ABCG2 polymorphisms and susceptibility to ARV-associated hepatotoxicity.

BACKGROUND: The ABCG2 421C/A polymorphism contributes significantly to the distribution and absorption of antiretroviral (ARV) regimens and is associated with the undesirable side effects of efavirenz. METHODS: To investigate this, we examined ABCG2 34G/A (rs2231137) and 421C/A (rs2231142) genetic variations in 149 HIV-infected patients (116 without hepatotoxicity, 33 with ARV-induced hepatotoxicity) and 151 healthy controls through the PCR-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS AND DISCUSSION: The ABCG2 34GA genotype and 34A allele indicated a risk for antiretroviral therapy-associated hepatotoxicity development (p = 0.09, OR = 1.58, 95% CI: 0.93-2.69; p = 0.06, OR = 1.50, 95% CI: 0.98-2.30). The haplotype GA was associated with hepatotoxicity (p = 0.042, OR = 2.37, 95% CI: 1.04-5.43; p = 0.042, OR = 2.49, 95% CI: 1.04-5.96). Moreover, when comparing HIV patients with hepatotoxicity to healthy controls, the haplotype GA had an association with an elevated risk for the development of hepatotoxicity (p = 0.041, OR = 1.73, 95% CI: 1.02-2.93). Additionally, the association of the ABCG2 34GA genotype with the progression of HIV (p = 0.02, OR = 1.97, 95% CI: 1.07-3.63) indicated a risk for advanced HIV infection. Furthermore, the ABCG2 421AA genotype was linked to tobacco users and featured as a risk factor for the progression of HIV disease (p = 0.03, OR = 11.07, 95% CI: 1.09-270.89). CONCLUSION: The haplotype GA may enhance the risk of hepatotoxicity development and its severity. Individuals with the ABCG2 34A allele may also be at risk for the development of hepatotoxicity. Additionally, individuals with an advanced stage of HIV and the ABCG2 34GA genotype may be at risk for disease progression.

Resveratrol: A potential therapeutic natural polyphenol for neurodegenerative diseases associated with mitochondrial dysfunction.

Most polyphenols can cross blood-brain barrier, therefore, they are widely utilized in the treatment of various neurodegenerative diseases (ND). Resveratrol, a natural polyphenol contained in blueberry, grapes, mulberry, etc., is well documented to exhibit potent neuroprotective activity against different ND by mitochondria modulation approach. Mitochondrial function impairment is the most common etiology and pathological process in various neurodegenerative disorders, viz. Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. Nowadays these ND associated with mitochondrial dysfunction have become a major threat to public health as well as health care systems in terms of financial burden. Currently available therapies for ND are limited to symptomatic cures and have inevitable toxic effects. Therefore, there is a strict requirement for a safe and highly effective drug treatment developed from natural compounds. The current review provides updated information about the potential of resveratrol to target mitochondria in the treatment of ND.

TLR3 polymorphisms in HIV infected individuals naïve to ART.

BACKGROUND: TLR3 polymorphisms affect the risk of HIV infection and modify the disease course. Consequently, we analyzed the association of TLR3 polymorphism (rs5743312, rs3775296, and rs3775291) with susceptilbity to HIV-1 acquisition and disease progression. METHOD: This is a cross-sectional study. Genotyping of TLR3 polymorphisms were completed by the utilization of the PCR-RFLP technique in 153 HIV naive subjects and 158 healthy controls. RESULT: A haplotype is a physical grouping of genomic variants that tend to be inherited together. The TCC haplotype was increased in HIV infected individuals compared with healthy controls (0.05% versus 0.03%). TLR3 rs3775291CT genotype was associated to the early stage of HIV infection (OR=2.19, P=0.04), with a higher occurrence in advance stage of HIV infection when contrasted with healthy controls (41.2% versus 32.3%). TLR3 rs3775296 CA genotype was likely to be associated with intermediate stage of HIV infection (19.5% versus 31.6%, OR=0.42, P=0.06). TLR3 rs5743312TT genotype was used to be greater prevalence in advanced stage of HIV infection compared with healthy controls (2.9% versus 1.9%). TLR3 rs3775296CA genotype was less prevalent in HIV subjects devouring tobacco when contrasted with non-users (9.1% versus 34.9%, OR=0.25, P=0.09). TLR3 rs3775296AA and rs3775291CT and TT genotypes have been overrepresented in HIV subjects using alcohol when contrasted with non-users (5.6% versus 1.1%, OR=1.83, P=0.67; 50.0% versus 42.2%, OR=1.84, P=0.31; 5.6% versus 3.3%, OR=2.70, P=0.50). In multivariate examination, rs5743312TT genotype showed a greater risk for HIV infection (OR=1.86, P=0.50). CONCLUSION: TLR3 rs3775291 C/T polymorphism may assist the risk of disease progression in alcohol consumers. TLR3 rs3775291 CT genotype may enhance the disease progression whereas the TLR3 rs3775296 CA genotype may protect for disease progression.

