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Virology > HIV > Flashcards

HIV Flashcards

1
Q

How can pace of progression to AIDS be predicted?

A

Viral load after initial infection - a high set point predicts rapid progression

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2
Q

What is the structure of gp160?

A

gp40 is the stalk through the membrane, gp120 is the globular top

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3
Q

What are the binding receptors for HIV?

A

Binds CD4, also needs co-receptors CCR5 and/or CXCR4

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4
Q

Describe the initial stages of HIV infection

A

Get acute infection - R5 virus normally transmits. Get a burst of viral replication and depletion of CD4 T cells in the gut. Flu like symptoms associated with the cytokine response

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5
Q

Describe the asymptomatic phase of HIV infection

A

Viral infection is contained after initial burst. High viral turnover but is asymptomatic. CD4 cells are activated and slowly decline in number. When thymic function becomes impaired, T cell depletion increases. At the end, T cells are so low that the host is susceptible to tumours and infection

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6
Q

Describe the AIDS stage of HIV infection

A

Increase in viral replication and collapse of immune system. The host is susceptible to opportunistic infections and tumours. Leads to death. Can take 2-20 years to arise with no drugs

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7
Q

How is a HIV infection established?

A

Mucosal infection - free virus particles or infected cells move across the mucosal barrier and establish a small foci of infection. Virus spreads locally then to lymphoid tissues (containing CD4 T cells). Infection then spreads systemically to all lymphoid tissues, including gut lymphoid. When the virus starts to deplete CD4 T cells there is large damage to the immune system and a high viral titre so the virus can’t be eradicated.

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8
Q

What factors affect the persisting viral load in an HIV infection?

A

Viral type - CXCR4 virus is rarely passed on but has a higher pathogenicity. Deletions in virulence genes such as Nef cause lower pathogenicity
Host genetics - deletions in CCR5 promoter region: if homozygous no CCR5 for infection. If heterozygous lower levels of viral replication. Immune response may also be infected e.g. some HLA alleles are associated with good viral control - suggests that control by early immune response is important in determining persisting viral load and therefore disease progression

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9
Q

What is the immune response to an initial HIV infection?

A

Dendritic cells produce lots of cytokines and chemokine at the local infection site. CD4 cells are recruited by beta chemokine (not good). Inflammatory cytokines active the immune system. HIV is not a stealth infection as needs to infect the immune system.

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10
Q

What is the immune response as HIV spreads systemically?

A

Get a cytokine storm: type 1 IFNs mediate antiviral activity and act as an adjuvant to other immune responses.

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11
Q

What are the pros and cons of the initial immune response to HIV infection

A

Type 1 IFNs have direct antiviral activity and act as an adjuvant
Chemokines that attract T cells fuel viral replication. Activation of the immune response by inflammatory cytokines drives viral replication
Pro apoptotic effects of TFNalpha and IFNalpha may contribute to declining T cell numbers

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12
Q

How does interfering with the IFN response affect HIV early infection?

A

Blocking type 1 IFN receptors at the early stage of HIV infection reduces antiviral gene expression and results in more virus production and faster T cell depletion, leading to AIDS even when block is removed
If type 1 IFN is given immediately before infection, antiviral gene expression is increased and infection is blocked
If type 1 IFN is given for a while before infection, negative feedback turns off antiviral gene expression but the immune system is still activated leading to high viral replication titre.

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13
Q

How do NK cells act in early HIV infection?

A

Important - up regulating NK receptors and ligands helps control of the virus
NK cells can control HIV replication in vivo
NK cells can lyse HIV specific CD4 cells which is detrimental

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14
Q

How does HIV evade cytokines?

A

Not in acute infection
Accessory proteins later act to interfere with some ISGs e.g. degradation of APOBEC3G by Vif and sequestering of tetherin by Vpu
Viruses that are transmitted tend to be more resistant to IFN - suggests a bottle neck in selection

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15
Q

How does HIV evade NK cells?

A

In chronic infection there is altered NK functionality - increased number of inhibitory receptors and decreased numbers of activating receptors
Tat protein may aid resistance to NK cell lysis by blocking calcium influx and inhibiting degranulation

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16
Q

How does HIV interfere with HLA allele expression?

