Role of Homozygous DC-SIGNR 5/5 Tandem Repeat Polymorphism in HIV-1 Exposed Seronegative North Indian Individuals

Abstract

Despite multiple sexual exposures to HIV-1 virus, some individuals remain HIV-1 seronegative. Although several genetic factors have been related to HIV-1 resistance, the homozygosity for a mutation in CCR5 gene (the 32-bp deletion, i.e., CCR5-Delta32 allele) is presently considered the most relevant one. The C-type lectins, DC-SIGN (present on dendritic cells and macrophages) and DC-SIGNR (present on endothelial cells in liver and lymph nodes) efficiently bind and transmit HIV-1 to susceptible cell in trans, thereby augmenting the infection. A potential association of the DC-SIGN and DC-SIGNR neck domain repeat polymorphism and risk of HIV-1 infection is currently under debate. To determine the influence of host genetic factors on HIV-1 resistance, we conducted genetic risk association study in HIV-1-exposed seronegative (n = 47) individuals, HIV-1 seronegative (n = 262) healthy control, and HIV-1-infected seropositive patients (n = 168) for polymorphism in neck domain of DC-SIGN and DC-SIGNR genes. The DC-SIGN and DC-SIGNR genotypes were identified by polymerase chain reaction method in DNA extracted from peripheral blood and confirmed by sequencing. Fisher exact or chi (2) test was used for static analysis. DC-SIGN genotype and allele distribution was fairly similar in HIV-1-exposed seronegative, HIV-1 seropositive, and HIV-1 seronegative control. There was no statistical significance in the differences in the distribution of DC-SIGN genotypes. A total of 13 genotypes were found in DC-SIGNR neck repeat region polymorphism. Among all the genotypes, only 5/5 homozygous showed significant reduced risk of HIV-1 infection in HIV-1-exposed seronegative individuals (p = 0.009). A unique genotype 8/5 heterozygous was also found in HIV-1 seropositive individual, which is not reported elsewhere.

Polymorphisms in DC-SIGN and L-SIGN genes are associated with HIV-1 vertical transmission in a Northeastern Brazilian population

“…No differences in genotype distribution were found when comparing HIV + and HIV À children, however we observed that the 5/5, 6/6 and homozygous genotypes were significantly more frequent in HIV + children than healthy controls. Even if our findings evidenced a lack of association between L-SIGN gene polymorphisms and HIV vertical transmission, the different distribution of L-SIGN exon 4 alleles in HIV + and unexposed uninfected children may however suggest a possible involvement of L-SIGN in HIV infection, as reported in other studies [12,19,31] In Table 5 we summarize the main association reported up to now for DC-SIGN and HIV-1 infections in different populations. The different findings obtained in distinct populations indicate that ethnicity can play a role in the genetic susceptibility to HIV vertical transmission, a complex and multifactorial trait, so replica studies are needed.…”

“…Different studies have shown that polymorphisms in DC-SIGN and L-SIGN genes can influence susceptibility and/or resistance to HIV-1 [11][12][13]18,19].…”

“…DC-SIGN and L-SIGN exon 4 tandem repeat polymorphism were analyzed as described by Rathore et al [12] and Bashirova et al [16].…”

“…DC-SIGN and L-SIGN genes polymorphisms have been involved in protection and susceptibility to infections, including HIV-1, in different ethnic groups [6,[11][12][13][14].…”

Association of RANTES −403 G/A, −28 C/G and In1.1 T/C polymorphism with HIV‐1 transmission and progression among North Indians

“…HIV-1 infected individuals have widely different rates of disease progression and several SNPs are reported to be effective in different clinical stages of HIV/AIDS patients. Among North Indians, we recently reported that homozygous DC-SIGNR 5/5 showed significant reduced risk of HIV-1 infection [Rathore et al, 2008a] while repeat region polymorphism in the DC-SIGN neck domain does not effect risk of HIV-1 transmission [Rathore et al, 2008b]. Till date, only single study was conducted in which effect of RANTES genetic variants was assessed for HIV/AIDS transmission among North Indians [Suresh et al, 2006].…”