To determine the effects of haplotype pairs (diplotypes) on progression, we examined the distribution of diplotypes among SP, RP, and the intermediate control group (Table 1). The P2-4/P2-4 diplotype was neutral, because the frequency was nearly identical among the 3 groups (f = 21%-22%). Individuals carrying 1 CCR5 Δ32 haplotype, regardless of the second haplotype, tended to be underrepresented in RP and overrepresented in SP. By comparing RP with the intermediate control group, we observed that the CCR5 P2-4/Δ32 diplotype is strongly protective (OR = 0.11; P = 0.01).
Of SP, 150 had follow-up clinical visits over 3 years: 45 remained slow SP with no treatment and stable CD4+ cell counts (<20% decline in CD4+ T-cell count); 47 progressing SP had sharp declines in CD4+ cell counts to <400/mm3 and/or received antiretroviral therapy; and 58 had a slow decrease in CD4+ cell counts that remained >500/mm3. There were no significant differences among progressing SP, slow SP, and the remaining 58 SP (P > 0.3; Table 2), confirming that the AIDS-modifying genetic factors that influence viral cell entry exert their effects early in HIV-1 infection.
In this study, comparison of subjects progressing in the first three years after HIV-1 infection with average progressors showed that CCR5 Δ32 and CCR5 P1 have a strong influence early in HIV-1 infection. The effect of these factors tended to be stronger on early progression than on late progression, although this tendency was significant only for CCR5 Δ32. It is likely that initial viral load is diminished by the presence of CCR5 Δ32 and increased by CCR5 P120,21; however, we could not access this because early set point RNA levels were not available for the GRIV cohort. Carrying CCR5 Δ32 and not CCR5 P1 might provide an initial advantage in limiting CD4+ cell depletion early in infection. As a consequence, patients with CCR5 Δ32 would be more likely to be SP according to our criteria (CD4+ cell counts of >500/mm3 for at least the first 8 years after HIV-1 seroconversion) as shown by the increase of patients with CCR5 Δ32 and the decrease of those with CCR5 P1 among SP compared with the intermediate control group (Table 1).
The authors are grateful to all the patients and the medical staff who kindly collaborated in this project.
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