Current HIV research [journal]
- Spatiotemporal Analysis of AIDS Incidence among Adults in Brazil. [JOURNAL ARTICLE]
- Curr HIV Res 2016 Aug 2.
AIDS is the fourth leading cause of death worldwide and, currently, the overall prevalence rate of HIV infection in Brazil is 0.5% among men and 0.3% among women.To evaluate the spatiotemporal trend of AIDS in Brazil from 2006 to 2012 and its relationship with human development index (HDI) and their components income, education and life expectancy.This ecological study evaluate the spatiotemporal trend of standardized incidence ratio of AIDS among adults in Brazil from 2006 to 2012 and its relationship with HDI by using a Bayesian analysis, considering the Brazilian Federal Units as units of analysis. The proposed statistical model allows obtaining a standardized incidence ratio (SIR, adjusted by gender and age).Among the men, our results show higher incidence rates in the States of the Southern regions as well as in the state of Amazonas (Northern Brazil). In females, we found other patterns for SIR, with higher incidence rates in the states of Rio de Janeiro (Southeast region), Rio Grande do Sul and Santa Catarina (both in Southern region). Among the men it was observed an expressive association between the SIR values and the overall HDI and income and education components, but it was observed an inverse association with the life expectancy component. Among the women, it is noted that the SIR values are associated with the overall HDI and the education components only at the beginning of the studied period.AIDS remains a major public health problem in Brazil, mainly in the southern and southeastern regions of the country. Considering its association with HDI, it is noted that the disease still remains related to the pattern observed in the early years of the studied period, at least in the more developed regions of Brazil. This certainly happens because of the chronicity of the disease, thus affecting people with good socioeconomic status.
- HIV Infection and Myocardial Infarction. [JOURNAL ARTICLE]
- Curr HIV Res 2016 Aug 3.
After the advent of the potent combination antiretroviral therapy (cART) the incidence of acquired immune deficiency syndrome (AIDS) has declined dramatically and HIV infection became a chronic disease with a significant increase in the life expectancy of HIV-positive people. Consequently, chronic comorbidities as coronary heart disease raised an increasing concern in this population. An increased risk of myocardial infarction has been reported among HIV-infected subjects compared to the general population, but the pathogenic mechanism of this accelerated atherosclerotic process is complex and certainly multifactorial. The occurrence of myocardial infarction may be the consequence of traditional risk factors (that are overrepresented in the HIV-infected population), direct viral replication, and long-term toxicity of the antiretroviral drugs. Moreover, despite the persistent viral suppression induced by cART usually reduces the cardiovascular risk, several studies show in HIV-positive subjects a condition of chronic inflammation and immune activation that could lead to both accelerated endothelial dysfunction and atherosclerotic disease. Therefore, cardiovascular risk reduction and coronary heart disease prevention are today a leading challenge for all the clinicians involved in the HIV patients' care.
- Design-Based Peptidomimetic Ligand Discovery to Target HIV TAR RNA Using Comparative Analysis of Different Docking Methods. [JOURNAL ARTICLE]
- Curr HIV Res 2016 Jul 19.
Discovering molecules capable of binding to HIV trans-activation responsive region (TAR) RNA thereby disrupting its interaction with Tat protein is an attractive strategy for developing novel antiviral drugs. Computational docking is considered as a useful tool for predicting binding affinity and conducting virtual screening. Although great progress in predicting protein-ligand interactions has been achieved in the past few decades, modeling RNA-ligand interactions is still largely unexplored due to the highly flexible nature of RNA. In this work, we performed molecular docking study with HIV TAR RNA using previously identified cyclic peptide L22 and its analogues with varying affinities toward HIV-1 TAR RNA. Furthermore, sarcosine scan was conducted to generate derivatives of CGP64222, a peptide-peptoid hybrid with inhibitory activity on Tat/TAR RNA interaction. Each compound was docked using CDOCKER, Surflex-Dock and FlexiDock to compare the effectiveness of each method. It was found that FlexiDock energy values correlated well with the experimental Kd values and could be used to predict the affinity of the ligands toward HIV-1 TAR RNA with a superior accuracy. Our results based on comparative analysis of different docking methods in RNA-ligand modeling will facilitate the structure-based discovery of HIV TAR RNA ligands for antiviral therapy.