A 
Down regulates HLA-A,B, and C expression which presents HIV peptides to CTLs but not HLA-E which presents peptide from signal sequence of class 1 molecules to inhibit NK cells
Does this by 2 exon Tat decreasing activity of MHC class 1 promoter and Nef stimulating endocytosis and degradation of surface HLA-A/B. Vpu induces HLA-C down regulation in a similar way
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17
Q

Describe the profile of antibody expression in an HIV infection

A

Increase in antibody response as acute infection starts to be controlled. May aid in viral control through ADCC and complement fixation
Neutralising antibodies aren’t produced for a few months

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18
Q

Why does it take so long for neutralising antibody to be expressed in HIV infection?

A

Not many B cells are specific as many antigens look like ‘self’.
Lack of CD4 T cell help
Cytokine storm drives polyclonal B cell amplification so neutralising B cells are diluted out
Apoptotic microparticles on the surface of B cells?

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19
Q

How is HIV resistant to detection by antibodies?

A

Does antigenic variation
Envelope protein is trimeric (part of protein hidden at interfaces) with a dense glycan shield that antibodies have to be able to get past
CD4 binding site is protected by variable protein loops
Chemokine receptor binding site is only exposed transiently after binding to CD4

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20
Q

What are the 5 sites that would be ideal for antibody targeting on HIV? What are the problems with this?

A

CD4 binding site
V1V2V3 loops
Interface between gp41 and gp120
Foot of protein where it attaches to the lipid
Only one of these sites is just protein (CD4 binding), rest are partially sugar/lipid which is similar to host - have to be very specific. Need a lot of somatic hypermutation to form neutralising antibody

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21
Q

What is the importance of the CD4 T cell response in controlling HIV infection?

A

Is important - could be cause or effect: if there is a good response get good viral control OR if there is less virus can have a good CD4 T cell response

22
Q

Why is a weak CD4 T cell response associated with HIV infection?

A

Virus can infect CD4 T cells by binding to the surface of APCs (e.g. virus binds DCs by DC-SIGN) - when (HIV specific) cells bind APCs are infected and destroyed by lytic replication/virus specific immune response

23
Q

What is the importance of CD8 T cells in controlling HIV infection?

A

Strong CD8 T cell response is important in controlling initial acute burst of viral replication (depletion of CD8 T cells is bad; virus is selected for CD8 T cell resistance)

24
Q

Why can’t CD8 T cells control initial HIV infection effectively?

A

HIV evades control
Response is impaired
CD8 T cell recognition is avoided

25
Q

How does HIV impair the CD8 T cells response?

A

Chronically infected individuals have low levels of granzymes/perforin
Exhaustion of T cells due to a prolonged antigenic stimulation and little aid from CD4 T cells

26
Q

How does HIV avoid recognition of CD8 T cells?

A

Latency in resting CD4 T cells and macrophages
Replication in immune privileged sites
Down regulation of MHC and adhesion molecules
Antigenic variation and evolution of viral escape variants

27
Q

How does HIV evolve escape variants from CD8 T cells?

A

RNA polymerase and reverse transcriptase used to replicate genome is error prone leading to quasi species of viruses. Gives quick evolution
Escape variants will have effects in epitope processing, peptide binding to MHC and TCR recognition

28
Q

What host factors mediate escape of virus from CD8 T cell response?

A 
Breadth of T cell response (how many epitopes respond to - if many less likely to mutate and number of different T cell clones recognising each epitope). Fitness costs of escaping a broad response will be higher.
Epitope conservation (if response against functionally important protein such as Gag will have better response. HLA alleles can aid presentation of Gag). If response against early proteins e.g. Gag and Pol can be expressed on MHC before it is down regulated
29
Q

What does the Nef protein in HIV do?

A

Inhibits Fas and TNF-R apoptosis

Inhibits ASK-1 (apoptosis signalling kinase)

30
Q

What are the challenges facing HIV vaccine development?

A

Inducing broadly neutralising antibodies is very difficult - clades A-J to have antibodies against, and HIV is resistant to antibody neutralisation
T cell responses are unlikely to be capable of blocking infection so a T cell prophylactic vaccine is questionable…
Therapeutic vaccines (when infected) are required but difficult to make as immune system is compromised and virus can have escape mutants. Also doesn’t target latency

31
Q

How can the challenge of inducing a broadly neutralising antibody response to HIV be tackled?

A

Improving immunogens - design of glycopeptides to mimic conserved sites
Sequential immunogen - kick start B cell replication, then further immunisation to increase antibody response and encourage somatic hypermutation
Strong CD4 helper response may aid this
Even a non-neutralising antibody would have a protective effect through APCC

32
Q

How can the problem of creating an effective T cell response against HIV in a vaccine be tackled?

