lecture 14 Flashcards
natural history of HIV diseas
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
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
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)
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
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
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
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
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
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
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)
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
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
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
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
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
