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