- Naringin Ameliorates HIV-1 Nucleoside Reverse Transcriptase Inhibitors-Induced Mitochondrial Toxicity. [JOURNAL ARTICLE]
- Curr HIV Res 2016 May 20.
Mitochondrial reactive oxygen species (ROS) generation and defective oxidative phosphorylation (OXPHOS) have been proposed as possible mechanisms underlying the development of nucleoside reverse transcriptase inhibitors (NRTIs)-induced mitochondrial toxicities. Available options in managing these complications have, so far, produced controversial results, thus necessitating further research into newer agents with promise. Antioxidant and free-radical scavenging effects of naringin, a plant-derived flavonoid, have previously been demonstrated.This study was designed to investigate the effects of naringin on NRTIs-induced mitochondrial toxicity.Wistar rats were randomly divided into Zidovudine (AZT)-only (100 mg/kg body weight (BW); AZT+Naringin (100+50 mg/kg BW); AZT+Vitamin E (100+100 mg/kg BW); Stavudine (d4T)-only (50 mg/kg BW); d4T+Naringin (50+50 mg/kg BW); d4T+Vitamin E (50+100 mg/kg BW) and Vehicle (3.0 mL/kg BW)-treated groups, respectively. After 56 days of oral daily dosing, rats were euthanized by halothane overdose, blood collected by cardiac puncture and livers promptly excised for further biochemical and ultrastructural analyses.AZT- or d4T-only caused significant mitochondrial dysfunction and mitochondrial ultrastructural damage compared to controls, while either naringin or vitamin E reversed indices of mitochondrial dysfunction evidenced by significantly reduced mitochondrial malondialdehyde (MDA) and blood lactate concentrations, increased liver manganese superoxide dismutase (MnSOD) activity and upregulate expression of mitochondrial-encoded subunit of electron transport chain (ETC) complex IV protein compared to AZT- or d4T-only treated rats. Furthermore, naringin or vitamin E, respectively, ameliorated mitochondrial damage observed in AZT- or d4T-only treated rats.Naringin ameliorated oxidative stress and NRTI-induced mitochondrial damage and might, therefore, be beneficial in managing toxicities and complications arising from NRTI use.
- Effects of Antiretroviral Molecules on Survival and Gene Expression of an Osteoblast-like Cell Line. [JOURNAL ARTICLE]
- Curr HIV Res 2016 May 18.
Background The advent of combined antiretroviral therapy effectively undermined the evolution of HIV disease. Nevertheless, clinical observations indicated a clear association between therapy and the impairment of bone mineral density. Objective We selected some antiretroviral compounds used in clinical practice, to study their impact on bone health and their possible implication in the onset of bone disease. Method Scalar concentrations of several antiretroviral drugs (used in single and in combination) were tested on an osteoblast-like cell line, HOBIT cells, to analyse cell survival and gene expression of selected bone markers. Results None of the tested concentrations of Tenofovir, Emtricitabine, Nevirapine, Maraviroc or Raltegravir induced any significant apoptosis activation at our experimental conditions. Only some protease inhibitors and Efavirenz, at high concentration, determined a significant activation of programmed cell death. In parallel experiments, protease inhibitors used in combination with Tenofovir and Emtricitabine, increased apoptosis . Furthermore, we performed a study of mRNA expression of specific genes involved in osteoblast biology and in bone synthesis and observed that some protease inhibitors induced a selective decrease of some osteogenic markers. Conclusion All the protease inhibitors included in this study trigger apoptosis at the highest concentration analysed, suggesting great caution in HIV-patients co-infected with HBV or HCV, where elevated plasma concentrations of drugs could be reached as a consequence of liver failure. Lastly, an increased apoptosis rate and an impairment of osteogenic markers were recorded only in presence of Nelfinavir, suggesting a role of protease inhibitors in the alteration of osteoblast biology.
