lecture 14 Flashcards by Molly Fowler

What is the clinical course of HIV?

measure HIV viral load
measure CD4 cells - hallmark immunological abnormality in HIV
many many immunological abnormalities with HIV but CD4 count is the one that is most commonly measured in the clinic

viral load

days to weeks before you start to see HIV in the plasma
w/i a couple of weeks you get massive replication so that if you measure someones virus in plasma shortly after infection you get Acute HIV syndrome - wide dissemination of virus, seeding of lymphoid organs
millions of copies/mL
then immune response kicks in, CD4, CD8, (relatively useless) antibody
causes viral load to decline (some level of control of viral replication)
viral load sits at a steady state for many years
steady state ≠ no viral replication, it means that production = clearance
this set point is variable amongst people
on average for 10 years stays under control
after 10 years lose control and viral load continues to increase again

CD4 T cell count

at the same time you have very dramatic changes of CD4 T cell count
this is essentially what makes you unwell
after primary infection you get “acute phase of CD4 depletion”
this is a transient decline, sometimes to very low levels
but then you get recovery, usually to a normal level
normal CD4 T cell count believed to be > 500 ( probably > 900)
rarely returns to pre-infection levels
overtime: gradual, slow depletion of T cells (~ 50 cells/year)
while the virus is chipping away at these T cells you can remain pretty well for a period of time
until you reach a critically low level of T cells and that’s when you start running into trouble
development of constitutional symptoms, opportunistic diseases (AIDS), and invariable death

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What happens in the GIT/mucosa during acute infection?

massive depletion of CD4+ T cells from GIT
normally have lots of active CD4+ T cells here
wiped out
the amount of T cells that we lose in blood is probably an underestimate of the amount of T cells that we lose in the whole body bc of the number we lose in the GIT

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What is the chronology of CD4 T-cell loss and disease?

Primary infection

glandular fever like illness in about 50% of people
- fever
- myalgia
- lymphadenopathy
other 50% are completely asymptomatic and have no idea that they have picked up HIV
very rarely you can get quite sick during this period with meningo encephalitis

advanced (CD4 500), things aren’t quite right

see a range of autoimmune diseases that don’t necessarily ring a bell that suggests this must be HIV
seen in people without HIV
Guillan-Barre
idiopathic thrombocytopenia
even in this early stage there is immune dysregulation

500 > CD4 > 200

not normal CD4 cell count but still don’t see HIV defining diseases
range of other illnesses
e.g. Tuberculosis (probably the most important co-infection globally that occurs with greater frequency and greater severity in people with HIV, even when they only have intermediate immunosuppression)

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What is CD4+ T-cell homeostasis?

arise from CD34+ progenitor cells in the bone marrow
progenitor cells move to the thymus where they are educated to recognise self and non-self antigens
undergo maturation in the thymus and exit as naive T cells
maintained over life largely through homeostatic proliferation
when they contact an antigen that they are designed to recognise they expand, become effector cells that remove that foreign antigen, once business is done they revert back to a central memory state/cell
this forms immunological memory for life

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What are causes of CD4+ T-cell decline?

Increased destruction

direction infection
- GIT»_space;» blood
- incomplete reverse transcription in naive T-cells, don’t have to get productive infection to eliminate the T cell
Indirect effects
- syncitium formation, non-infected cells start to gather around the infected cell because it presents gp120 on the surface , therefore eliminating uninfected cells
- apoptosis
- immune activation - in the effort to respond to HIV you get significant clonal expansion of HIV specific CD8 T cells and CD4 T cells, it’s as if the immune system goes into overdrive, immune activation of lots of cycles of proliferation will ultimately kill the cell because it reaches the end of its proliferative capacity
- lymph node fibrosis

Impaired production

thymus
CD34+ progenitor cells

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Why is CD4 T-cell depletion variable?

Viral factors

CXCR4 virus accelerated T-cell loss
Nef deleted virus limits T-cell loss
co-infection with other viruses e.g. CMV, GBV-C

Host factors

immune response
- HLA type (lower viral set point, lose T cells at a slower rate)
genetic factors
- e.g. CCR5 delta 32 heterozygote has slower disease progression
Age
- impaired thymic function in very young and very old
- if you are very young when your thymus is developing and it takes a hit you notice the loss of thymic function

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Why is HLA type important for immune response?

B13, B27, B51, B57 good prognosis
A23, B37, B49 rapid disease progression
certain HLA molecules present HIV epitopes more effectively which enhances the adaptive immune response

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What is HIV-induced immunopathology associated with depletion and/or dysfunction of other cells?