Debelalactone Prevents Hepatic Cancer via Diminishing the Inflammatory Response and Oxidative Stress on Male Wistar Rats.

The current study was conducted to exemplify the effect of debelalactone on tissue protection, chronic hepatic inflammation, hepatic protection and oxidative stress induced by diethyl nitrosamine in Wistar rats. Therefore, DEN (200 mg/kg) was used for the induction the hepatocellular carcinoma (HCC) and the level of serum alpha fetoprotein was used for the estimation and confirmation of HCC. The study illustrated that debelalactone (DL) significantly downregulated the hepatic, non-hepatic parameters such as aspartate aminotransferase, alanine aminotransferase, alpha fetoprotein, NO levels, total protein, albumin, blood urea nitrogen, total bilirubin, and direct bilirubin in dose dependent manner, as well as noticeably improving the body weight, of treated animals. The macroscopically observation of DEN-induced rat liver showed the formation of informalities in liver tissue, which was reduced with treatment of DL at dose dependent manner. However, antioxidant markers and inflammatory mediators such as lipid peroxidation, catalase, superoxide dismutase, glutathione peroxidase and transferase, TNF-α, IL-1ß, IL-6, and NF-kB restored up to the normal level by DL. The histopathology studies showed that the treated group of animals returned to a normal status. Collectively, it can be concluded that debelalactone mediated chemoprevention in the DEN-induced rats via an increase in the activities of endogenous enzymes and/or inhibition the precancerous cells.

KDR polymorphism (1192G/A, 1719A/T) and modulation of ARV drug-induced hepatotoxicity.

Kinase insert Domain containing Receptor (KDR)/Vascular Endothelial Growth Factor Receptor (VEGFR-2) participate in endothelial dysfunction, which can lead to chronic liver disease. KDR reflects naturally against the toxicants from the damaged liver cells. Association of KDR polymorphism has been reported with many diseases including liver disease, but its role has not been described in ARV induced hepatotoxicity. Hence, we examined the exonic regions KDR (1192G/A, 1719A/T) polymorphism from 165 HIV-infected individuals (34/165 had ARV induced hepatotoxicity, 131/165 were with no hepatotoxicity) and 160 normal uninfected individuals by PCR-RFLP. In univariate analysis, KDR 1719 TT genotype presented at greater frequency from all HIV positive individuals in contrast with normal uninfected individuals (7.87% vs. 4.4%, OR = 1.72, P = 0.38). Individuals with KDR 1719 TT genotype had a risk for increasing hepatotoxicity and its severity (OR = 1.91, P = 0.38). Individuals with haplotype AT had risk for increasing hepatotoxicity and its severity (OR = 1.60, P = 0.50; OR = 2.35, P = 0.27). Whereas haplotype AA was associated with reduced risk of developing hepatotoxicity (OR = 0.40, P = 0.04). Individuals with KDR 1719 TT genotype were at greater risk of advancement of HIV disease (OR = 2.31, P = 0.23). Individuals with KDR 1719 TT genotype had more vulnerability for developing hepatotoxicity among alcohol users (OR = 2.57, P = 0.23). Individuals with KDR 1719 TT genotype were at higher risk of developing hepatotoxicity and its severity among nevirapine and alcohol consumers (OR = 2.47, P = 0.24; OR = 5.42, P = 0.42). In multivariate analysis, hepatotoxicity patients taking ART inclusive of nevirapine was associated with the severity of hepatotoxicity (OR = 4.82, P = 0.002). In conclusion, KDR 1719 TT genotype and haplotype AT may have a risk for development of hepatotoxicity and its severity. Haplotype AA may have influence to reduce the risk of developing hepatotoxicity.

Impact of MBL-2 coding region polymorphism on modulation of HAND and HIV-1 acquisition.