- Disease Progression in HIV Late Presenters: the Role of HIV Clinical Indicator Diseases Prior to HIV Diagnosis. [Journal Article]
- Curr HIV Res 2016; 14(4):346-53.
Late diagnosis represents a major challenge in the control of HIV epidemics. The rate of disease progression is higher among late presenters. In Europe, HIV Clinical Indicator Diseases (CIDs) have been proposed to improve early diagnosis.Our observational study evaluated the presence of these HIV CIDs prior to HIV diagnosis among a population of late presenters and assessed its correlation to disease progression.A retrospective cohort study was conducted in HIV late presenters diagnosed from 2007 to 2013 at University Hospital of Ferrara (Italy). Hazard Ratios (H.R.s) for disease progression (new AIDS-events and death) were estimated by Cox proportional hazard model.We analysed 77 patients and we found that those with CIDs prior to HIV diagnosis (22%) had a 2.8 fold higher rate of disease progression compared to those without HIV CIDs (H.R. 2.82; 95% CI 1.21-6.53; P 0.02). Other factors associated with disease progression were AIDS presentation, HCV coinfection and Haemoglobin levels, with H.R.s of 3.14 (95%CI 1.23-7.99), 2.95 (95% CI 1.14-7.61) and 0.74 (95% CI 0.60-0.91), respectively.HIV CIDs confer a higher risk for disease progression even after adjustment for these confounding factors. Evaluation of previous HIV CIDs at HIV diagnosis could be an additional tool to identify and better manage HIV late presenters with higher risks of disease progression.
- Baseline CD4/CD8 T-cell Ratio Predicts Prompt Immune Restoration upon cART Initiation. [JOURNAL ARTICLE]
- Curr HIV Res 2016 Apr 14.
The reversal of CD4/CD8 ratio is considered an independent predictor of death in the general population, where the ratio physiologically decreases with aging. Despite effective cART, CD4/CD8 normalization does not always occur in HIV-positive subjects. In the setting of HIV, low CD4/CD8 T-cell ratio correlates with immune activation and non-AIDS events. The aim of the study was to evaluate the rate and predictors of CD4/CD8 ratio normalization in a cohort of HIV-positive subjects starting combination antiretroviral therapy (cART). Methods This is a retrospective-prospective observational cohort study conducted at the Unit of Infectious Diseases of the University of Catania. Our cohort included naive individuals who initiated cART from January 2007 to December 2013. Results A total of 123 individuals were enrolled. The median age was 38 years (IQR 29-44). The median baseline CD4+ T-cell count was 288 cells/µl (IQR 105-400). 83 (67.5%) had a CD4+ T-cell count <350/µl; baseline median CD4/CD8 ratio was 0.24 (IQR 0.13-0.4); 65 patients (52.8%) had a HIV viral load >100,000 copies/ml. At 24 months, 33 individuals (26.8%) normalized their CD4/CD8 ratio, with a median time to CD4/CD8 ratio normalization of 17 months (IQR 12-30). In univariate analysis, a baseline CD4+ T-cell count >350/µl (p <0.01), a baseline CD4/CD8 ratio >0.5 (p <0.01), CDC stage A (p<0.01) and an efavirenz-based first-line regimen (p<0.05) were associated with CD4/CD8 ratio normalization. In multivariate logistic analysis, the only predictor of CD4/CD8 normalization was a baseline ratio >0.5 (OR 4.3 (1.7-11.2), p=0.003) Conclusion Starting cART with a ratio >0.5 is associated with an increased likelihood to normalize CD4/CD8 ratio. Early diagnosis should be encouraged in order to treat patients promptly and favor a more robust immunological reconstitution.
