HIV - disease processes Flashcards
explain how the HIV outbreak came about
In 1980 workers at the CDC noticed an abrupt and unexpected increase in requests of pentamidine isethionate, a drug distributed by the CDC to treat Pneumocystis carinii pneumonia (PCP).
At the same time in New York City an unusually aggressive form of Kaposi’s sarcoma (KS) was being diagnosed. Until now KS had been viewed as a rare, benign cancer affecting a few people each year in their sixties and often associated with at least one other primary cancer.
Both PCP and KS are associated with immune deficiency
1984 - HIV isolated by Luc Montagnier (Pasteur Institute) and Robert Gallo (U.S. National Cancer Institute).
1985 - CD4 entry receptor identified
2009 - The RV144 trial demonstrates 31% lower risk of infection
in 2013, how many HIV-related deaths where there?
In 2013, 1.5 million people died from HIV-related causes globally.
HIV-1 genome
HIV-1 has a 9.2 kilobase single stranded RNA genome
The genome has multiple reading frames and contains 9 genes producing 9 proteins
Gag and pol are processed to produce 6 and 4 proteins respectively
HIV-1 virion structure
ssRNA genome two copies of those
Viral enzymes reverse transcriptase, integrase, protease
Envelope – from the infected cell when the virus buds
HIV-1 life cycle
- Binding of the enveloped trimer to CD4 and to one of the co receptors CC4 or CXCR5
- Binding of the envelope to these receptors results in a conformational change which brings them to contact with gp41 fusion domain with the cell membrane, fusion of viral and cell membrane
- RNA is reverse transcribed, DNA is transported into the nucleus and integrated using viral integrase
- Using viral and host transcription factors, the viral DNA is transcribed into viral RNA -> used as the new genome for budding virion
Also used to translate various virion proteins - Assembly and budding
Immune response to HIV-1
Multiple components of the immune response are involved in anti-HIV immunity, including cytotoxic T cell responses
DCs – can present antigen from the virus from virally infected cells to CD4 and CD8 T cells to induce TH1 to promote cytotoxic immunity and TH2 cell to induce B cell immunity. B cell produce large amount of antibody specific for various proteins on the surface of HIV
-generation of neutralising antibody
ADCC mediated by NK-cells
80% of HIV infections are initiated by?
a single founder virus
how does HIV enter the body and where does it travel to?
Entry via the genital mucosal epithelium or intravenous routes
Entry virus reaches draining lymph nodes and spreads to the GALT.
GALT has a large number of CD4+ T-cells susceptible to infection.
At the early stage of infection, what are a critical determinant of control?
anti-HIV CD8+ T cell responses
3 main stages of HIV disease?
Three main stages of HIV infection
Within four week significant damage has occurred to lymphoid and germinal centres and viremia exceeds one million RNA copies/ml of blood.
CD4+ T cell numbers decline dramatically.
Symptoms include fever, enlarged lymph nodes, sore throat, muscle and joint pain and lethargy.
The chronic phase lasts between 3-10 years and is characterised by low level viral replication and gradual decline in the numbers of CD4+ T cells.
HIV-1 associated co-morbidities
Infection with HIV-1 is associated with dozens of other diseases:
Opportunistic infection Co infection malignancies, Autoimmune and inflammatory diseases Cardiovascular disease (CVD) Liver disease HIV associated neurological disease Immune reconstitution inflammatory syndrome (IRIS)
Non-AIDS malignancy, CVD and liver disease combined appear to account for >80% of HIV-1 associated co-morbidities
About 6-14% of HIV-infected patients have HBV and about 25-30% have HCV infection
HIV-1 patient phenotypes
Fast progressor
Slow progressor/long term non progressor
Elite controller
Resistant
Factors influencing HIV-1 pathogenicity
HIV-1 pathogenicity is caused by the progressive damage to the host immune system resulting in AIDS and non-AIDS HIV-1 associated co-morbidities.
Host and viral factors influence pathogenicity
Host
- Receptor polymorphisms
- HLA alleles
Viral
- Genomic variability (source of variability unknown)
Through studying these factors the mechanisms behind HIV-1 pathogenicity can be understood.
Set point viral load is the most robust and widely used measure of infection severity.
HIV set point
The HIV set point is the viral load of a person infected with HIV, which stabilizes after a period of acute HIV infection.
The set point is reached after the immune system has developed specific Cytotoxic T cells and begins to attempt to fight the virus.
Set point viral load
Large variation between individuals
Host and viral factors.
GWAS studies have identified >300 SNPs in HLA-class I genes but none elsewhere -Implicates T-cell immune responses
Δ32 deletion in the CCR5 co receptor
Copy number in KIR genes
Age and sex
- Only about 22% of SPVL is explained by these variables
- About 33% of SPVL variation is based upon variability within HIV-1
Factors influencing pathogenicity
Strong and consistent relationship between the level of viremia and the level of both CD4+ and CD8+ T-cell activation during acute HIV infection.
These factors are inextricably linked but:
- High viral load can be observed without disease progression
- Immune activation is more closely associated with disease progression.
Disease progression
Viral load indirectly associated with disease progression
Immune activation (activated CD8+ T cells) directly associated with disease progression
What causes immune activation?
What prevents the reconstitution of CD4+ T –cells and immune function upon antiretroviral therapy?
Immune activation predicts disease progression, pathogenicity and morbidity in HIV-1 infection
Early stages of infection
Permanent damage is done to the immune system early in infection
The sooner antiretroviral therapy is administered the less severe the immune deficiency
Transmitter viruses with low replicative ability due to the accumulation of escape mutations is unable to increase viral load upon reversion of the escape mutations.
These observations point towards early stages of infection being disproportionately important for the pathogenicity of chronic infection
Markers of immune activation in HIV-1 infection
CD38 and HLA-DR on CD4+ and CD8+ T-cells are markers of immune activation
Other markers include: Monocyte activation Serum LPS Soluble CD14 D-dimer CRP
Immune activation in HIV-1 infection precedes what?
Precedes immune deficiency
why is not fully understood?
how HIV-1 infection causes immune activation and disease progression
Even after successful antiretroviral therapy patient immune systems may fail to fully recover
Possible causes of Immune activation
LPS translocation across the gut mucosa - Addition of LPS to SIV models of disease doesn’t fully recapitulate progressive disease
Co-infection - Co-infections such as CMV, EBV, HBV or HCV are not always present
Innate immune activation - Triggers for innate immune signalling not fully known
Pyroptosis during cell-cell infection by HIV-1 - The extent of pyroptosis and its effect on immune activation are unknown
consequences of immune activation?
Inflammation
Damage to lymphoid and germinal centres in the gut
B-cell dysfunction
Innate immune activation
CD4+ T cell decline
AIDS
Co-infection
HIV treatment - Combined antiretroviral therapy
Zidovudine (ZDV/AZT) was the first drug to demonstrate efficacy against HIV-1 - High doses of ZDV toxic and associated with escape mutations
Mechanistic studies and modelling of viral protein structure and function, resulted in a breakthrough in antiretroviral therapy.
Between 1994-1998, a number of new antiviral drugs gained FDA approval.
There are 30 FDA approved anti-retroviral drugs targeting viral entry, the reverse transcriptase, protease and integrase.
This allowed for the first time combinations of antiretroviral therapy (cART).
This dramatically increased the efficacy and durability of therapy by reducing the ability of the virus in generate escape mutations.
In HIC’s, HIV-1 infection is now a chronic immunological disease
