The CCR5Delta32 mutation does not account for HIV-1 resistance in the majority of persons who are repeatedly exposed to HIV-1 by high-risk activities but remain seronegative and uninfected. Therefore, we investigated the impact of CCR5 59029 A/G and CCL3L1 copy number polymorphism on HIV-1 disease susceptibility and progression among HIV-1-infected and HIV-1-exposed seronegative North Indians. HIV-1-seropositive (HSP, n = 196) patients, stratified on the basis of disease severity (Stages I, II, and III) and HIV-1-exposed seronegative (HES, n = 47) individuals were genotyped for CCR5-59029 A/G polymorphism by PCR-RFLP and CCL3L1 copy number by the real-time TaqMan PCR method. A group of ethnically matched HIV-1-seronegative (HSN, n = 315) healthy volunteers were also genotyped as controls. Statistical analysis was done by SPSS software. The CCR5-59029 AG genotype was significantly higher in the HES compared with the HSP group (57.44% vs. 37.24%, p = 0.014). The CCL3L1 mean copy number of HES was higher compared with the HSP groups (3.148 +/- 0.291 vs. 2.795 +/- 0.122, p = 0.212), but was not significant when compared with independent samples t test. Possession of CCL3L1 copies < or = 2 or >2 was not associated with enhanced or reduced risk of HIV-1 acquisition. Gene-gene interaction studies showed enrichment of the CCR5-59029AG*CCL3L1>2 genotype in the HES group when compared with the HSP group (31.91% vs. 15.81%, p = 0.021, OR = 0.401, CI = 0.194-0.826). The increased frequency of the CCR5-59029AG*CCL3L1>2 genotype among HES individuals led us to conclude that the CCR5-59029 AG genotype and CCL3L1 gene dose appeared to have synergistic or interactive effects and are expected to be involved in the host innate resistance to HIV-1 infection.