BACKGROUND: Mannose-binding lectin 2 (MBL2) gene has a significant role in the essential protective mechanism of the body. Variations reported in the genetic makeup of this gene influence the circulating MBL levels that could lead to the vulnerability to various viral infections including HIV. Hence, we assessed the MBL2 coding region (52A/D, 54A/B, and 57A/C) variations in HIV-associated neurocognitive disorders (HAND). METHOD: In this proposed study, 208 HIV seropositive individuals were included, 104 were on ART undergone for IHDS evaluation (44 HAND+60 without HAND), and 104 HIV seropositive individuals naïve to ART, and 130 unrelated HIV uninfected individuals. PCR-RFLP was used to genotype the MBL2 coding region polymorphism (52A/D, 54A/B and 57A/C). RESULTS: MBL-2 57AC genotype was associated with risk of HAND severity (OR = 4.69, P = 0.0009). MBL-2 57AC and 57C alleles were associated with susceptibility to HAND (OR = 3.14, P = 0.003). Furthermore, the MBL-2 57AC genotype and 57C allele were found to be significantly linked with the susceptibility to HIV disease severity. (OR = 6.34, P = 0.001; 16.82% vs. 3.46%, OR = 5.64, P = 0.001). Haplotype ACA was significantly linked with susceptibility to HAND and its severity (OR = 3.23, P = 0.004, 26.1%-8.1%, OR = 4.70, P = 0.0024), similarly, haplotype ACA was linked with the acquisition of HIV-1 (OR = 4.26, P = 0.005). MBL-2 57AC genotype in presence of tobacco showed a significantly higher risk for HIV disease severity (48.0% vs. 12.5%, OR = 7.00, P = 0.035). Alcohol-taking HIV seropositive individuals on ART showed a greater MBL-2 57AC genotype than with alcohol-taking naïve to ART (32.3% vs. 15.4%, OR = 2.75, P = 0.40). CONCLUSION: MBL-2 57AC genotype and haplotype ACA were associated with the modulation of HAND. Individuals with haplotype ACA were at higher risk of HIV-1 acquisition.

ACE2 and TMPRSS2 polymorphisms in various diseases with special reference to its impact on COVID-19 disease.

BACKGROUND: A carboxypeptidase protein called ACE2 is found in many organs. ACE2 protein can play a pivotal role to regulate the pathological changes of several diseases including COVID-19. TMPRSS2 gene is expressed in many human tissues and plays a critical role in spreading the infection of the viruses including coronavirus and progression of prostate cancer, and hence could be used as a potential drug target. There are limited reports on occurrence of genetic polymorphism of ACE2 and TMPRSS2 in general population, expressions in pathological conditions, and its impact on COVID-19 disease. Hence we comprehended the occurrence of ACE2, TMPRSS2 polymorphism in general population, expression in various diseases and its impact on COVID-19 disease. METHOD: We utilized multiple databases, PubMed (Medline), EMBASE and Google Scholar for literature search. DESCRIPTION: ACE2 polymorphisms have significant linkages with various diseases, including severity of SARS-CoV-2 infection. Genetic variations of these genes contribute to individual's genetic susceptibility to viral infection and its subsequent clearance. The diversity and variations in the population distribution of these genes, might greatly influence and in turn reflect into the observed population and gender differences of the severity and clinical outcomes of SARS-CoV-2 infection. CONCLUSION: There are diversities in distribution of ACE2 and TMPRSS2 polymorphisms among different populations. Analyzing the genetic variants and expression of ACE2 and TMPRSS2 genes, in a population may provide the genetic marker for susceptibility or resistance against the coronavirus infection, which might be useful for identifying the susceptible population groups for targeted interventions and for making relevant public health policy decisions.

TLR7 Polymorphism (rs179008 and rs179009) in HIV-Infected Individual Naïve to ART.

Toll-like receptors (TLRs) play an important role in the innate immune response to HIV infection. Single nucleotide polymorphism (SNP) in TLR7 (Gln11Leu) gene has been associated with a rapid decline of CD4T cell count. Hence, we assessed the TLR7 (rs179008, Gln11Leu (A/T) and rs179009, IVS2-151 (A/G)) polymorphism in 150 HIV-infected individuals naïve to ART and 158 healthy controls. The genotyping of TLR7 Gln11Leu (A/T) and IVS2-151 (A/G) polymorphisms was done using the PCR-RFLP method. In univariate analysis, none of the genotype and haplotype of TLR7 Gln11Leu (A/T) and IVS2-151 (A/G) polymorphism differed significantly between HIV-infected individuals and healthy controls. The occurrence of TLR7 rs179009AG genotype in the codominant model and rs179009 AG-GG genotype in the dominant model was significantly reduced in HIV-infected individuals as compared to healthy controls (18.0% vs. 29.1%, OR = 0.42, P = 0.016; 26.7% vs. 36.7%, OR = 0.52, P = 0.016). TLR7 rs179009AG genotype was significantly underrepresented in the intermediate HIV disease stage compared with healthy controls (OR = 0.03, P = 0.04). TLR7 rs179009AG genotype expressed higher in tobacco-consuming HIV-infected individuals compared with nonusers (OR = 1.71, P = 0.47). In conclusion, rs179009 AG-GG and AG genotypes were found reduced in HIV-infected individuals as compared to healthy controls; their higher prevalence in health individuals clearly support that they are associated with reduced risk of acquisition of HIV-1 infection.

