Transcript Host Susceptibility and Resistance to HIV

Host Susceptibility and
Resistance to HIV
Relative hazards for genetic
associations with progression to AIDS
Non-HLA
genetic associations
with progression
To AIDS
Genetic associations
including HLA effects,
with progression
To AIDS
CCR5 D32 allele
ccr5/ccr5
81% of Caucasian
Get infected normally
Progress to AIDS normally
ccr5/Dccr5
15-18% of Caucasians
Get infected normally
But progress to AIDS 2-4 years more slowly
Dccr5 /Dccr5
1% of Caucasians
Highly Resistant to Infection
Loss of CCR5 function but
otherwise normal (no side effects)
CCR5 cell surface density on CD4+ T
cells correlates with delayed disease
progression
Other genetic polymorphisms
in CCR5
ECL2
N-term
Extracellular
Intracellular
ECL1
ECL3
Genetic Variants in CCR5
HIV-infected CCR5D32 heterozygotes
have lower viral loads
wt/wt
wt/D32
CCR2-V64I
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V64I is a conservative change in the
first transmembrane domain of CCR2,
a minor coreceptor
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Protective effect similar to ccr5D32
heterozygotes
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10% in Caucasians
15% in African-Americans
17% in Hispanics
25% in Asians
2-4 years delayed disease progression
Lower viral loads 9-12 months postseroconversaion
Mechanism of protective effect is
unclear
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Never found on the same haplotype
with ccr5D32 allele
Effects of ccr2-64I and ccr5D32 are not
additive
May be found in complete linkage
disequilibirum with CCR5 promoter
point mutation
CCR5 Promoter Polymorphism
P1 promoter allele can accelerate
disease progression
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P1 promoter effects
can be overcomed
by protective
CCR2/CCR5 or
sdf-1 allele
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P1 promoter allele
frequency drops in
long-term nonprogressors
ccr2-64I and
ccr5D32 allele
frequency increases
in long-term nonprogressor
IL-10 promoter polymorphism
accelerates disease progression
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IL-10 inhibits T cell cytokine
secretion;
immunosuppressive cytokine
IL-10 may control virus
proliferation in macrophages
IL-10 promoter polymorphism
(-592 C-->A) linked to
diminished IL-10 production
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Would expect association with
accelerated progression to
AIDS
Effect of IL-10 promoter
polymorphism (5’A) is
dominant
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Heterozygotes and homozygotes
have same influence on disease
progression
Polymorphism in 3’ untranslated
region of SDF-1 gene may be
Chemokine Ligand
associated with delayed
progression to AIDS
SDF-1
SDF-1[3’A/3’A]
SDF-1[+/3’A]
SDF-1[+/+]
CXCR4
CXCR4/SDF-1 Knock-Out Mouse
phenotype is lethal
Fraction AIDS Free
HLA and HIV:
heterozygous advantage
0
10
20
0
10
20
years since seroconversion
An individual who is homozygous at HLAA,HLA-B, and HLA-C displays a limited
variety of class I molecules available for antigen presentation to cytotoxic T
lymphocytes (CTLs) relative to an individual heterozygous for each class I locus.
HLA and HIV:
heterozygous advantage
Overall Kaplan Meier
survival analysis