- Prevalence of Drug Resistance Associated Mutations Among the Anti Retroviral Therapy Exposed HIV-1 Infected Individuals in Manipur, Northeast India. [Journal Article]
- Curr HIV Res 2016; 14(4):360-70.
Manipur is one of the highest HIV prevalence states of India because of its geographical location at the international border near the golden triangle of South-East Asia, but no study on drug resistance associated mutations (DRAMs) has been reported yet.A population-based study on DRAMs of HIV-1 among the anti-retroviral therapy (ART) exposed HIV-1 infected individuals of Manipur was conducted.110 HIV-1 positive individuals who had initially exposed to first line anti-HIV drugs were recruited for the surveillance of DRAMs. Reverse transcriptase and protease genes of HIV-1 were amplified, sequenced and analyzed.Significant prevalence of DRAMs of HIV-1 was found among the ART exposed HIV-1 infected individuals of Manipur. The results revealed that 37%, 29% and 7% individuals harbor HIV-1 strains mutated at the target sites of nonnucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors and protease inhibitors respectively. Predominant DRAMs at RT genes were M184V, T215Y, M41L and V108I and H221Y while at PR genes were M46I and I47V. Among the high risk groups, intravenous drug users have the highest number of DRAMs followed by heterosexual individuals. Analysis of viral subtype based on pol gene revealed 83% subtype C, 11.8% recombinant forms and 5.2% subtype B.DRAMs at the target sites of reverse transcriptase inhibitors are high and these were found to have developed resistance to the primary ART drugs that are used in Manipur. The findings of this study will help the clinicians to guide patients during the course of ART treatment regimes.
- Opioids and Opioid Maintenance Therapies: Their Impact on Monocyte- Mediated HIV Neuropathogenesis. [JOURNAL ARTICLE]
- Curr HIV Res 2016 Mar 24.
HIV-1 enters the CNS within two weeks after peripheral infection and results in chronic neuroinflammation that leads to HIV associated neurocognitive disorders (HAND) in more than 50% of infected people. HIV enters the CNS by transmigration of infected monocytes across the blood brain barrier. Intravenous drug abuse is a major risk factor for HIV-1 infection, and opioids have been shown to alter the progression and severity of HAND. Methadone and buprenorphine are opioid derivates that are used as opioid maintenance therapies. They are commonly used to treat opioid dependency in HIV infected substance abusers, but their effects on monocyte migration relevant to the development of cognitive impairment are not well characterized.Here, we will discuss the effects of opioids and opioid maintenance therapies on the inflammatory functions of monocytes and macrophages that are related to the development of neuroinflammation in the context of HIV infection.
- Mechanisms of HIV Neuropathogenesis: Role of Cellular Communication Systems. [JOURNAL ARTICLE]
- Curr HIV Res 2016 Mar 24.
One of the major complications of Human Immunodeficiency Virus (HIV) infection is the development of HIV-Associated Neurocognitive Disorders (HANDs) in approximately 50-60% of HIV/AIDS patients. Despite undetectable viral loads in the periphery owing to highly active anti-retroviral therapy, neuroinflammation and neurocognitive impairment are still prevalent in HIV/AIDS patients. Several studies indicate that the central nervous system (CNS) abnormalities observed in HIV infected individuals are not a direct effect of viral replication in the CNS, rather these neurological abnormalities are associated with amplification of HIV pathogenesis by unknown mechanisms.We propose that some of these mechanisms of damage amplification are mediated by gap junction channels, pannexin and connexin hemichannels, tunneling nanotubes and microvesicles/exosomes. Our laboratory and others have demonstrated that HIV infection targets cell to cell communication by altering all these communication systems resulting in enhanced bystander apoptosis of uninfected cells, inflammation and spread of toxicity and viral infection.In the current manuscript, we have described the mechanisms by which HIV "hijacks" these host cellular communication systems, leading to exacerbation of HIV neuropathogenesis, and to simultaneously promote the survival of HIV infected cells, resulting in the establishment of viral reservoirs.