Prevalence of ABCC3-1767G/A polymorphism among patients with antiretroviral-associated hepatotoxicity.

BACKGROUND: Plasma concentrations of antiretrovirals (ARVs) regimens have considerably varied in individuals of human immunodeficiency virus (HIV) because of variations in the expression of drug-metabolizing and transporter genes. Transporter genes play an important role in the disposition of drugs. Polymorphism in transporter gene (ABCC3) affects the MRP3 expression and varies the treatment outcome. METHOD: We examined the polymorphism of ABCC3-1767G/A gene in a total of 165 HIV patients (out of 165 HIV patients, 34 were with and 131 were without hepatotoxicity) and 156 healthy individuals using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: In univariate analysis, we found a decreased prevalence of ABCC3 1767GA, 1767GA+AA genotypes, and 1767A allele in patients with hepatotoxicity as compared to patients without hepatotoxicity (23.5% vs. 28.2% and 23.5% vs. 30.53%; 11.76% vs. 16.41%), while a higher prevalence of 1767AA genotype was observed in HIV patients in comparison with healthy controls (2.3% vs. 1.3%, odds ratio [OR] = 1.71, 95% confidence interval [CI]: 0.23-15.03, p = .89). The frequency of ABCC3-1767AA genotype was dispersed higher in individuals with early and advanced HIV disease stage in comparison with healthy controls (5.3% vs. 1.3%, OR = 4.73, p = .70; 8.9% vs. 1.3%, OR = 1.89, p = .91). A higher occurrence of ABCC3-1767AA genotype was found in tobacco using HIV patients without hepatotoxicity compared with nonusers (4.7% vs. 1.1%, OR = 4.28, p = .52). The distribution of ABCC3-1767GA genotype was higher in nevirapine receiving HIV patients irrespective of their hepatotoxicity status as compared to nonusers (30.4% vs. 9.1%, OR = 3.34, p = .22; 29.4% vs. 16.7%, OR = 1.69, p = .77). In multivariate analysis, HIV patients receiving nevirapine and with hepatotoxicity was found to have a significant risk for severity of hepatotoxicity (OR = 4.56, 95% CI: 1.60-12.99, p = .004). CONCLUSION: ABCC3 1767G/A polymorphism was not significantly associated with susceptibility to ARV-associated hepatotoxicity, although ABCC3 1767AA genotype designated a risk for acquisition of hepatotoxicity and advancement of the disease. Nevirapine usage emerged as an independent risk factor for hepatotoxicity severity.

Intraoral Soft Tissue Fibrosarcoma in a Four-Year-Old Child: An Unusual Case Report.

Fibrosarcoma is a rare soft tissue tumor of connective tissue origin that includes about 0.05% of all the malignancies in the head and neck region of which almost 23% is seen in the oral cavity. This paper describes a rare case of 4-year-old boy who presented with swelling on the right side of face diagnosed as soft tissue fibrosarcoma of the intraoral region. The histopathological and immunohistochemistry confirmed the diagnosis by the presence of spindle-shaped cells arranged in fascicles with mitotic figures and cellular proliferation reproducing fibroblasts. The patient was successfully treated with combination of chemotherapy and surgery with a good clinical outcome. This case report is presented to highlight the rarity of fibrosarcoma in orofacial region of children which requires special attention of pediatric dentist and should be considered as differential diagnose of soft tissue mass in orofacial region of children. Clinical and histopathological features must be correlated with immunohistochemistry in the final diagnosis in fibrosarcoma.

Tissue Inhibitor of Metalloproteinase-2 Polymorphisms and Risk for HIV-Associated Neurocognitive Disorder.

