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
