Synthesis and bioevaluation of substituted chalcones,coumaranones and other flavonoids as anti-HIV agents

A series of chalcone, flavone, coumaranone and other flavonoid compounds were screened for their anti HIV-1 activity in two cell culture models using TZM-bl and PM1 cells. Within the systems evaluated, the most promising compounds contained either an α- or β-hydroxy-carbonyl motif within their structure (e.g., 8 and 9). Efficacious substituents were identified and used to design new HIV inhibitors with increased potency and lower cytotoxicity. Of the scaffolds evaluated, specific chalcones were found to provide the best balance between anti-HIV potency and low host cell toxicity. Chalcone 8l was shown to inhibit different clinical isolates of HIV in a dose-dependent manner (e.g., IC₅₀ typically ⩽ 5 μM). Inhibition of HIV infection experiments using TZM-bl cells demonstrated that chalcone 8l and flavonol 9c had IC₅₀ values of 4.7 μM and 10.4 μM, respectively. These insights were used to design new chalcones 8o and 8p. Rewardingly, chalcones 8o and 8p (at 10 μM) each gave >92% inhibition of viral propagation without impacting PM1 host cell viability. Inhibition of viral propagation significantly increased (60–90%) when PM1 cells were pre-incubated with chalcone 8o, but not with the related flavonol 9c. These results suggested that chalcone 8o may be of value as both a HIV prophylactic and therapy. In summary, O-benzyl-substituted chalcones were identified as promising anti-HIV agents for future investigation.     

Effect of methamphetamine on expression of HIV coreceptors and CC-chemokines by dendritic cells

The United States is currently experiencing an entangled epidemic of HIV infection and use of different drugs of abuse, especially of methamphetamine (Meth). Blood monocyte-derived dendritic cells (DC) are the first line of defense against HIV-1 infection, and are the initial target of HIV-1 infection in injection drug users. DC-SIGN present on dendritic cells is the first molecule that facilitates HIV-1 infection independent of CD4 or HIV coreceptors. Aims: The aim of this study was to evaluate whether Meth acts as a cofactor in the pathogenesis of HIV-1 infection. Main methods: Monocyte derived DCs, obtained from normal subjects were cultured with and without Meth ± HIV-1B, followed by analyzing the gene and protein expression by real-time quantitative polymerase chain reaction (RT-PCR) and fluorescence-activated cell-sorting analyses, respectively. Key findings: Our results show that Meth significantly enhances HIV infection, and downregulates the gene expression of chemokines and costimulatory molecules with reciprocal upregulation of HIV coreceptors and DC-SIGN by dendritic cells. Significance: Better understanding of the role of Meth in HIV-1 disease susceptibility and the mechanism through which Meth mediates its effects on HIV-1 infection may help to devise novel therapeutic strategies against HIV-1 infection in Meth using HIV-1 infected population.     

Hypothalamic-pituitary-gonadal function in men and women using heroin and cocaine,stratified by HIV status

Background: Most studies of hypothalamic-pituitary-gonadal (HPG) function in illicit drug users either focus on men or do not consider the impact of HIV.Objective: This study investigated the relationships between cocaine and/or opiate use, HIV status, and HPG function in both men and women.Methods: Men and women between 18 and 50 years of age were stratified by sex, drug use, and HIV status. Information on demographics, HIV disease and treatment, and illicit drug use patterns was collected. To determine potential effects on HPG function, free testosterone (free T), estradiol, and gonadotropin concentrations were measured.Results: In a total of 197 men and women, free T concentrations were lower in men who used cocaine and/or opiates and in women infected with HIV Gonadotropin concentrations were elevated in seropositive men only. In women who received highly active antiretroviral therapy, HIV infection and illicit drug use had an additive or synergistic impact on free T concentrations.Conclusions: Our data reveal the importance of considering the independent effects of illicit drug use and HIV status for both men and women, so that risks may be identified and potential treatments designed for HPG dysfunction in these groups.     