The imbalance between MMPs and TIMPs is associated with the HIV dissemination tissue damage pathology neurodegenerative disorders, including HAND. Genetic variations in the TIMP gene may modulate the neurocognitive disorder in HIV patients. Hence, we evaluated the genetic variants of TIMP-2 (-418G/C, 303G/A) gene with the risk of HAND. Genotyping of TIMP-2 polymorphism was performed in 50 patients with HAND, 100 no HAND, and 154 healthy controls by PCR-RFLP. TIMP-2 -418GC and 303AA genotypes represented a predominant risk for HAND severity (OR = 1.55, P = 0.30; OR = 4.58, P = 0.24). The variant -418CC genotype, -418A allele, had exhibited a significant risk for the acquisition of HAND (OR = 12.55, P = 0.026; OR = 2.66, P = 0.004). TIMP-2 303GA, 303AA genotype, and 303A allele evinced a higher risk for HAND severity (OR = 1.82, P = 0.14; OR = 1.70, P = 0.63; and OR = 1.68, P = 0.12). In HIV patients, TIMP-2 -418CC genotype and -418C allele significantly occurred in comparison to healthy controls (OR = 10.10, P = 0.006; OR = 2.02, P = 0.009). In the intermediate and early HIV disease stage, TIMP-2 -418CC genotype was significantly increased compared with healthy controls (11.1% vs. 1.3%, OR = 14.63, P = 0.01; 16.9% vs. 1.3%, OR = 14.51, P = 0.002). In patients with HAND among tobacco and alcohol users, TIMP-2 -418CC genotype displayed a risk for HAND severity (OR = 3.96, P = 0.26; OR = 4.83, P = 0.19). On multivariate logistic regression, TIMP-2 303AA genotype, advanced stage, and gender had a risk for HAND severity (OR = 28.98, P = 0.02; OR = 2.35, P = 0.070; and OR = 2.36, P = 0.04). In conclusion, TIMP-2 -418G/C polymorphism independently, along with alcohol and tobacco, may have an impact on the acquisition of HAND and its severity. TIMP-2 303G/A polymorphism bare a risk for HAND severity.

Interleukin-10 polymorphisms and susceptibility to ARV associated hepatotoxicity.

Interleukin-10 (IL-10) is an anti-inflammatory cytokine associated with the inhibition of HIV replication. IL-10 polymorphisms were found to be linked to drug-induced hepatotoxicity. Hence we examined the prevalence of IL-10 (-819C/T,-1082A/G) polymorphisms in a total of 165 HIV patients which included 34 patients with hepatotoxicity, 131 without hepatotoxicity and 155 healthy controls by the PCR-RFLP method. In HIV patients with hepatotoxicity, the IL-10-819TT genotype increased the risk of ARV associated hepatotoxicity severity (OR = 1.61, P = 0.35). IL-10-819TT genotype was overrepresented in patients with hepatotoxicity as compared to healthy controls (26.5% vs. 13.5%, OR = 1.61, P = 0.46). IL-10 -819CT genotype was associated with advance HIV disease stage (OR = 0.49, P = 0.045). In HIV patients without hepatotoxicity, the IL-10-819TT genotype was more prevalent in patients consuming tobacco as compared to non-users (OR = 1.60, P = 0.41). In HIV patients without hepatotoxicity using both alcohol + efavirenz along with IL-10 -819CT genotype resulted in increased risk for the acquisition of ARV associated hepatotoxicity (OR = 4.00, P = 0.36). In multivariate logistic regression, taking nevirapine was associated with the risk hepatotoxicity severity (OR = 0.23, P = 0.005). In conclusion, an insignificant association between IL-10 polymorphisms and susceptibility to ARV associated hepatotoxicity.

Occurrence of Interleukin-2 (330 G/T) Promoter Polymorphism in ARV associated hepatotoxicity.

BACKGROUND: IL-2 cytokine is involved in HIV replication and is also known to cause hepatic injury. Polymorphisms in the IL-2 gene are associated with altered interleukin-2 production. METHODS: Hence, we assessed the prevalence of IL-2-303G/T polymorphism in 165 HIV patients (34 with and 131without hepatotoxicity) and 155 healthy controls using the PCR-RFLP method. RESULTS: In patients with hepatotoxicity, IL-2-303GT, -303GT+TT genotypes were less prevalent as compared to without hepatotoxicity and healthy controls (29.4% vs. 42.7%, 58.8% vs. 69.5%; 29.4% vs. 40.6%, 58.8% vs. 66.5%, respectively). In patients with hepatotoxicity using tobacco and alcohol, IL-2-303GT,-303TT genotypes were distributed higher as compared to non-users (42.9% vs. 25.9%, OR=8.52, 42.9% vs. 25.9%, OR=9.09, and 28.6% vs. 29.6%, OR=1.63, 42.9% vs. 25.9%, OR=2.93), while IL-2-303TT genotype occurred more often in HIV patients consuming alcohol (34.1% vs. 23.0%). Nevirapine users with hepatotoxicity overrepresented the IL-2-303GT,-303TT genotypes as compared to efavirenz (34.8% vs. 18.2%, OR=4.64, 34.8% vs. 18.2%, OR=3.88). Among nevirapine users, IL-2-303GT genotype was associated with susceptibility to the acquisition of hepatotoxicity with borderline significance (OR=4.24, P=0.06). HIV patients using nevirapine majorly represented the IL-2-303TT genotype (26.9% vs. 25.0%, OR=2.35) while HIV patients with nevirapine + alcohol usage presented the IL-2 -330TT genotype at a higher frequency (34.2%% vs. 23.5%, OR=1.51). In patients with hepatotoxicity using nevirapine + alcohol, the genotype IL-2 - 330TT was predominant (60.0% vs. 27.8%, OR=3.16). CONCLUSION: Thus, IL-2-303G/T polymorphism did not confer the susceptibility to ARV associated hepatotoxicity. However, IL-2-303G/T polymorphism with nevirapine usage may facilitate the risk for acquisition of ARV associated hepatotoxicity.

