Lecture 16 (9B) - HIV Flashcards
Acquire Immune Deficiency Syndrome
• immune deficiency
- opportunistic infections (TB, Candida, pneumonnia)
- opportunist cancers (Kaposi’s sarcome, lymphoma, cervical cancer)
• wasting syndrome
- weight loss
- fatigue
• brain
- AIDS dementia
AIDS and … are caused by the same virus
SLIM disease
People living with AIDS in 2010
34 million
Proportion of adults living with aids in 2011 who were women
50
Children living with HIV/AIDS in 2011
3.4 million
People newly infected with HIV in 2011
2.7 million
Children newly infected with HIV in 2011
390,000
AIDS deaths in 2011
1.8 million
Sub-saharan Africa take the brunt
- in 2012 about 68% of all people living with HIV resided in sub-Saharan Africa, a region with only 12% of the global population
- sub-Saharan Africa also accounted for 70% of new HIV infections in 2012
HIV infection from
- unprotected sexual intercourse with an infected partner
- vertical transmission (mother to child - in utero, during deliver, breastmilk)
- injection drug use (rare infected blood-blood products)
Effect of HIV on life expectancy
- in 1970-1975 = around 50-55
- 1985-1995 = around 50-65
- 2005-2011 = 30-45
Origins of HIV
- HIV-1M - chimpanzee
- HIV-1O - gorilla
- HIV-2 - sooty mangabey
Origins of HIV - zoonotic transmission
trans-species
simian to human
Origins of HIV-1
from SIV cpz
• evidence: viral genetic homology, geography of viruses
• at least 3 transmission events gave rise to HIV-1 groups M, N, O
• the group M viruses are estimated to have entered humansin the 1930s
Origins of HIV-2
from SIV sm
• evidence - viral genetic homology, geography
Origins of HIV - multiple transfers
- HIV-1 groups M, N, O, P
- only HIV-1 group M became pandemic
• primate species with no natural SIV infection often show now symptoms or illness
the closest viral species to HIV
the primate retroviruses called simian immunodeficiency viruses or SIV
• thought that HIV evolved from a common ancestor as these viruses and at some point in evolution it made the species jump to humans by spontaneous mutation endowing it with the ability to infect human CD4 T cells by binding to CD4 and CCR5
HIV viruses mutated and given the ability to infect human
CD4 T cells by binding to the CD4 and CCR5 proteins
3 groups exist
each thought to have arisen via a separate chimpanzee-to-human transmission event
• group M
• group N
• group O
Group M
majority
• cause of the global HIV-1
• many strains: ABCD FGHJK
Group N
non-O/non-M
• only found in cameroon
• very few strains known
Group O
outlier
• found in cameroon, equatorial guinea and gabon
• very few strains known
HIV-2
- non-pandemic
- restricted to west africa
- suggests HIV-2 may be less efficiently transmitted than HIV-1
- less pathogenic than HIV-1
- HIV-2 infected persons seem symptom-free longer than persons with HIV-1
Composition of the HIV-1 virus
- envelope
- matrix
- capsid
- lipid bilayer
- encapsulated + membrane from cell + spikes
- RNA
The replication of HIV
- absorption to CD4 and co-receptor
- fusion with cell
- penetration
- reverse transcription
- integration
- transcription
- translation
- capsid assembly
- budding
- maturation
into cyto, RNA reverse transcribed to DNA, DNA into nucleus, replicated, into cell membrane and takes some of membrane with it
HIV binds to
CD4
and CCR5
HIV infection usually requires both
CD4 and a chemokine receptor to infect target cells
(CXCR4/CCR5)
• CXCR4 on lymphocytes
• CCR5 on lymphocytes and macrophages
Co-receptor use and HIV infection
the most important coreceptors used by HIV-1 in vivo are CXCR4 expressed on lymphocytes and CCR5 expressed on lymphocytes and macrophages
• T-tropic isolates use CXCR4
• macrophage tropic isolates use CCR5
• dual tropic isolates use both
CCR5 is key
- individuals with a mutation in the CCR5 gene delta35 in both alleles are largely resistant to infection by HIB
- those with a heterologous mutation in only a single allele suffer less disease