CD8+ CTLs: abnormally high during acute phase, decline at later stages
NK cells: impaired numbers and function
monocytes and macrophages: defects in chemotaxis, inability to promote T-cell proliferation, defects in Fc receptor function
B-cells: increased production of IgG and IgA but decreased antibody responses

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How do we see chronic immune activation in people with HIV?

even though we think about HIV as immunodeficiency, the other way to think about it is the immune system going into overdrive
markers of immune activation that are elevated in HIV infection
e.g. T-cells: HLA-DR, CD38, sCD26, sCD30
cellular and soluble markers found in T-cells, monocytes, B-cells, NK cells, DCs, hepatocytes

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What causes immune activation?

Mucosal depletion of CD4 T-cells

increased microbial translocation
activation of TLR4 by bacterial products (LPS)

Activation of innate immune response (pDCs)

HIV RNA is a TLR7/8 ligand
increased plasma IFN-alpha

Cytomegalovirus (CMV)-specific response
- expansion of CMV-specific activated CD4+ and CD8+ T-cells
(also seen in the elderly in the absence of HIV)

Loss of T regulatory cells
(normally inhibits immune response)

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What is HIV-induced immunopathology associated with innate immune cells?

plasmacytoid dendritic cell –> IFN-alpha –> CD4+ T-cell
HIV stimulates monocyte/macrophage to release IL-6, TNF-alpha, IL-10, CXCL10
- stimulate CD4
HIV stimulates CD4 directly

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How can we use animal models to understand CD4 decline and immune activation?

rhesus macaque
sooty mangabey

if you put SIV into a rhesus macaque (not natural host) it develops a very similar illness to HIV, loses CD4 T cells and develops AIDS

if you put it into a sooty mangabey, the animals remain healthy
many in west africa where they are endemic, many are naturally infected with SIV, and it seems to cause no problem
tends to ignore the virus which seems to help it, unlike us

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How do these models of pathogenic and non-pathogenic SIV compare to HIV?

HIV/SIV RNA is high in all
CD4 decline in humans and RM (pathogenic), but not SM (non-pathogenic)
immune activation in humans and RM, not SM
LPS increased in humans and RM, low in SM
GIT depletion in humans in RM but only early in SM, otherwise no

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How do the antiretroviral therapy drugs act?

cellular chemokine receptor antagonists (attack co-receptor binding step)
fusion inhibitors
reverse transcriptase inhibitors (NRTIs and NNRTIs)
integrase inhibitors
protease inhibitors
probably around 30 drugs that act on these different pathways
main principle of treatment is that we never just use a single drug
if you target multiple steps etc you limit the capacity for the virus to escape

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How does the pill burden compare between 1996 and 2014?

much less, now can take one pill instead of 20

- one tablet will contain three antiretroviral drugs

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What happens when you put people on treatment?

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cART leads to rapid decline in HIV RNA and CD4 recovery
within a month the virus will disappear from blood –> still there but beneath the detection of the assays we have available (20/mL)
once you can control the virus like this, the CD4 T cells are able to recover in most patients
recovery phase of CD4 T cells usually takes a lot longer
in most patients if you start not too late, CD4 T cell count will return to above 500

How has patient survival changed with the introduction of ARTs?

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dramatic improvement of life expectancy
danish cohort study
before ART dramatic reduction in life expectancy - chance of getting to 50 with HIV was virtually negligible
early ARTs saw dramatic improval in survavl to 50 (but not perfect)
later ARTs in early 2000s improved on this but still not normal
recent data suggests that if you start treatment before your CD4 T cell count gets less than 200 and you don’t have other co-whatevers your life expectancy is normal

What about access to cART in low and middle income countries?

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10 million people in low and middle income countries now on cART
in 2012 about 60% of people who needed treatment were getting treatment

What is one of the challenges in treatment?

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finding people with HIV
getting them onto treatment and making sure they stay on it
the ‘HIV cascade’
of all the people living with HIV, probably only about 50% know that they are infected
and of those that know only about 60% are on ART (30% of total)
only 25% of all with HIV are living with a suppressed viral load
people think now that we could see the end of HIV infections if you treated everyone
lots of implementation research
e.g. in australia 80% of people with HIV have undetectable viral loads due to being on treatment

What is persistence of non AIDS deaths?

