Dominant effects of CCR2-CCR5 haplotypes in HIV-1 disease progression

Area of Science:

• Immunogenetics
• Virology
• Human Genetics

Background:

• Haplotypes in the CCR2-CCR5 region are known to influence the progression of Acquired Immunodeficiency Syndrome (AIDS).
• The temporal effect of these genetic variations on Human Immunodeficiency Virus type 1 (HIV-1) infection progression remains unclear, with potential early or late stage impacts.

Purpose of the Study:

• To investigate the specific contributions of CCR2 64I, CCR5 Delta32, and CCR5 promoter haplotype +.P1.+ to AIDS progression.
• To determine whether the effects of these genetic factors are constant throughout infection or are specific to early or late stages of HIV-1 infection.

Main Methods:

• Analysis of the GRIV cohort, comparing rapid progressors (RP) and slow progressors (SP) with a seroconverter control group.
• Genotyping for CCR2 64I, CCR5 Delta32, and CCR5 promoter haplotype +.P1.+ in patient groups representing disease progression extremes.
• Statistical analysis using odds ratios and p-values to assess the significance of genetic associations with AIDS progression.

Main Results:

• CCR5 Delta32 demonstrated a significant early protective effect (OR=0.25, P=0.007) against AIDS progression.
• CCR5 +.P1.+ showed a significant early susceptible effect (OR=2.1, P=0.01) on AIDS progression.
• The influence of these genetic factors was more pronounced in early disease progression, with diminishing significance in later stages or long-term non-progressors.

Conclusions:

• The genetic variants CCR2 64I, CCR5 Delta32, and CCR5 +.P1.+ exert their primary influence on the early stages of HIV-1 infection and AIDS progression.
• These genetic polymorphisms have a limited role in maintaining non-progression beyond 8 years of HIV-1 infection.
• Long-term non-progression is likely mediated by factors other than the studied CCR2 and CCR5 genetic variants.