- drugs that inhibit entry through CCR5 reduce viral load
a man with HIV needed bone marrow transplant but had HIV, donor with a mutation in CCR5 –> CCR5 not on cell surface, has no HIV
Buds off membrane
proteins cleave it
HIV infects
CD4 lymphocytes and macrophages
CD4 cells are vital
• CD4+ T cells licence DC for stimulation of CD8+ T cells
CD4 for T cell help (antibodies)
HIV binds to
dendritic cells
• HIV binds receptor on DC, meets CD4 –> HIV given to the CD4 cell
Course of HIV infection
• primary infection - immediate huge dip in T cells, huge increase of virus RNA
- primary infection , seeding of lymphoid organs/brain, dissemination
- clinical latency - T cells decreasing, RNA virus increasing (0.1 log per year rise in HIV load)
- around 5/6 years get AIDS and opportunistic infections, T cells almost 0
Primary HIV-1 infection
- uncontrolled viral replication leads to marked cell mediated immune response
- increased numbers of activated CD4 and Cd8+ cells expressing CD38, CD45R0, and HLA-DR
- increased number of NK cells
- elevated concentration of immune markers
- increased concentration of cytokines: IFN-γ, TNF-α, ILK-1β
Clinical features of HIV infection
Acute primary infection syndrome
flu-like illness, with high levels of virus replication until the infection is brought under immune control
Clinical features of HIV infection
Asymptomatic infection
no outward sign of disease although there is a slow decline in the CD4 count, and very active viral replication
• this stage can persist for 10+ years
Clinical features of HIV infection
Symptomatic HIV infection and AIDS
the immune system ceases to function and disease progresses, resulting in death
Viral dynamics of HIV infection
Primary infection
10hr doubling time with peak viremia at 21 days
• each infected cell seeds 20 infected cells
• virus load drops rapidly as the immune response kicks in
Viral dynamics of HIV infection
Asymptomatic phase
- 10^10 virus particles made and eliminated daily
- 10^9 CD4+ T cells made and eliminated daily
- virus replication and elimination are nearly in equilibrium (steady state)
Viral dynamics of HIV infection
Virus reservoir
- approximately 10^6 - 10^7 T cells sustain the HIV-1 infection (productively infected, activated T cells)
- the sze of the latent HIV-1 reservoir is similar
Long-term survivors
definition
stable CD4 count for > 10 years
• no disease symptoms
• account for up to 5% of HIV infected people
Long-term survivors
explanations
- host factors - genetic factors that confer resistance (CCR5D32 mutation), ability to mount very strong immune responses to the virus
- viral factors - infection with attenuated viral strains
Vaccine requirements
- cytotoxic T cells
* neutralizing antibodies
Cytotoxic T cells kill infected cells
• DC with MHC-I and viral peptide
• TCR recognizes
= activated/armed CD8+ cytotoxic T cells
Costimulation
is not needed once the cytotoxic T cell is armed
• repeat killing can then occur
CD8+ T cells can also make cytokines
• inducing apoptosis of infected cells is the main way CD*+ CTl eliminate infection
• also contribute by producing cytokines:
IFNγ
TNFα
LTα
IFNγ
• increases MHC-I expression
• upregulates antigen processing machinery
• increases macrophage recruitment and activation
IFNγ
- increases MHC-I expression
- upregulates antigen processing machinery
- increases macrophage recruitment and activation
In support of cell mediated immunity as a correlate of immune system protection of disease
- virus specific CD8 cells have been found in individuals exposed to HIV-1 but remain uninfected
- after interruption of HAART preservation of CD4+ helper T cells is associated with the virus
- depletion of Cd8+ T cells results in loss of viral control in SIV infected monkeys
- HIV-1 CD4+ and Cd8+ T cells are preserved in LNTPs and the memory population are poly-functional and similar to that of EBV or CMV induced responses
What 5 things do protect us against infections?
