Th1 cytokine gene polymorphism and the corresponding plasma cytokine levels: A comparative study in HIV-1 positive and exposed uninfected infants.

The pro-inflammatory (Th1) cytokines namely interleukin (IL)-2, IL-6, IL-12, interferon (IFN)-γ, tumor necrosis factor-α (TNF-α) are vital in the clearance of HIV infection. This prospective cohort study aimed to evaluate the polymorphisms of Th1 cytokine genes and their corresponding plasma cytokine levels in HIV-1 positive and exposed uninfected (EU) infants born to HIV-1 positive mothers. CD4 count, viral load of HIV-1 positive mothers was done using commercially available reagents. Cytokine genotyping analysis and levels were done in 20 HIV-1 positive and 54 EU infants. The polymorphisms of Th1 cytokines were done using the PCR-SSP method. Plasma cytokine levels were estimated using Bio-Plex-Pro cytokine assay (BIO-RAD; USA). Results revealed treatment status of the mothers and viral load were the two confounding factors having a significant effect on HIV status of the infant. TNF-α GG genotype is significantly higher in EU infants as compared with HIV-1 positive infants. GG genotype was associated with high TNF- α levels in HIV-1 positive infants but the difference was not statistically significant. HIV-1 positive infants with -IFN-γ (+874) TT genotype was significantly associated with high IFN-γ levels. To the best of our knowledge, this is the first study reporting the role of Th1 cytokine gene polymorphisms and their corresponding plasma cytokine levels in HIV-1 positive and EU infants from India.

Anti-retroviral therapy failure in HIV-1 infected pregnant women and its associated risk of HIV transmission.

BACKGROUND: The HIV perinatal transmission in India even after interventions is still high. The anti-retroviral therapy failure rate and the risk of HIV vertical transmission to infants from women with failed treatment during pregnancy also largely remains unevaluated. METHODS: This is a prospective, observational and follow-up study of 18 months to determine the association of ART failure in pregnant women and the subsequent risk of HIV transmission to their infants. A total of 81 mothers were evaluated for ART success/failure by analysing their viral loads. RESULTS: Analyses revealed that a high percentage (19.75%) of women on ART had high viral loads, while the overall HIV transmission rate to the infants was 8.64%. The rate of transmission from women with high viral load was significantly high compared to women with low viral load (37.5% vs. 1.54%; p = 0.0015). CD4 level was not associated with HIV transmission. However, CD4 levels in women, who had successful or failed ART, were significantly different (p = 0.0031). Factors such as mother's age, baby's sex and weight as well as delivery mode were not associated with HIV transmission, however, breastfeeding and viral loads were found to be independently associated with HIV transmission to the neonates. CONCLUSIONS: This study highlights that a significant proportion of women on ART had impaired viral load control. The rate of HIV transmission to infants was also significantly high among these women. This warrants viral load monitoring of HIV infected women to reduce the overall transmission to the infants.

Distribution of human leucocyte antigen-C in HIV-1-infected patients in Mumbai, India.

HIV pathogenesis is known to be highly influenced by host genetic factors, such as human leucocyte antigens (HLAs) HLA-A and HLA-B. However, the role of HLA-C remains largely unexplored. We evaluated HLA-C distribution in 186 HIV-1-infected individuals and compared them to ethnically matched data derived from the Allele Frequency Net Database using Chi-square test with Fisher's exact two-tailed test. The frequency of HLA-C*05 and HLA-C*15 was higher in infected group, whereas the frequency of HLA-C*04 and HLA-C*14 was higher in control group. HLA-C*17, a rare allele, was significantly higher in infected group. These data could be useful in designing and testing vaccines in Indian population.

Polymorphisms in TH1-TH2 cytokine and receptor genes associated with risk of vertical HIV transmission, in Mumbai, India.

