OBJECTIVE Individuals homozygous for a deletion in the CCR5 gene (CCR5delta32/CCR5delta32) are resistant to HIV infection, indicating that this particular chemokine receptor plays a crucial role in the initiation of in vivo HIV infection. We investigated the effect of the heterozygote genotype (CCR5/CCR5delta32) on susceptibility of peripheral blood mononuclear cells (PBMC) to HIV infection. METHODS Sensitivity to HIV infection of PBMC from volunteers with either the CCR5/CCR5, CCR5/CCR5delta32, or CCR5delta32/CCR5delta32 genotypes was examined 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 infection with either three M-tropic HIV-1 isolates, (92RW009A, HIV-1ada, and HIV-1(59)), one dual-tropic HIV-1 isolate (92BR021), or two T-tropic HIV-1 isolates (92UG021 and 92UG029). RESULTS PBMCs from the CCR5/CCR5delta32 group required a significantly higher inoculum (p value from .036 to .003) to become infected with these three M-tropic HIV-1 isolates than did PBMC from the CCR5/CCR5 group, but became infected after exposure to an inoculum of T-tropic HIV-1 isolates that was comparable to that which infected PBMCs from the CCR5/CCR5 individuals. CONCLUSIONS The decreased susceptibility of PBMCs from individuals heterozygous for the CCR5 deletion to HIV infection by M-tropic HIV-1 isolates may provide a mechanistic explanation for the delayed progression of disease in some CCR5/CCR5delta32 individuals.