- agglutination
- neutralization
- opsonization
- complement activation
- antibody dependent cellular cytotoxicity (ADCC)
Agglutination
crosslinking by antibodies creates larger particles that are taken up more efficiently by phagocytes
Neturalization
antibodies can block attachment of pathogens to receptors on cells
Opsonization
FcR mediated uptake enhances pathogen clearance by macrophages and neutrophils
Complement activation
classical pathway alternative pathway lectin pathway • make C3 --> C3 convertase --> C3a and C3b --> C3b + C5 --> C5 convertase --> C5a and C5b C5b + C6-9 --> MAC (membrane attack complex)
Antibody dependent cellular cytotoxicity
- infected cell puts virus antigen on surface
- antibodies stick to the antigen on the surface
- NK cell or macrophage has receptor for Fc part of antibody
- come together
- NK cell or macrophage release particles that destroy virally infected cell
So what causes humoral immunity in HIV vaccines?
- passive immunization of chimps with neutralizing antibodies protects (but chronic establishment infection)
- low levels of SIV viral load are associated with high levels of neutralizing antibodies in chronic infection
- rapid escape from neutralizing antibodies in infected cells
- neutralizing antibodies are the immune correlate of protection from infection (rather than disease as in CTL)
Viral quasispecies
for a given virus population, the genome sequences cluster around a consensus or average sequence but every genome can be different
wild type
with genome space of possibilities
Most common occurring worldwide
clade C, A, and AG
HIV vaccine trials
• 2003 the first AIDS vaccine of envelope protein to undergo a major trial is found to be ineffective
• 2007 Step AdV trial of capsid protein - possible increased risk
• 2009 RV144 trial of ALVAC canarypox capsid envelope gp120 prime boost - 16,000 Thai volunteers - possible slight protection
2013 - HTNV505 - halted by Data and Safety Monitoring Committee
Viral reservoir
- a cell type or site within the body where the HIV accumulates and persists with greater stability than the main pool of actively replicating virus
- a reservoir is termed latent if the cells that harbour the virus are not actively producing virus but retain the capacity to do so
- the reservoir may be resilient to eradication because of poor penetration of ARVs or special biological properties of the compartments such as being an immuno privileged site
… and … are a reservoir for HIV infection
brain and CNS are a reservoir for HIV infection
The gut
may be a reservoir for HIV
• in the acute phase of infection, HIV depletes the gut’s CD4 immune cells and their numbers never bounce back
A long way to go with ART alone
• a patient with the lowest level of the reservoir measured during ART
1 infected cell / 1.700,000,000 CD4s
• rebound occurred after ART cessation
Critical to explore other interventions
- activate the dormant viruses and encourage the body’s immune system to attack them
- we need to reconsider immunological interventions as complementary it ART
- IL-15 target memory CD8 T cells and increase the survival of these cells
- neutralizing antibodies
- gene therapy interventions
Drug therapy as a cure?
- so far drug therapy can’t cure HIV
- no restoration of functional immunity, the damage is already done shortly after acute infection
- the replicative capacity of the virus is never overcome
3 strategies being pursued to cure HIV
- eradication of the latent reservoir
- gene engineering an HIV resistant immune system
- therapeutic vaccination
- gene engineering an HIV resistant immune system - a stem cell-based approach to treating HIV infection
Berlin patient - acute myeloid leukemia
- heterologous transplant of HSC from delta32/delta32 patient
- viral clearance
- phase I trials with 2 patient cohorts (1 for which therapy has failed, the other doing well)
CCR5 is key
- individuals with a mutation in the CCR5 gene in delta35 in both alleles are largely resistant to infection by HIV
- those with a heterologous mutation in only a single allele suffer less disease
- drugs that inhibit entry through CCR5 reduce viral load
HIV infects
Cd4 lymphocytes and macrophages
Hematopoietic stem cells
- can reconstitute immune cells for long periods
* amenable to genetic manipulation (antigen recognition or insensitivity to infection, probably both)
How might we engineer stem cells
introduce delta32/delta32 mutations in the CCR5 gene
• introduce cellular restriction factors
Untreated HIV infection
is fatal