A

Inducing a CD4 T cell response could increase viral replication, but may be a window in the first few days, potentially reducing viral load
Using a persisting vector virus to stimulate the T cell response in effector memory cells (in primates) has been partially successful in clearing infection if the T cell response is broad and is restricted to MHC-E and MHC–2 which aren’t down regulataed

33
Q

How are the problems in creating an effective therapeutic vaccine being tackled?

A

Improve immune function in chronic infection e.g. inhibiting checkpoints such as PD-1 blockade to counteract T cell exhaustion
Reagents to target non-HIV specific T cells to HIV infected cells
Induce a broad T cell response to protect against escape variants
Reactivate virus from latently infected cells to aid ‘flushing out’

34
Q

What is the prevalence of HIV in the UK?

A

Around 80,000 diagnosed with a further 10-20,000 undiagnosed. Most common in men who have sex with men and black african people.

35
Q

What opportunistic infections seen in AIDS?

A

Mycobacteria, yeasts, protozoa, persistent DNA viruses. Often get reactivation of intracellular infections with a high density of organisms and a poor immune response. Often get concurrent or sequential infections, some of which are human-adapted and difficult to eradicate. Can be treated with antimicrobial drugs until immune system function improves with HIV treatment

36
Q

What are the symptoms of an HIV infection?

A

Unexplained gradual weight loss or cognitive impairment. Enlarged lymph nodes. Emergence of herpes zoster and oral candida. Increase in polyclonal serum IgG, low lymphocyte count, unexplained low haemoglobin and platelets

37
Q

Describe the treatment of HIV infection?

A

Can begin at any T cell count
Test virus for drug-resistance
Drugs tend to inhibit viral enzymes e.g. reverse transcriptase, protease, integrase
Drugs used in combination to prevent resistance
Treatment has to be taken consistently and viral load is monitored
Anti-microbial drugs to prevent opportunistic infections
Also have psychological/social support

38
Q

What are some examples of drugs that target the HIV reverse transcriptase?

A

Nucleoside reverse transcriptase - Abacavir, Tenofovir.

Non-nucleoside reverse transcriptase - Efavirenz, Nevirapine

39
Q

What are some examples of drugs that target the HIV protease

A

Atazanavir, Darunavir

40
Q

What are some examples of drugs that inhibit HIV entry?

A

Enfuvirtide gp41

Maraviroc CCR5

41
Q

What are some examples of drugs that target the HIV integrase

A

Raltegravir

Elvitegravir

42
Q

What are the risks of using the drug Abacavir to treat HIV?

A

A drug that targets the reverse transcriptase. Can bind in the groove of HLA-B5701. Allows a different set of of peptides to bind leading to polyclonal activation of CD8 T cells and a fever and rash

43
Q

What are the non-physical health side effects of HIV?

A

People with HIV are likely to have depression, drug/alcohol use, lack of accommodation/job/support network/visa/passport/asylum, or refuse to inform their GP

44
Q

When is HIV transmitted from mother to baby?

A

50% late in pregnancy; 30% during birth. Can be prevented with intervention (if none, get transmission in 20-25%). Risk increases with high HIV viral load
Can also be transmitted during breast feeding (10-15% chance if no intervention)

45
Q

How can risk of transmission of HIV from mother to baby be reduced?

A

Caesarean section reduces rate of transmission from 20-25% to 12%
Drugs can also help - use of combination therapy and C section reduces rate to 1-2%
Avoiding breast feeding where possible

46
Q

How can HIV infection by sexual transmission be prevented?

A

Education
Treatment of co-existing STDs
Male circumcision reduces transmission by 50%
Anti-HIV treatment reduces transmission by over 92%

47
Q

How can HIV infection by blood-borne transmission be prevented?

A

Needle exchange programs for drug users
Testing and heat treatment of blood transfusions
Post-exposure prophylactic anti-retroviral therapy

48
Q

How can risk of HIV infection be reduced post exposure?

A

Treat with anti-retroviral drugs such as Zidovudine for 4 weeks (80% reduction in infection)

49
Q

What are the risk factors following exposure to HIV infected blood?

A

Deep injury
Visible blood on the sharp device
Device previously in lumen of blood vessel
Advanced HIV in the source patient

50
Q

What is the response if a health care worker is exposed to HIV positive blood?

A

Blood tests and anti-HIV therapy commenced (ideally within 4hrs)
Drugs are Truvada (Tenofovir and Emtricitabine) once a day and Raltegravire twice a day for 4 weeks
Follow up - avoid blood donation, practise safe sex, blood tests

Virology (13 decks)

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