HIV
Disease
Delta32 CCR5 Mutation
RANTES
SDF1
CCR5/CCR2
Case-control analysis
Response to therapy
HIV-1 retrovirus infects T cells/macrophages via CD4 receptor
destruction leads to AIDS
death within 10yrs due to oppertunistic infection and organ failure
Receptors
early infection
CCR5 on macrophage and CD4 by HIV gp120 (M-trophic non-syncytium inducing)
later infection
binds CXCR4 and CD4 on most T cells (T-tropic)
Natural Immunity
exposed-uninfected or slow progressors (MHC)
candidate for exposed-uninfected phenotype
32bp deletion in CCR5 gene conferred resistance in 2 studies
non-funtional CCR5 can't be trafficked to membrane - HIV can't bind
carried by 10% caucasian pop
homozygotes 100% protected - therapy/prophylatic in future?
may have been maintained in pop by resistance to something like ebola/smallpox
West Nile Virus
Heterozygote advantage too - delayed progression
delta 32 CCR5 increases susceptibility to early manifestation WNV
cytokines from brain no longer recruit lymphocytes to infection
involved in pathogenesis not infection of WNV
low in asia/africa - others affecting natural ligands
Regulated upon Activation, Normally T cell Expressed, Presumably Secreted
C-C chemokine, natural ligand for CCR5
1.1C intron SNP associated with accelerated AIDS
decreases affinity for nuclear binding proteins, 4x lower expression, more CCR5 available for HIV-1 binding
Stromal Derived Factor 1
CxC chemokine - natural ligand of CXCR4
3' UTR A variant delays progression of HIV
affects sub-cellular localisation and stability of transcript
increasing SDF1 expression blocking more CXCR4
haplotypes have complex effect on HIV1
CCR5 promoter and upstream CCR2 - strong linkage of delta32 CCR5, promoter and and CCR2 V 64 I
Gonzalez 1999 identified 9 haplotype groups for these genes in humans
HHA (human haplotype A) most common
combination of two inherited haplotypes affects risk ethnicity dependent
HHA/HHF*2 delay in african not caucasian
HHC delayed in causasian, not a american
HHC offset if paired with HHA/HHF*2
Candidates
GWAS
adaptive immunity
cytokines
innate immunity TLR
initially HLA-B27/57 protective against progression
important in HIV peptide presentation
HLA homozygosity accelerated progression
HLA-Bw4 delays AIDS by enchancing NK (altered/absent MHC no longer negatively regulated)
HLA-B*35 allele rapid progression in caucasian
HIV MHC
HLA-B*35-PY slower progression to AIDS - increased CD8+ T cell response to HIV peptide fragements like Gap p24
HLA-B*35 PX faster progression
5/6 aa associated with HIV control in peptide groove
Cytokines
IL10/IFN G powerful HIV replication inhibitors
polymorphisms in promoters leading to decrease can accelerate HIV association
Abacavir - HIV anti-viral therapy
nucleoside analogue, inhibitor of viral reverse transcription
5-8% patients hypersensitive
HLA-B*57:01 - increases abacavir hypersensitivity risk
all hypersensitive carry , 39% of all with genotype hypersensitive - COMPLEX
lower risk if black
viremia during acute infecion, CD4+ T cell depletion, progression to AIDS all vary between individuals
2-15 years difference
Conversely, CCR5P1 haplotype - independent variants in CCR5 promoter accelerate disease progression as higher expression - Martin/McDermott 1998
inhibitors approved in 2007 by FDA
Epigenetics
Involved in latency and infection
HIV latency controlled by epigenetic silencing of viral promoter on 5' long terminal repeat
current therapeutics aiming to reactivate all virus then kill for curative therapy but currently Vorinostat latency reversing agent has been unsuccessful
Infection HIV downreguate IFNg and increase DNMT of promoter
de novo methylation in p16/INK4A tumour-supressor gene