Activity of phosphino palladium(II) and platinum(II) complexes against HIV-1 and <Emphasis Type="Italic">Mycobacterium tuberculosis</Emphasis>

Treatment of human immunodeficiency virus (HIV) is currently complicated by increased prevalence of co-infection with Mycobacterium tuberculosis. The development of drug candidates that offer the simultaneous management of HIV and tuberculosis (TB) would be of great benefit in the holistic treatment of HIV/AIDS, especially in sub-Saharan Africa which has the highest global prevalence of HIV-TB coinfection. Bis(diphenylphosphino)-2-pyridylpalladium(II) chloride (1), bis(diphenylphosphino)-2-pyridylplatinum(II) chloride (2), bis(diphenylphosphino)-2-ethylpyridylpalladium(II) chloride (3) and bis(diphenylphosphino)-2-ethylpyridylplatinum(II) (4) were investigated for the inhibition of HIV-1 through interactions with the viral protease. The complexes were subsequently assessed for biological potency against Mycobacterium tuberculosis H37Rv by determining the minimal inhibitory concentration (MIC) using broth microdilution. Complex (3) showed the most significant and competitive inhibition of HIV-1 protease (p = 0.014 at 100 µM). Further studies on its in vitro effects on whole virus showed reduced viral infectivity by over 80 % at 63 µM (p < 0.05). In addition, the complex inhibited the growth of Mycobacterium tuberculosis at an MIC of 5 µM and was non-toxic to host cells at all active concentrations (assessed by tetrazolium dye and real time cell electronic sensing). In vitro evidence is provided here for the possibility of utilizing a single metal-based compound for the treatment of HIV/AIDS and TB.     

HIV/AIDS epidemic in Eastern Europe: Recent developments in the Russian Federation and Ukraine among women

Background: The Russian Federation and the Ukraine are among the Eastern European countries with the fastest growing number of cases of HIV. According to data from the Joint United Nations Program on HIV/AIDS, nearly 90% of newly reported HIV diagnoses in Eastern Europe in 2006 were from the Russian Federation (66%) and the Ukraine (21%). A growing number of women are infected with HIV. The impact of gender on HIV/AIDS is an important factor in understanding the development and evolution of the HIV/AIDS epidemic in Eastern Europe.Objective: The aim of this study was to assess the importance of integrating gender consideration into the creation of HIV programs and to examine the effect of gender on HIV/AIDS.Methods: Reported HIV/AIDS cases from the official epidemiological register of the Ukrainian Centre for AIDS Prevention alongside data from the Russian Federal AIDS Center were analyzed. Joint United Nations Program on HIV/AIDS country fact sheets were reviewed and analyzed, and this information was supplemented with published HIV prevalence and sexually transmitted disease case reporting information, unpublished reports, and expert evaluations.Results: Of the newly registered cases of HIV, the proportion of women rose from 13.0% in 1995 to 44.0% in 2006 in the Russian Federation, and from 37.2% in 1995 to 41.9% in 2006 in the Ukraine. There has also been a considerable increase in mother-to-child transmission of HIV since 1995. Between 1987 and 1994, the proportion of children among the people newly infected with HIV in the Ukraine was 2.2%; in 2006 it was 17.6%. In 2006, 16,078 new HIV cases were registered in the Ukraine and 39,652 new HIV cases in the Russian Federation. Large increases in the number of HIV-infected women were reported from both countries.Conclusions: The data examined in this study suggest subregional differences in the magnitude of the HIV/AIDS epidemic in the Russian Federation and the Ukraine and the importance of the impact of gender on the rapid spread of the HIV/AIDS epidemic among women and women of child-bearing age. To protect women from HIV infection, it is important to find ways to empower them by implementing policies and specific prevention measures that increase their access to knowledge about HIV/AIDS; the empowerment of women is vital to reversing the HIV/AIDS epidemic.     

Dual inhibition of HCV and HIV by ring-expanded nucleosides containing the 5:7-fused imidazo[4,5-e][1,3]diazepine ring system. In vitro results and implications

Examples of ring-expanded nucleosides (RENs), represented by general structures 1 and 2, exhibited dual anti-HCV and anti-HIV activities in both cell culture systems and the respective target enzyme assays, including HCV NTPase/helicase and human RNA helicase DDX3. Since HCV is a leading co-infection in late stage HIV AIDS patients, often leading to liver cirrhosis and death, the observed dual inhibition of HCV and HIV by the target nucleoside analogues has potentially beneficial implications in treating HIV patients infected with HCV.     

