Lecture 9: HIV Flashcards
HIV:
Genus
Family
Subfamily
Grouped to the genus Lentivirus within the family of Retroviridae, subfamily Orthoretrovirinae
HIV-1 vs HIV-2
HIV-1
Infectivity: High
Virulence: High
Heterosexual spread: Higher
Vertical transmission: 20-25%
Genetics diversity: -
Time to AIDS: Less than 10 years
HIV-2
Infectivity: Low
Virulence:Low
Heterosexual spread: Lower
Vertical transmission: Less than 5%
Genetics diversity: Lower
Time to AIDS: over 20 years
How is HIV spread
Sexual contact
Pregnancy, childbirth, breast feeding
Injection
blood transfusiions
organ transplant
Process of HIV infecting cell
- Fuses to host cell (CD4 to gp120)
2.HIV RNA, transcriptase, intergrase enter host cell
3.Viral DNA is formed from reverse transcription
4.Viral DNA is transported across the nucleus and intergrates into the host DNA
5.New viral RNA is used as the genomic RNA and makes viral proteins
6.New virla RNA and proteins move to cell surface and form new immature HIV
7.Virus is released and protease cleaves polyproteins to make it mature
HIV fuses with the surface of the host cell. A capsid containing the virus’s genome and proteins then enters the cell. The shell of the capsid disintegrates and the HIV protein called reverse transcriptase transcribes the viral RNA into DNA. The viral DNA is transported across the nucleus, where the HIV protein integrase integrates the HIV DNA into the host’s DNA. The host’s normal transcription machinery transcribes HIV DNA into multiple copies of new HIV RNA. Some of this RNA becomes the genome of a new virus, while the cell uses other copies of the RNA to make new HIV proteins. The new viral RNA and HIV proteins move to the surface of the cell, where a new, immature HIV forms. Finally, the virus is released from the cell, and the HIV protein called protease cleaves newly synthesized polyproteins to create a mature infectious virus
Symptoms of acute HIV infection
Headache, chills, fever, muscle aches, night sweats, sore throat, joint pain, fatigue, enlarged lymph nodes in neck, mouth ulcers.
AID symptoms
Systemic:
Fever
Weightloss
Central:
Fatigue
Headache
Neuropathy
Skin:
Rash
Gastric:
Nausea
Vomittting
Liver and Spleen:
Enalrgement
Muscles:
Weakness
Mouth/Throat
Sore throat
Mouth ulcers.
Neurological:
Meningitis
encephalitis
Eyes:
retinitis
Lungs:
pneumonia
tumours
tuberculosis
Skin
Tumours
Gastric
chronic diarrhoea
Tumours
3 step process to AID
- Acute infection
flue like symptoms first 24 hours - Clinical latency
chronic HIv infection after acute infection - AIDs
CD4 count less than 200
Describe the process of HIV progression + DIAGRAM
Stage 1: Acute HIV Infection
People have a large amount of HIV in their blood.
Some people have flu-like symptoms. due to this being the bodies response to the viral infection.
Onlyantigen/antibody tests or nucleic acid tests (NATs)can diagnose acute infection
Stage 2: Chronic HIV Infection
This stage is also called asymptomatic HIV infection or clinical latency.
HIV is still active but reproduces at very low levels.
People may not have any symptoms or get sick during this phase.
Without taking HIV medicine, this period may last a decade or longer, but some may progress faster.
People can transmit HIV in this phase.
At the end of this phase, theviral load goes up and the CD4 cell count goes down. The person may have symptoms as the virus levels increase in the body, and the person moves into Stage 3.
Stage 3: Acquired Immunodeficiency Syndrome (AIDS)
The most severe phase of HIV infection.
People with AIDS have such badly damaged immune systems that they get an increasing number of severe illnesses, calledopportunistic infections.
People receive an AIDS diagnosis when their CD4 cell count drops below 200 cells/mm
People with AIDS can have a high viral load and be very infectious.
