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  32 allele ccr5/ccr5 81% of Caucasian Get infected normally Progress to AIDS normally ccr5/  ccr % of Caucasians Get infected normally But progress to AIDS 2-4 years more slowly  ccr5 /  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 Extracellular Intracellular N-term ECL2 ECL3 ECL1

Genetic Variants in CCR5

HIV-infected CCR5  32 heterozygotes have lower viral loads wt/wt wt/  32

CCR2-V64I V64I is a conservative change in the first transmembrane domain of CCR2, a minor coreceptor 10% in Caucasians 15% in African-Americans 17% in Hispanics 25% in Asians Protective effect similar to ccr5  32 heterozygotes 2-4 years delayed disease progression Lower viral loads 9-12 months post- seroconversaion Mechanism of protective effect is unclear Never found on the same haplotype with ccr5  32 allele Effects of ccr2-64I and ccr5  32 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 P1 promoter effects can be overcomed by protective CCR2/CCR5 or sdf-1 allele

P1 promoter allele frequency drops in long-term non- progressors ccr2-64I and ccr5  32 allele frequency increases in long-term non- progressor

IL-10 promoter polymorphism accelerates disease progression 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 Would expect association with accelerated progression to AIDS Effect of IL-10 promoter polymorphism (5’A) is dominant Heterozygotes and homozygotes have same influence on disease progression

CXCR4 SDF-1 CXCR4/SDF-1 Knock-Out Mouse phenotype is lethal Chemokine Ligand SDF-1[3’A/3’A] SDF-1[+/3’A] SDF-1[+/+] Polymorphism in 3’ untranslated region of SDF-1 gene may be associated with delayed progression to AIDS

HLA and HIV: heterozygous advantage 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 Fraction AIDS Free years since seroconversion

HLA and HIV: heterozygous advantage

Overall Kaplan Meier survival analysis