Recent 5-year Findings and Technological Advances in the Proteomic Study of HIV-associated Disorders

Human immunodeficiency virus-1 (HIV-1) mainly relies on host factors to complete its life cycle. Hence, it is very important to identify HIV-regulated host proteins. Proteomics is an excellent technique for this purpose because of its high throughput and sensitivity. In this review, we summarized current technological advances in proteomics, including general isobaric tags for relative and absolute quantitation (iTRAQ) and stable isotope labeling by amino acids in cell culture (SILAC), as well as subcellular proteomics and investigation of posttranslational modifications. Furthermore, we reviewed the applications of proteomics in the discovery of HIV-related diseases and HIV infection mechanisms. Proteins identified by proteomic studies might offer new avenues for the diagnosis and treatment of HIV infection and the related diseases.     

Frequency of discussing HIV prevention and care topics with patients with HIV: Influence of physician gender,race/ethnicity,and practice characteristics

Background: Because people living with HIV now have greater life expectancy and reduced morbidity, there is a greater need for physicians to discuss HIV transmission risk reduction with these patients. Very limited data are available examining how frequently this discussion is held.Objective: We examined the frequency of discussing HIV prevention and HIV care topics, as well as the associations of gender, race/ethnicity, and practice characteristics of physicians caring for persons with HIV.Methods: In a 4-city (Miami, Atlanta, Baltimore, Los Angeles) survey, 417 licensed physicians who primarily cared for patients with HIV were mailed a 58-item questionnaire about how frequently they discussed HIV transmission risk reduction, adherence to HIV antiretroviral treatment (ART), adherence to opportunistic infection (OI) prophylaxis, and how to take medicines. Multivariate logistic regression analyses were used to examine the association between physician gender, race/ethnicity, and practice characteristics, and the frequency of discussing these topics.Results: A total of 317 physicians responded to the mailed questionnaire. Less than 40% of the physicians reported always discussing HIV transmission risk reduction with patients. In contrast, 83.9% and 65.0% reported always discussing adherence to ART and to OI prophylaxis, respectively. Of these physicians, 65.1% strongly agreed or somewhat agreed that they had sufficient time to provide the care and information needed to their patients. In multivariate analysis, the frequency of discussing HIV transmission risk reduction was higher for physicians who were Hispanic (P = 0.03) or Asian/Pacific Islander (P = 0.001), for physicians who reported they had enough time to provide care and information to patients (P = 0.003), and for physicians who cared for fewer patients (P = 0.05). The frequency of discussing HIV transmission risk reduction was suggestive of a higher rate for female physicians, but did not quite reach statistical significance.Conclusions: We observed a lower frequency of discussing the topic of HIV prevention compared with that of HIV care among the physicians surveyed. This infrequent discussion with patients with HIV represents a missed opportunity, and physicians should be encouraged to include discussion of prevention as a standard of care.     

Synthesis and biological evaluation of water-soluble derivatives of chiral gossypol as HIV fusion inhibitors targeting gp41

A series of novel or known water-soluble derivatives of chiral gossypol were synthesized and screened in vitro for their anti-HIV-1 activity. (?)-gossypol derivative was more active against HIV-1 than the corresponding (+)-gossypol derivative, respectively. Among these derivatives, d-glucosamine derivative of (?)-gossypol, oligopeptide derivative of (?)-gossypol and taurine derivative of (?)-gossypol, such as compounds 1a, 3a and 14a, showed significant inhibitory activities against HIV-1 replication, HIV-1 mediated cell-cell fusion and HIV gp41 6-helix bundle formation as some amino acid derivatives of (?)-gossypol.     

Phomoeuphorbins A-D, azaphilones from the fungus Phomopsis euphorbiae

Four azaphilones, named phomoeuphorbins A-D (1-4) were isolated from cultures of Phomopsis euphorbiae, an endophytic fungus isolated from Trewia nudiflora. Structures of 1-4 were established on the basis of spectroscopic analyses, including application of 2D NMR spectroscopic techniques. Phomoeuphorbins A and C exhibited very weak inhibitory activities against HIV replication in C8166 cells in vitro.     