Occurrence of CYP2B6 516G>T polymorphism in patients with ARV-associated hepatotoxicity.

BACKGROUND: Hepatic enzyme cytochrome P450 2B6 (CYP2B6) plays a role in the metabolism of efavirenz drugs. CYP2B6 516G>T variation showed an implication for HIV treatment. METHODS: CYP2B6 516G>T polymorphism was genotyped in a total 165 HIV patients that include 34 with and 131 without hepatotoxicity and 155 healthy individuals by the PCR-RFLP. RESULTS: In patients with hepatotoxicity, the prevalence of CYP2B6 516TT genotype was higher as compared to healthy individuals (35.3% vs. 30.5%, OR = 1.74). Patients with hepatotoxicity using tobacco had a higher prevalence of genotypes CYP2B6 516GT, 516TT, 516GT+TT as compared to healthy individuals (28.57% vs. 25.93%; 57.14% vs. 29.63%; 85.71% vs. 55.56%). Likewise, hepatotoxicity in patients consuming alcohol showed higher distributions of CYP2B6 516GT, 516TT, 516GT+TT genotypes (57% vs. 25.93%; 42.86% vs. 33.33%; 71.43% vs. 59.26%). Nevirapine users with hepatotoxicity overrepresented genotypes CYP2B6 TT and 516GT+TT as compared to efavirenz users (47.83% vs. 45.45%, OR = 6.88, 65.22% vs. 54.55%, OR = 1.56). Similarly, in nevirapine +alcohol users with hepatotoxicity, the frequency of CYP2B6 516GT, 516GT+TT genotypes was higher than with nevirapine +alcohol nonusers (40.0% vs. 11.11%, OR = 8.00, 80.0% vs. 27.78%, OR = 4.00). In HIV patients, nevirapine users had higher frequency of CYP2B6 516GT, 516GT+TT genotypes as compared to efavirenz users (42.02% vs. 25.00%, OR = 2.53; 72.27% vs. 58.33%, OR = 1.86). Likewise, in HIV patients, genotypes CYP2B6 516GT, 516GT+TT were predominant with nevirapine +alcohol users as compared to nevirapine +alcohol nonusers (57.89% vs. 34.57%, OR = 2.46; 78.95% vs. 69.14%, OR = 1.67). In multivariate logistic regression, taking nevirapine had a protection for severity of ARV-associated hepatotoxicity (OR = 0.23, p = 0.005). CONCLUSIONS: No significant association was detected between CYP2B6 516G>T polymorphism and susceptibility to ARV-associated hepatotoxicity.

Genetic variation of matrix metalloproteinase enzyme in HIV-associated neurocognitive disorder.

Matrix metalloproteinases (MMPs) play a key role in several diseases such as rheumatoid arthritis, HIV-associated neurological diseases (HAND), multiple sclerosis, osteoporosis, stroke, Alzheimer's disease, certain viral infections of the central nervous system, cancer, and hepatitis C virus. MMPs have been explained with regards to extracellular matrix remodeling, which occurs throughout life and ranges from tissue morphogenesis to wound healing in various processes. MMP are inhibited by endogenous tissue inhibitors of metalloproteinases (TIMPs). Matrix metalloproteases act as an interface between host's attack by Tat protein of HIV-1 virus and extracellular matrix, which causes breaches in the endothelial barriers by degrading ECM. This process initiates the dissemination of virus in tissues which can lead to an increase HIV-1 infection. MMPs are diverse and are highly polymorphic in nature, hence associated with many diseases. The main objective of this review is to study the gene expression of MMPs in HIV-related diseases and whether TIMPs and MMPs could be related with disease progression, HIV vulnerability and HAND. In this review, a brief description on the classification, regulation of MMP and TIMP, the effect of different MMPs and TIMPs gene polymorphisms and its expression on HIV-associated diseases have been provided. Previous studies have shown that MMPs polymorphism (MMP-1, MMP-2 MMP3, and MMP9) plays an important role in HIV vulnerability, disease progression and HAND. Further research is required to explore their role in pathogenesis and therapeutic perspective.

Prevalence of CYP2D6*4 1934G/A polymorphism in Western Indian HIV patients.

