The CCR5 gene acts as one of the coreceptors for the entry of M-tropic strains of HIV-1 [28]. The global distribution pattern of CCR5-∆32 reveals that most susceptible populations such as African populations lack the protective CCR5-∆32 allele [19,29]. In less susceptible populations, the majority of persons carry the CCR5-∆32 allele in the heterozygous condition [19]. For the first time, we have reported the approximate absence of the CCR5-∆32 allele in such a large sample of the Indian population. Our results have exhibited that either the CCR5-∆32 mutation is completely absent or found in very low frequencies in various ethnic populations of India. Lack of the homozygous CCR5-∆32 mutation and low prevalence of heterozygous CCR5-∆32 mutations suggest that Indians are highly susceptible to HIV/AIDS, and this correlates with the highest number of HIV/AIDS infected individuals in India. The presence of low frequencies of CCR5-∆32 in some individuals of upper castes and Muslims of North India (2%, χ2 value 0.0277%) implies that these communities may have a better resistance toward HIV/AIDS. These results are in accordance with previous studies that reported a high allelic frequency of 5.36% in Muslims of North India and upper castes [30,31].

The spread of HIV in India has been variable, with the epidemic being most intense in Southern India [32]. Our results suggest that the distribution frequency of CCR5-∆32 (Table 1) decreases significantly as we go down (North to South) along with the latitudes. The distribution of CCR5-∆32 (Figure 2) and the significant variance in its mean frequency between South and North India (Figure 3) also propose that there is southward decreasing cline in CCR5-∆32. These results suggest that South Indian populations might lack a genetic make-up, which is protective against HIV/AIDS. This is in accordance with an antenatal clinical HIV prevalence survey in 2005, which reports a higher frequency of HIV/AIDS in South Indian populations [32]. Therefore, our data reveal that the CCR5-∆32 mutation may be one of the important factors for HIV/ AIDS prevalence in India.

A possible reason for the presence of CCR5-∆32 in some populations is hypothesized to be the strong selective pressure for increased resistance against an infectious agent like small pox [33]. Smallpox was present in India as early as 1000 B.C. The presence of a low frequency of the CCR5-∆32 mutation, in spite of having significantly higher cases of small pox in India than estimated, for unprotected populations in 18th century Europe, does not support the hypothesis of positive selection pressure of smallpox for CCR5-∆32 [34]. But the presence of heterozygous mutations in some ethnic populations of North India, in our results, is consistent with the historical and Y chromosome marker studies that North Indian upper caste and middle caste are descendants of Europeans [9,35,36]. Indo-European languages (i.e., Indian classical languages and most European languages) also suggest that contemporary Hindu Indians are descendants of primarily West Eurasians who migrated from Europe, the Near East, Anatolia, and the Caucasus 3000-8000 years ago [37]. Therefore, the possible cause of higher frequencies of CCR5-∆32 among Muslims and North Indians may be because of admixture as the Eurasians migrated through Europe [38]. Our results also suggest a sporadic presence of CCR5-∆32 mutations in some of the South Indian populations, which may be accredited to the presence of Eurasian Y chromosome haplotype groups in some of these populations [39,40]. Thus, the genetic admixture of Eurasians and Caucasians could possibly be one of the reasons for such distribution patterns and frequencies in India. The absence of the CCR5-Δ32 allele frequency in eastern states may be attributed to the common ancestry that they share with the Myanmar population [38].

Collectively, it is evident from our data that the genetic protection conferred by the CCR5-∆32 mutation is absent in Indian populations and corresponds to the HIV/AIDS dynamics in India. It suggests that apart from behavioral factors, host genetics also play an important role in influencing the dynamics of HIV infection in India. Thus, determining the genetic make-up and understanding the role and consequence of variable distributions of host susceptibility factors in India, may help in identifying the correct drug to be administered and help patients survive longer. Our study may help in developing a therapeutic or preventive strategy based on targeting the CCR5 gene. As per international estimates, India could have 20-25 million HIV cases by 2010 [41]. With this new information of the absence of host resistance factors in Indians, the effort to control the HIV epidemic in India needs to be further strengthened to curb the epidemic menace.

Gene Accession Numbers. The sequencing results led to the identification of 441 nucleotide length (wild type; encoding 147 amino acids) and 409 nucleotide length (mutant type; encoding 87 amino acids), that were submitted to NCBI with EF202087 and EF202088 accession numbers, respectively.