THE LATITUDE WISE PREVALENCE OF THE CCR5-∆32-HIV RESISTANCE ALLELE IN INDIA
Bhatnagar I#, Singh M#, Mishra N, Saxena R, Thangaraj K, Singh L, Saxena SK*
*Corresponding Author: Shailendra K. Saxena, Laboratory of Infectious Diseases & Molecular Virology, Centre for Cellular and Molecular Biology (CSIR), Uppal Road, Hyderabad 500007 (AP), India; Tel.: +91-40-27192630 (direct); +91-40-27160222-41, Ext. 2630; Fax: +91-40-27160591; +91-40-27160311; E-mail: shailen@ccmb.res.in ; shailen1@gmail.com
page: 17

INTRODUCTION

The role of CCR5 as a primary coreceptor for HIV-1 during CD4-mediated entry in macrophages is well defined [1], although its role has also been implicated in many diseases like the West Nile virus infection [2], tick borne encephalitis [3], coronary artery disease [4], type-2 diabetes and renal insufficiency [5] and even atopic asthma [6] etc. CCR5 is expressed on macrophages, monocytes, memory T-cells, dendritic cells and microglia and activates cells by chemokine macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1β (MIP-1β) and RANTES-mediated signaling [7]. Human CCR5 consists of 352 amino acids and is a member of the serpentine G protein coupled receptors [8]. The CCR5 gene, CKMBR5, is present on the p21.3-p24 location of human chromosome-3 [9,10]. Several genetic polymorphisms have been identified within the CCR5 regulatory/promoter region and coding regions that affect HIV transmission and/or disease progression [11]. Studies have suggested that the distribution of the CCR5 polymorphisms and their possible role in the progression of the disease varies between individuals of different racial, ethnic and risk groups [12].

As reported earlier, a 32 bp deletion in the CCR5 gene (CCR5-∆32), corresponding to the second extracellular loop of CCR5, in the homozygous condition confers almost complete resistance to HIV infection [13]. The individuals homozygous for the CCR5-∆32 allele do not express any of the CCR5 receptor on their cell surfaces because of a frameshift mutation in the reading frame of CCR5 leading to an early incorporation of a stop codon and premature termination of the protein (Figure 1a) [14]. Although role of CCR5-∆32 as an HIV suppressive allele is already well defined [15], this protection is not absolute as a few individuals homozygous for this deletion were found infected with the X4 virus, which infects T-lymphocytes [16]. Individuals heterozygous for the CCR5-∆32 mutation showed less susceptibility and delayed progression of HIV/AIDS towards an M-tropic HIV-1 infection [17] as they express only 20-30% of CCR5 on the cell surface and therefore have a reduced risk of HIV infection and, on average, a 2-4 year delay in the progression to AIDS [10,13]. The heterozygous condition of this mutation does not provide protection against vertical HIV-1 transmission, but it is associated with a delayed disease progression in HIV-infected children [18].

Geographical distribution of the CCR5-∆32 allele has previously been reported by various investigators around the globe [19-23]. The allelic frequency of CCR5-∆32 has been found to be highest among Caucasians (10-20%), particularly in those of Northern European descent (with a 1% homozygosity) [20], and a Southeast decrease in the frequency has been observed towards the Mediterranean Sea. It has been seen at low frequencies, i.e., 5% in the near east of Europe, 5.6% in Asia and 3.2% in Africa, and is absent elsewhere apart from isolated occurrences [19,21-23]. Variable distribution of this mutant allele throughout the globe may be attributed either to selection pressure of some pathogen, infectious diseases and/or admixture of the population leading to the diversity.

Host genetic makeup determines susceptibility/protection of any individual against HIV/AIDS [24]. India has the largest number of persons living with HIV/AIDS in the world, with the epidemic getting more intense as we move from North to South in India (higher to lower latitude). The highest rates of HIV prevalence are found in Andhra Pradesh, Maharashtra, Tamil Nadu and Karnataka in the South (comprising of ~63% of all people living with HIV in India) [25]. In this context, although distribution of the CCR5 promoter polymorphisms has been reported in a representative study on a limited number of individuals from Delhi and around (in North India) [26], no extensive information is available regarding the distribution pattern and frequency of the host chemokine receptor CCR5 gene polymorphism (CCR5-∆32) with the corresponding latitude, in vast and different representative Indian populations. Therefore, it is imperative to study the diverse population of India, with special reference to the presence and absence of this protective mutation, which is known to be genetically diverse, due to their endogamous nature. This prompted us to examine the frequency and trend of CCR5-∆32 in different ethnic Indian populations. To the best of our knowledge this is the first study that has taken such a large number of ethnic populations of India (n = 43) comprising such a large number of individuals (1,882) and worked out the prevalence and latitude-wise distribution of the CCR5-∆32 allele to show the North to South cline of the same.




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