Typical immune response to HIV:
CD4+
CD8+
Viral load
Lecture Slide
Transmission, dissemination (of the virus to the lymphoid tissues), control
- A decline in CD4+ T cells coincides with the increase in viral load.
- HIV-specificCD8+ CytotoxicT cellresponses 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
- During chronic infection, CD4+ T cells decline slowly and 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 infection and AIDS.
Draw the process of HIV transmission and explain
Lecture Slide
HIV enters the gential epidermal cell layer where epidermal langerhan cells reside. When the virus is sampled by this cell, the cell becomes activated and migrates to the gential draining lymph node.They express surface CD207 (langerin) that captures virus by binding to gp120, which induces internalisation and degradation of virus particles.
This migrates to the T-cell zone where it presents to CD4+ and CD8+ cells and causes activation of CD4+ cells. This causes T cell proliferation and prompts T-cell migration and virus desimination.
Activated epidermal cells further release IL-6, IL-1 and TNF-a which stimulate more T cell proliferation due to being pro-inflammatory.
In the process, CD4+ T cells can also become infected by virus bound to theLangerhans cellsurface (trans-infection). OR any cell expressing CD4+ receptors
Describe HIV dissemination + DIAGRAM
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 B lymphocytes proliferate to form germinal centres and the entire lymph node enlarges (lymphadenopathy)
HIV infected CD4+ T cells, activated in genital draining lymph nodes, migrate to mucosal tissues such as the gut and skin.
Dissemination of virus results in increased viral replication, mainly in lymph organs and leads to high viral loads in peripheral blood.
There is also a rapid depletion of CD4+ T cells, particularly in the gut lymphoid tissues.
Tissue macrophages express CD4 and CCR5 receptors and also become infected.
Describe control of viremia + diagram
The partial resolution of peak viral load observed during the acute stage of HIV infection is associated with robust T cell immunity
Tissue dendritic cells engulf virus detected in 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 HIV-specific 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 reduces viral load and allows CD4+ T helper lymphocyte numbers to increase.
The absolute CD4+ count does not however return to baseline levels but remains reduced.
Describe Seroconversion + diagram
In order for HIV-specific antibodies to be generated there must be sufficient presentation of HIV antigens to B lymphocytes.
Antibodies to HIV (seroconversion) only begin to appear in peripheral blood 4-6 weeks after transmission, but in rare instances can take up to 3 months.
This is achieved by capture of viral particles and proteins on the surface of follicular dendritic cells located in the lymphoid follicles (B cellzone) of the lymph node. B-cells bind to the follicular dendritic cell where the antigen is presented causing hald activation. However it needs full activatio by binding to CD4+ cell. So the B cell goes to the T-cell zone and binds to the CD4+ allowing full activation and proliferation into plasmaocytes causing antibody production.
7 immune evasion methods
- CD4+ cell depletion (decreased immune function)
- Intergration of proviral genome, latency, dissemintation (immunosilent)
- Virus variability (immune escape)
- Low density of env spikes (immune evasion)
5.High degree of glycosylation (shielding epitopes)
- gp120 shedding (non-functional epitopes)
7.Consectutive binding of 2 receptors (protection of entry epitopes)
HIV-1 infects CD4 + cells, major players in adaptive immunity (1). Proviral integration results in lifelong persistence (2). Virus variability leads to immunological escape (3). Antigenicity is lowered by low number of HIV-1 envelope (Env) spikes (4) and extensive glycosylation (5). Non-functional Env epitopes are exposed through shedding of gp120 (6). Functional entry epitopes are protected through consecutive receptor interactions linked to conformational changes in Env
- CD4+ cell depletion (decreased immune function)
Describe 5 mechanisms of this
- CD4 role in immune system
-CD4 and HIV interaction
- memory t cells and HIV
1.Direct Attack by HIV
2.Chronic Immune Activation
3.Immune Activation and Inflammation
4.Pyroptosis and Apoptosis
5Regulatory T-cells (Treg)
CD4+ Th-cells are the central mediators of immune response in humans as they co-ordinate cellular and humoral immune responses against infections
HIV binds to the CD4 molecule on the surface of helper T-cells and replicates within them, resulting in destruction of CD4+ T-cells
and leads to a steady decline in this population of T-cells
During the course of HIV infection, about 1 billion of HIV particles are produced per day
Results in increasing numbers of infected CD4+ T-cells
Subsequently, infection spreads to the memory cells in the thymus and the virus starts to replicate there.
