DECREASED SUSCEPTIBILITY OF PERIPHERAL-BLOOD MONONUCLEAR-CELLS FROM INDIVIDUALS HETEROZYGOUS FOR A MUTANT CCR5 ALLELE TO HIV-INFECTION

Objective: individuals homozygous for a deletion in the CCR5 gene (CCR 5 Delta 32/CCR5 Delta 32) are resistant to HIV infection, indicating t hat this particular chemokine receptor plays a crucial role in the ini tiation of in vivo HIV infection. We investigated the effect of the he terozygote genotype (CCR5/CCR5 Delta 32) on susceptibility of peripher al blood mononuclear cells (PBMC) to HN infection. Design: Sensitivity to HIV infection of PBMC from volunteers with either the CCR5/CCR5, C CR5/CCR5 Delta 32, or CCR5 Delta 32/CCR5 Delta 32 genotypes was examin ed by challenging their PBMCs with serial titers of HIV isolates with different cellular tropisms. The genotype of the PBMCs was correlated with the lowest viral inoculum required to initiate productive infecti on with either three M-tropic HIV-1 isolates, (92RW009A, HIV-1(ada), a nd HIV-1(59)), one dual-tropic HIV-1 isolate (92BR021), or two T-tropi c HIV-1 isolates (92UG021 and 92UG029). Results: PBMCs from the CCR5/C CR5 Delta 32 group required a significantly higher inoculum (p value f rom .036 to .003) to become infected with these three M-tropic HIV-1 i solates than did PBMC from the CCR5/CCR5 group, but became infected af ter exposure to an inoculum of T-tropic HIV-1 isolates that was compar able to that which infected PBMCs from the CCR5/CCR5 individuals. Conc lusions: The decreased susceptibility of PBMCs from individuals hetero zygous for the CCR5 deletion to HIV infection by M-tropic HIV-1 isolat es may provide a mechanistic explanation for the delayed progression o f disease in some CCR5/ CCR5 Delta 32 individuals.