Hepatic CYP2D6 enzyme metabolizes antiretroviral drugs (ARVs) including nevirapine. Polymorphism in CYP2D6 gene affects drug metabolism and displays distinctive phenotypes in the population. Hence, we investigated the prevalence of CYP2D6*4 1934G/A polymorphism in a total of 165 HIV patients that include 34 with and 131 without hepatotoxicity and 160 unrelated healthy controls by the PCR-RFLP method. The prevalence of CYP2D6*4 1934AA genotype was higher in total HIV patients as compared to healthy controls (1.81% vs 0.6%, OR = 2.86). Similarly, CYP2D6*4 1934AA genotype was much more prevalent in HIV patients without hepatotoxicity as compared to healthy controls (2.3% vs 0.6%, OR = 2.87). Likewise, CYP2D6*4 1934AA genotype was predominant in advanced HIV disease stage as compared to healthy controls (3.8% vs 0.6%, OR = 6.15). CYP2D6*4 1934GA genotype was distributed higher in HIV patients taking tobacco and nevirapine as compared to non-users (23.3% vs 19.3%, OR = 1.21, 21.0% vs 16.7%, OR = 1.2). Likewise, CYP2D6*4 1934GA genotype was overrepresented in patients with hepatotoxicity taking alcohol + nevirapine as compared to alcohol non-users + nevirapine users (20.00% vs 16.67%, OR = 1.25). Thus, there was no significant difference in genotype or allele frequencies of CYP2D6*4 1934G/A polymorphism between the patients with hepatotoxicity and those without or healthy controls.

Occurrence of APOBEC3G variations in West Indian HIV patients.

The genetic variations in APOBEC3G gene are correlated with HIV disease progression. These variations differ in different ethnic groups. The prevalence of APOBEC3G (-90C/G, -571G/C) variations have not been studied in Indian population. Hence, we assessed the occurrence of APOBEC3G polymorphisms in HIV patients and its association with acquisition of HIV and disease progression. Polymorphisms in APOBEC3G were genotyped in a total of 153 HIV patients, naïve to ARV and 156 healthy controls by PCR-RFLP method. In single locus model, the frequency of distribution of APOBEC3G -90CG, -571 GC genotypes were higher in HIV patients as compared to healthy controls (57.5% vs. 50.0%, OR = 1.22; 17.0% vs. 12.8%, OR = 1.39). In double locus model, the dominant -571 GC + CC genotype was distributed at a much higher frequency in HIV patients as compared to healthy controls (18.3% vs. 14.1%, OR = 1.50). The frequency of APOBEC3G -571CC and CC + GC genotypes were higher in early HIV disease stage as compared to healthy controls (23.9% vs. 12.8%, OR = 2.23, P = 0.08; 28.3% vs. 14.1%, OR = 2.40, P = 0.04). APOBEC3G-571 GC and GC + CC genotypes were more prevalent in HIV patients consuming tobacco and alcohol as compared to non-users (22.7% vs. 15.3%, OR = 1.71, P = 0.56; 27.3% vs. 16.5%, OR = 1.90, P = 0.39 and 31.6% vs. 13.6%, OR = 2.31, P = 0.08; 36.8% vs14.8%, OR = 2.49, P = 0.04, respectively). In conclusion, APOBEC3G-571G/C polymorphism was associated with the early stage of HIV infection and could potentially influence HIV disease progression in alcohol users. The distribution of APOBEC3G polymorphisms and its haplotypes were not significantly different between HIV patients and healthy controls.

IL-1RN and IL-1ß Polymorphism and ARV-Associated Hepatotoxicity.

The severity of hepatic injury depends upon cytokines. Previous studies associated IL-1RN allele 2 with IL-1ß production. Hence, we examined the association of IL-1 RN and IL-1ß polymorphisms with ARV-associated hepatotoxicity. Genotyping of IL-1RN (VNTR), IL-1ß (-511C/T) polymorphisms was done in 162 HIV-infected patients, 34 with ARV hepatotoxicity, 128 without hepatotoxicity, and 152 healthy controls using PCR and PCR-RFLP method. The haplotypes 1T and 2C enhanced the risk for severe hepatotoxicity (OR = 1.41, P = 0.25; OR = 1.67, P = 0.31). IL-1ß-511TT genotype significantly represented among tobacco using HIV-infected individuals compared to nonusers (OR = 3.74, P = 0.05). IL-1ß-511TT genotype among alcohol users increased the risk for hepatotoxicity (OR = 1.80, P = 0.90). IL-1ß-511CT and -511TT genotypes overrepresented in alcohol using HIV-infected individuals (OR = 2.29, P = 0.27; OR = 2.64, P = 0.19). IL-RN 2/2 and 1/3 genotypes represented higher in nevirapine using hepatotoxicity patients (OR = 1.42, P = 0.64, OR = 8.79, P = 0.09). IL-1ß-511CT and -511 TT genotypes among nevirapine users enhanced the risk for severe hepatotoxicity (OR = 4.29, P = 0.20; OR = 1.95, P = 0.56). IL-1ß-511CT and -511TT genotypes were overrepresented in combined nevirapine and alcohol using HIV-infected individuals as compared to nevirapine users and alcohol nonusers (OR = 2.56, P = 0.26; OR = 2.84, P = 0.24). IL-1ß-511TT genotype with tobacco, alcohol, and nevirapine usage revealed a trend of risk for the development of ARV-associated hepatotoxicity and its severity.

