HIV Flashcards
Why can HIV be classed as a complex trait?
The majority of traits conferring resistance and susceptibility are genetically complex! The allele is neither necessary not sufficient to confer resistance or susceptibility but the allele does decrease or increase the risk of disease.
How can the genetics conferring susceptibility/ resistance to HIV be identified?
candidate gene approach/ hypothesis-driven - commonly used in infectious disease as we know quite a lot about the pathogenesis
GWA - lots of pitfalls to GWA in infectious disease
What is primary receptor for HIV?
CD4 receptor on macrophages and T-cells. Destruction of T-cells –> aids.
What are co-receptors for HIV infection?
CCR5 and CXCR4
What co-receptor is involved in early stage infection? what co-receptor is involved in late stage infection?
early - CCR5 - M-tropic. The CCR5 receptor is on macrophages and some CD4+ cells
late CXCR4 - T-trophic. On most CD4+ t-cells
When infection switches to the T-trophic stage that’s when see rapid progression to AIDS
What are the two types of people that confer natural immunity to HIV infection?
- Exposed -uninfected - No matter how many times exposed to the virus still no infection
- Long-term non-progressors - HIV positive but do not progress to full blow aids.
Give an example of a mt that confers immunity (exposed-uninfected) to HIV? What percentage of the Caucasian population have this?
(triangle)32CCR5 deletion
10% of Caucasian population have this - deletion results in non-functional CCR5. CCR5 is produced but it is not trafficked to the cell surface, therefore no co-receptor to bind to and results in no infection.
Homozygotes remain HIV negative despite repeated exposure to virus.
Heterozygotes show delayed disease progression
people that homozygous or heterozygous for (triangle)32CCR5 are perfectly healthy. Although CCR5 is a chemokine receptor there is a lot of redundancy in immune system.
(the 32CCR5 deletion is similar to the duffy antigen and malaria -> no receptor so infection can’t happen)
Why would a blocking (triangle)32CCR5 not be a good idea?
> still a lot of research going on into CCR5 antagonists in areas where West Nile Virus isn’t a threat. When blocking receptors as a therapeutic strategy, you need to be aware of the natural role of the receptor - CCR5 is naturally a chemokine receptor.
> Although (triangle)32CCR5 deletion is an advantage for HIV (reduces the risk of infection), it increases the risk of severe disease when infected with Western Nile Virus.
How is delta32CCR5 associated with WNV
> WNV and 32CCR5 associated with severe symptomatic WNV infection in patients
No difference in frequence of infection between homozygotes and controls suggesting mutation is not associated with risk of infxn. However, the mutation is associated with a worst clinical outcome - therefore important in the progression of the disease.
The virus infects the brain and causes encephalitis –> CCR5 is vital for chemokine detection and the recruitment of T-cells to the brain to reduce cerebral damage –> this is why mt. makes patients more at risk of severe disease.
Why can 32CCR5 mts not account for all exposed-uninfected phenotypes?
- Mt is very rarely found in African or Asian populations but exposed-uninfected individuals are found in these populations
- Other polymorphisms that increase/ decrease the risk of HIV infection have been found via GWA and candidate gene approach:
> polymorphisms in host proteins involved in HIV replication
Intrinsic anti-virus restriction factors
Give a haplotype that demonstrates haplotypes are important in HIV disease progression
Strong linkage between 32CCR5 snp and CCR2-V64I
> 9 different haplotypes have been identified - some conferring resistance and some conferring susceptibility.
> The frequency and effect of haplotypes varies substantially between ethnic group.
> HHA and HHA/HHF*F haplotypes are associated with delayed progression to AIDS in African Americans
> HHC haplotypes ASSOCIATED with delayed progression in Caucasians and accelerated progression in African-Americans.
C for Caucasian and A for African American
The difference that haplotype inheritance confers in terms of susceptibility to disease is extremely complex and this can be demonstrated by the above example
Why is haplotype pairing important in HIV infection?
> Argument that looking at a simple haplotype/ polymorphism is far too simple as various points in which infectious disease susceptibility can be altered by genetic makeup. Gene associated with HIV clearly do not work in a simple additive manner, but through a network of complex gene-gene and gene-environment interactions. In this case it is often argued that association approaches are far too simplistic and reductionist. Although the HHC haplotype is associated with accelerated progression to AIDs, it could be mitigated when combined with the protective effects of HHA as these confer slower progression.
Give some examples of candidate genes related to immunity for HIV?
- Adaptive immunity - HLA genes
- Cytokines and cytokine receptors
- Innate immunity e.g Toll-like receptors (TLRs)
What is HLA-B27 association with HIV
> Delayed progression to AIDs
Increased susceptibility to Ankylosing spondylitis (type of chronic arthritis affects parts of spine, muscle and ligament). Cause of ankylosing spondylitis not understood but linked to HLA-B27. around 9/10 people with ankylosing spondalitis so strong association but the allele is neither necessary nor sufficient to cause the disease.
role other genes that interact with HLA-B27, other genes that alone or gene-environment interactions.
What HLAs are associated with delayed HIV progression?
HLA-27 and HLA-57- delayed progression to AIDS - likely to be associated with their peptide