Each time a memory CD4+ T-cell is infected by HIV, it is destined to undergo the process of elimination, thus contributing to the progressive decline in CD4+ T-cell numbers
- Latency and evasion
HIV impacts this by..
Resting CD4 cells that are infected with HIV but not actively producing HIV
Latent HIV reservoirs
established during the earliest stage of HIV infection
continue to survive even when antiretroviral therapy (ART) is used
When a latently infected cell is reactivated, the cell begins to produce HIV again
- Virus variability
HIV diversity enables the virus population to escape from control by
the immune system.
Genetic variation is the hallmark of infections with lentiviruses
evades immune pressure by the continuous production of new mutants resistant to current immunological attack. This results in the accumulation of antigenic diversity during the asymptomatic period.
The existence of an antigenic diversity threshold is derived from the asymmetric interaction between the virus and the CD4 cell population: CD4 cells mount immune responses some of which are directed against specific HIV variants, but each virus strain can induce depletion of all CD4 cells and therefore impair immune responses regardless of their specificity.
Therefore, increasing HIV diversity enables the virus population to escape from control by the immune system.
HIV-1 continuously evolves within infected persons (driven by the high error rate of the viral reverse transcriptase). Besides fooling the immune system with a majority (>90%) of aberrant virus particles that are not functional, the high variability allows some mutant viruses to escape from the selection pressure imposed by the immune system
4.Envelope spikes
role of neutralising antibodies - prevent infection
Gp120 of the spike interacts with CD4 on T cells leading to conformational changes that allow interaction with the chemokine receptor CCR5. Further conformational changes are triggered in the spike leading to fusion of viral and target cell membranes and transmission of viral genetic material into the target cell. Neutralizing antibodies interrupt the viral entry process by binding to the envelope spike before CD4 binding or after CD4 binding but before fusion
Spikes bind receptors onto host cells to propagate infection
High spike densities (SDs) can promote infection
env spikes are targets of antibody-mediated immune responses
HIV-1 particles usually contain only 14 spikes on average – Low density
Remain infectious with as few as four spikes. This low number is enough for infection, but minimizes the particle’s immunogenicity.
- Glycosylation
General role and purpose with HIV
Carbohydrate is covalently attached to a target macromolecule
Important and highly regulated mechanism of secondary protein processing within cells
Critical role in determining protein structure, function and stability.
Plays a key role in determining the cellular response to exogenous factors
gp120 is one ofthe most heavily glycosylated viral proteins
Gp120 is essential for viral infection as itfacilitates
-HIV entry into the host cell
-Shedding of the epitope
HIV binding and entry Diagram and headings
- Envelope
- CD4 binding
- Co-receptor binding
- Fusion of membranes
To deliver the viral payload into cells, HIV Env, comprised of gp120 and gp41 subunits (1), first attaches to the host cell, binding CD4 (2). This causes conformational changes in Env, allowing coreceptor binding, which is mediated in part by the V3 loop of Env (3). This initiates the membrane fusion process as the fusion peptide of gp41 inserts into the target membrane, followed by six-helix bundle formation and complete membrane fusion (4).
HIV binding and entry:
What does CD4 bind to?
Purpose of CCR5? Switch to what? Effects?
HIV-1 infection of target cells is mediated by binding to the primary receptor CD4 and
chemokine coreceptors CCR5 alone
CCR5 and CXCR4 or,
rarely, CXCR4 only
Based on the coreceptor type, HIV exhibits different tropisms
HIV usually requires CCR5 to facilitate primary infection
half of infected individuals will switch to CXCR4 usage
which is generally associated with an accelerated decline in the CD4+ cell count and rapid disease progression