Effect of matrix metalloproteinase-21 (572C/T) polymorphism on HIV-associated neurocognitive disorder.

Remodeling of extracellular matrix (ECM) by matrix metalloproteinases (MMPs) is a presumed reason for the development of HIV-associated neurocognitive disorders (HAND). The coding region polymorphism in MMP-21 572C/T gene may have a potential functional effect on ECM remodeling. Hence, we aimed to examine the association of MMP-21 polymorphism with the modulation of HAND severity and its prevalence in HIV-infected and healthy individuals. Genotyping of MMP-21 572C/T polymorphism was performed by PCR-RFLP in total 150 HIV-infected individuals, 50 with HAND, 100 without HAND and 150 healthy controls. MMP-21 572TT genotype was predominantly higher in HAND patients compared with no HAND (OR = 1.63, p = 0.57). MMP-21 572T allele was associated with reduce risk for HAND severity (OR = 0.50, p = 0.04). Similarly, MMP-21 572TT genotype underrepresented in HIV-infected individuals compared to healthy controls (3.0% vs 6.7%, OR = 0.27, p = 0.08). MMP-21 572CT genotype and early HIV disease stage showed a higher risk for the advancement of HIV disease with marginal significance (OR = 1.89, p = 0.07). MMP-21 572CT genotype increased the risk for the modulation of HAND severity in tobacco users (OR = 1.98, p = 0.43). MMP-21 572CT genotype among tobacco and alcohol users showed elevated risk for the development of HAND in HIV-infected individuals (OR = 2.30, p = 0.15; OR = 1.86, p = 0.23). Similarly, MMP-21 572TT genotype enhanced the risk for the development of HAND in tobacco users (OR = 3.48, p = 0.40). In conclusion, the presence of coding region 572T allele may have protection for HAND severity. MMP-21 572C/T polymorphism and tobacco and alcohol usage may facilitate the development of HAND.

Prevalence of MMP-8 gene polymorphisms in HIV-infected individuals and its association with HIV-associated neurocognitive disorder.

Matrix metalloproteinases (MMPs) are well-known as mediators of neuroinflammation in HIV-associated neurocognitive disorder (HAND). Increased levels of MMP-8 have been observed in the HIV-infected patients. Thus, the aim of this study was to evaluate the association of MMP-8 gene polymorphisms with modulation of HAND severity and its prevalence in HIV-infected and healthy individuals. We enrolled a total of 150 HIV-infected individuals, 50 HAND patients, 100 HIV-infected and 150 healthy individuals. MMP-8 (-799C/T, +17C/G) polymorphisms were genotyped by PCR-RFLP. MMP-8 -799TT genotype and +17G allele showed the higher risk for modulation of HAND severity (OR=2.20, P=0.19; OR=1.97, P=0.23). MMP-8 -799TT genotype differed significantly in HIV-infected individuals compared to healthy controls (20.0% vs. 11.3%, OR=2.36, P=0.048). Haplotype TG increased the risk for modulation of HAND severity (OR=2.29, P=0.29). MMP-8 -799TT and +17CG genotypes were overrepresented in the intermediate HIV disease stage compared with healthy controls (25.9% vs. 11.3%, OR=4.34, P=0.021, 14.8% vs. 9.3%, OR=2.88, P=0.11). MMP-8 +17CG genotype enhanced the risk for modulation of HAND severity in tobacco using HAND patients (OR=5.01, P=0.17). MMP-8 -799TT genotype was more frequent in tobacco using HIV-infected individuals compared with nonusers (26.3% vs. 16.7%, OR=2.08, P=0.32). MMP-8 +17CG genotype increased the risk for modulation of HAND severity in alcohol using HAND patients (OR=4.99, P=0.18). In conclusion, MMP-8 polymorphisms independently and with alcohol and tobacco usage revealed a trend of higher risk for the modulation of HAND severity. MMP-8 -799TT genotype was associated with the advancement of HIV disease.