Interaction between allelic variation in IL12B and CCR5 affects the development of AIDS: IL12B/CCR5 interaction and HIV/AIDS.
OBJECTIVE
IL-12 is involved in immune surveillance and response that links the innate and adaptive arms of the immune system. Among its many effects, IL-12 increases the cell surface expression of the CCR5 co-receptor for R5 strains of HIV-1, which are predominantly involved in HIV-1 transmission and spread. In the present study we investigated the effect of epistasis between allelic variants of CCR5 and IL12B on the susceptibility to HIV-1 infection and HIV-1 disease progression.


METHODS
HIV-1-positive patients were genotyped for IL12Bpro from two groups of HIV-1 seroincident patients from Western Australia (n = 101 and 200), longitudinal clinical data were available for one of the Western Australian cohorts for a period of over 12 years and a group of seroprevalent individuals from Sydney (n = 112). A group of ethnically matched healthy volunteers (n = 200) was also genotyped as controls. Comparison of allele frequencies between HIV-1 patients and controls was performed to determine the influence on susceptibility to HIV-1 infection, and regression analysis was used to determine the influence on disease progression.


RESULTS
Individuals positive for CCR5Delta32 and who carry the IL12Bpro1.1 genotype were underrepresented across all three independent HIV-1-positive cohorts [odds ratio 0.5; 95% confidence interval (CI) 0.28-0.97; P = 0.038]. CCR5wt/wt and IL12Bpro2.2 individuals progressed to AIDS at a significantly faster rate than other CCR5 and IL12Bpro groups (hazards ratio 3.24; 95% CI 1.9-15.1; P = 0.002).


CONCLUSIONS
Epistatic interaction between allelic variants of CCR5 and IL12Bpro exert a significant influence on the clinical outcome of HIV-1 infection.
Gabutero
Elwyn
E
Institute for Immunology and Allergy Research, Westmead Millennium Institute, NSW 2145, Australia.
Moore
Corey
C
Mallal
Simon
S
Stewart
Graeme
G
Williamson
Peter
P
D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics* / Q000276:immunology / Q000635:transmission; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D015331:Cohort Studies; D018450:Disease Progression; D004198:Disease Susceptibility; D004843:Epistasis, Genetic; D005787:Gene Frequency; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics*; D019713:Receptors, CCR5 / Q000235:genetics*; D012044:Regression Analysis; D019562:Viral Load; D014904:Western Australia
D019713:Receptors, CCR5; D018664:Interleukin-12