BACKGROUND: Vertical HIV transmission does not occur in all exposed infants. Many infants remain HIV uninfected even after exposure. This is partly attributed to the host genes involving cytokine production, which is rarely documented in vertical transmission. METHODS: Here, an observational cohort study evaluated whether polymorphisms in cytokine, receptor and antagonist genes are associated with perinatal HIV transmission. Single nucleotide polymorphism (SNP) genotyping was performed via the polymerase chain reaction with sequence-specific primers method. Haplotype block structure was determined and statistical analysis was performed using appropriate software in each case. RESULTS: Twenty-two SNPs were analysed in 30 seropositive and 61 seronegative children. Confounding factors such as mother's viral load, treatment regimen, breast feeding options, etc., were documented. Analysis revealed the association of two SNPs: IL1R1 (rs2234650) and TNFA (rs1800629) with vertical HIV transmission. CT genotype at IL1R1 was observed at a higher frequency in positive children (76.66% versus 42.62%, p = 0.002), whereas the CC genotype was significantly increased in exposed uninfected children (47.54% versus 16.66%, p = 0.004). Similarly, the GG genotype of TNFA was significantly higher in uninfected children compared to infected ones (76.66% versus 46.66%, p = 0.005), whereas the GA genotype frequency was higher among infected children (53.33% versus 21.66%, p = 0.003). The frequency of the 'G' allele of TNFA and 'C' allele of IL1R1 was significant (p = 0.018) in negative children. Haplotypes of SNPs belonging to IL1, TNFA and IL4 were also found to associate with transmission. CONCLUSIONS: The present study confirms the association of SNPs IL1R1 (rs2234650) and TNFA (rs1800629) with the risk of vertical transmission. These SNPs can be exploited as possible predictive markers of HIV transmission.

Genetic variation in the promoter region of pro-inflammatory cytokine TNF-α in perinatal HIV transmission from Mumbai, India.

Various host factors such as cytokines and HLA, regulate the immune system and influence HIV transmission to infants exposed to HIV-1 through their mothers. Tumor Necrosis Factor Alpha (TNF-α) is a strong pro-inflammatory mediator and thought to influence vulnerability to HIV infection (and/or) transmission. Polymorphisms in regulatory regions are known to govern the production of this cytokine. However, the association of these variations in perinatal HIV transmission is yet to be established. Present study aimed to evaluate if polymorphisms in promoter region of TNF-α gene is associated with perinatal HIV transmission. With informed consent from parents, infants' blood was collected for HIV screening and SNPs analysis at 2 loci: TNF (rs1800629) and TNF (rs361525) using PCR-SSP method. HIV positive (n = 27) and negative (n = 54) children at the end of 18th month follow up were considered for this study. GG genotype, responsible for low expression of TNF (rs1800629) was significantly (p = 0.005) higher in uninfected children, while higher GA genotype frequency was observed in infected children. The 'G' allele frequency was significantly higher in negative children (p = 0.016). We conclude that genotypic variants of TNF (rs1800629) are a likely contributor to perinatal HIV transmission. This provides new insights in markers of differential susceptibility to perinatal HIV transmission.

Polymorphisms in IL-1 gene cluster and its association with the risk of perinatal HIV transmission, in an Indian cohort.

Host genetic diversity plays a very important role in protecting infants exposed to HIV-1 through their mothers. IL-1 family genes are key mediators of inflammatory responses and no studies are available on its association with perinatal HIV transmission. We aimed to evaluate if single nucleotide polymorphisms in IL-1 family genes are associated with perinatal HIV transmission. Infants of HIV positive women were genotyped for five polymorphic loci in IL1 gene cluster namely; IL1R1 (rs2234650), IL1A (rs1800587), IL1B (rs16944), IL1B (rs1143634), and IL1RN (rs315952) using polymerase chain reaction with sequence specific primers (PCR-SSP) method. Haplotype block structure was determined using Haploview and statistical analysis was done using PyPop. In this cohort based observational study significantly increased frequency of CT genotype in IL1R1 (rs2234650) was observed in positive vs. negative children (76.4% vs. 42.2%, p = 0.023), while CC genotype was significantly (p = 0.022) high in exposed uninfected children compared to infected ones (51.1% vs. 17.6%). These significances, however, did not stand the Bonferroni corrections. Haplotypic analysis demonstrated that the TCCCT haplotype was significantly associated (p = 0.002) with HIV transmission and remained significant even after Bonferroni correction. The children who had the protective CC genotype at IL1R1 (rs2234650) and were still positive had the TTC haplotype for IL1A (rs1800587):IL1B (rs1143634):IL1R1 (rs2234650). In contrast, 16 out of 19 (84.2%) children who had the CT genotype and were still negative had the protective CTC haplotype for IL1A (rs1800587):IL1B (rs16944):IL1B (rs1143634). IL1R1 (rs2234650) polymorphisms CT/CC along the specific haplotypes of the IL-1 gene family can be exploited as possible markers for prediction of perinatal HIV transmission.