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decline of AIDS but persistence of non AIDS deaths
range of illnesses seen that are more common in people with HIV on treatment than in age matched controls
people in the late 2000s are dying far less frequently from HIV/AIDS than in the late 90s
decline in people dying of chronic viral hepatitis
not much change in non-AIDS malignancy (e.g. lymphoma)
still see an increased rate of death in people with HIV due to acute myocardial infarction

How does significant morbidity perist on HAART?

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cART toxicity
HIV
immune dysfunction
phenotype of accelerated ageing

all contribute to:

cardiovascular disease
metabolic disorders
neurocognitive abnormality
liver disease
renal disease
bone disorders
malignancy
frailty

What is one reason why we still have immune dysfunction in patients on cART?

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CD4 T-cell recovery is variable
some recover really well
in others it takes a lot longer, or they never get up to normal

What are the reasons for this variability in CD4-T cell recovery?

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CD4+ T-cell recovery after 7 years of cART is associated with baseline CD4+ T-cell count

biological determinants:

viral factors
- CXCR4 using results in poorer reconstitution
- co-infection with other viruses e.g. hep C virus
host factors
– genetic factors
> CCR5 mutations
> IL-7 receptor mutations
– residual immune function
– thymus function
> age

What are some of the immune abnormalities in patients on cART?

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similar to ageing

Untreated HIV infection

expanded CMV-specific CD8 cells
expanded CD28-CD57+ CD8 T cells
reduced T cell repertoire
increased T cell activation
low IL-2, high IFN-gamma (CD8 T cells)
reduced thymus function
low CD4/CD8 ratio
low naive/memory ratio
increased IL-6
reduced response to vaccines
reduced innate immune function

Long-term (5-10years) treated HIV infection

expanded CMV-specific CD8 cells
expanded CD28-CD57+ CD8 T cells
reduced T cell repertoire (low CD4 nadir)
increased T cell activation
unknown if low IL-2, high IFN-gamma (CD8 T cells)
do not have reduced thymus function
low CD4/CD8 ratio
low naive/memory ratio (low CD4 nadir)
increased IL-6
possible reduced response to vaccines (CD4 nadir)
reduced innate immune function

What are strategies for HIV prevention?

Behavioural - education - testing - condoms Biomedical - vaccines - circumcision - microbicides - antiretroviral - - PREP - - treatment as prevention - treat sexually transmitted infection

What are components for an effective vaccine response?

- do not currently have a vaccine for HIV - what do we really want from a vaccine? - CTLs or B-cells/neutralising antibodies - A B cell based vaccine would prevent you ever getting infected as the HIV virus would be neutralised before it could enter the cell - T cell based vaccine that relies on very quick detection of an infected cell

What have been attempted vaccine approaches?

Recombinant proteins - good antibody but poor T-cell responses - no protection DNA vaccines - good T-cells responses but poor antibody responses Live vector vaccines - non-replicating poxvirus expressing HIV-1 genes --> good T-cell responses - Ad5 virus - - STEP trial 2008 - - not effective - - possibly increased risk of infection Live attenuated virus - potentially unsafe Prime boost - DNA + protein or vector Broadly neutralising antibodies CMV vectors - persistent antigen presentation

What is the only trial to have shown some level of effectiveness?

- Thai trial: prime/boost partially effective - ALVAC (canarypox) x2 + gp120 x3 - N=16,000 - reduced risk by 30% - some thought a good result because it showed vaccine efficacy - some thought it was a bad result because not high enough - big problem for the field is to know what vaccine in which to invest... lots of money

What did the DNA prime recombinant Ad5 boost show?

- no protection - DNA vaccine (gag, env, nef, and pol) - weeks 0, 4, and 8 - + rAD5 boost (gag-pol protein and env) week 24 - stopped part way through the study because of lack of efficacy - even perhaps a suggestion of increased infection - really made people re-think what are doing

What are broadly neutralising antibodies?

- can "neutralise" a large number of viruses - are directed against highly conserved regions of envelope that are "hidden" - detected after 1-2 years of infection and of limited help to patient

What do we hope for the future?

- synthesis of broadly neutralising antibodies in vitro - once you know the broadly neutralising Ab and know what it is binding to there are ways of engineering B cells in vitro to produce these bnAbs - look very promising in monkey models - CMV vectors promising in macaques

What are unusual features of CMV vectors?

have unique properties of: - unconventional MHC-II-restricted CD8+ T-cells - breadth of epitope recognition - promiscuity

How does circumcision reduce acquisition of HIV?

- by 70% | - due to langerhan cells in the foreskin

lecture 14 Flashcards

natural history of HIV diseas (33 cards)