide a source of target cells
- Nevertheless, viral replication is eventually controlled by host immune responses
Immune Responses against HIV
2 Listed
Virus specific Ab effective against
- Viral particles
Viral Specific Ab poor effectiveness against
Virally infected cells
Virus specific Ab not effective against
latently infected cells
Virus-Specific CTL Effective against
- Virus Infected cell
Virus-Specific CTL Not Effective against
2 Listed
- Latently infected cells
- Virus Particles
Clinical latency coincides with the?
Induction of anti-HIV antibody and CTL responses
Set point viral load is correlated with time to _______.
AIDS
Characteristics of Chronic HIV Infection
4 Listed
Viral Variation explanation
2 Listed
- Gradual loss of immune control
- Gradual increase in viral cytopathicity
Clinical Latency is not?
Humoral Immune Responses against HIV
5 Listed
Neutralizing antibodies in HIV
Clinical Latency is not?
Antibodies lose the ability to?
Neutralize Virus
Why is it so difficult to elicit broadly neutralizing antibodies against HIV?
HIV has evolved several strategies to escape humoral immune responses
Vaccines against HIV are based on?
Neutralizing Antibodies
Neutralizing Antibodies are likely ineffective at controlling HIV infection but…
There is still great interest in developing prophylactic vaccines based on neutralizing antibody activity
Major probles to HIV Vaccines
- Viral evolution
- HIV Variability
Summary of Humoral immunity and HIV
5 Listed
Cell mediated immune responses against HIV
2 Listed
In HIV patients _____% of all CD8 cells are HIV specific.
2-10%
CTL responses target?
Multiple Viral Proteins
Immune responses thought to be the most important for controlling viral replication.
CTL Responses
CTL Responses in HIV Properties
5 Listed
Why do CTL responses ultimately fail?
3 Listed
- Viral escape from CTL through mutation
- Viral gene product nef may downregulate MHC Class I
- Chronic stimulation CD8+ T cells can lead to loss of effector functions
Role of immunodominance in CTL escape
3 Listed
Immunodominance places individuals at risk for? And reason?
2 Listed
- Immune escape by epitope variation
- Epitope variation prompts a switch such that CTL response is directed against subdominant viral epitope which must be less efficient in stimulating T cells
CTL escape in early, intermediate, and late
HLA Types can be related to
more rapid or slower disease progression
CTL responses bad, good and ideal
ideal - no escape from CTL and is lethal to the virus (invariant region, virus isn’t able to mutate or escape)
Good - the virus can escape however virus suffers a loss of fitness
Bad - virus can escape and at no fitness cost
Which epitopes do you target for CTL inducing Vaccines for HIV?
Could depend on HLA type
How do you get protection against multiple strains/viral variants?
2 Listed
- 9 Major HIV subtypes, with up to 30% sequence variation in env
- every amino acid could change everyday
HIV Vaccines designed to induce CTL responses Considerations
The initial immune response to HIV reduces the virus levels by?
About 100 fold but no further
HIV infection summary
3 Listed
Why does HIV infection lead to CD4+ T cell depletion?
Virus Mediated
2 Listed
Why does HIV infection lead to CD4+ T cell depletion?
Immune System Mediated
2 Listed
HIV doesn’t cause disease, the __________ does.
Immune system does
The reason why HIv gets people sick is because
the adaptive immune responses against the virus
in absence of an adaptive immune response against the virus the virus causes no sickness
Gut barrier function followed by microbial translocation
- during HIV infection the gut is leaky
- immunostimulatory molecules can leak in an exacerbate the chronic inflammation in HIV