Synthesis of potent antitumor and antiviral benzofuran derivatives

A new series of potent antitumor and antiviral benzofuran derivatives was synthesized by the reaction of the furochromone-6-carboxaldehydes 1 and 2 with different heterocyclic amines to yield the benzofuran-5-carbonyl derivatives 4–11. The synthesized compounds 1, 3–11 were tested against twelve different human cancer cell lines and all of the compounds were more potent than the comparative standards. The HIV inhibitory activity of the tested compounds 1, 3–11 showed that they have higher potency than Atevirdine. Moreover, compound 6 was significantly potent with wider therapeutic index. The HIV-1 RT inhibitory activity showed that compounds 10, 11, 3 and 4 were notably potent but with lower therapeutic index than Atevirdine. The HCV NS3-4A protease inhibitor activity of the tested compounds revealed that they have weaker potency and less therapeutic index than VX-950, although compounds 1, 4, 9 and 6, respectively exhibited significant activity.     

Hospitalizations for HIV/AIDS: Differences between sexes

Background: Women are especially vulnerable to HIV infection because of biological, social, cultural, and economic factors. In Brazil, AIDS was initially seen predominantly in homosexual men, but the epidemic gradually reached a gender balance as increasing numbers of women became infected with HIV.Objective: The aim of the present study was to identify the clinical and epidemiologic characteristics of hospitalized patients with HIV/AIDS of both sexes and compare the differences between them.Methods: This epidemiologic cross-sectional study evaluated gender differences in demographic, social, clinical, and epidemiologic characteristics of patients diagnosed with HIV/AIDS who were admitted for any reason to the Public Hospital of the Medical School of the Federal University of Triângulo Mineiro, Uberaba, Minas Gerais State, Brazil.Results: A total of 363 patients were included in the analysis, with a male/female ratio of 1.1:1.0. Forty-one percent of women were pregnant. Mean age at hospitalization and duration of hospitalization were significantly greater among men (P<0.05). Men and nonpregnant women were admitted because of infection significantly more often than were pregnant women (P<0.05). Significantly more single men who reported homosexual, bisexual, or heterosexual behavior associated with drug use were admitted compared with women (P<0.05). Women admitted for treatment were significantly more likely than men to be employed (P<0.05). Adherence to antiretroviral treatment and T CD4+ lymphocyte count indicated important differences between the sexes, with better parameters observed among nonpregnant and pregnant women compared with men.Conclusions: In the present study, women with HIV/AIDS who were admitted to the hospital for any reason were in better clinical condition compared with men. This observation may be partially explained by the proportion of pregnant women in the study population. These findings suggest that future studies should examine pregnant women with HIV/AIDS as a separate population group to avoid bias in analysis.     

Additions comparées des halogenès sur le 3,4,6-tri-O-acétyl-1,5-anhydro-1,5-didésoxy-, d-arabino-hex-1-énitol et l'analogue 3,4,6-tri-O-benzylé; effets de solvant sur la formation spécifique des dérivés 1,2-didésoxy-1,2-dihalogéno-α-d-glucopyranoses

Comparison of the addition of chlorine and bromine to 3,4,6-tri-O-acetyl-1,5-anhydro-1,5-dideoxy-d-arabino-hex-l-enitol (1) and to the 3,4,6-tri-O-benzyl analog (2) shows a greater stereoselectivity for 2 in the formation of 1,2-dideoxy-1,2-dihalo-geno-α-d-glucopyranose derivatives. Stereospecific addition took place in nonpolar solvents, and a quantitative correlation was established between the polarity of the solvent and the stereospecificity of the addition of chlorine to 1 and 2. Similar results were observed for the halogenomethoxylation of 1 and 2.     

Polyfluoroaromatic stavudine (d4T) ProTides exhibit enhanced anti-HIV activity

Human Immunodeficiency Virus (HIV) damages the immune system and leads to the life-threatening acquired immunodeficiency syndrome (AIDS). Despite the advances in the field of antiretroviral treatment, HIV remains a major public health challenge.Nucleosides represent a prominent chemotherapeutic class for treating viruses, however their cellular uptake, kinase-mediated activation and catabolism are limiting factors. Herein, we report the synthesis and in vitro evaluation of stavudine (d4T) ProTides containing polyfluorinated aryl groups against two strains; HIV-1 (IIIB) and HIV-2 (ROD). ProTide 5d containing a meta-substituted pentafluorosulfanyl (3-SF₅) aryl group showed superior antiviral activity over the parent d4T and the nonfluorinated analogue 5a. ProTide 5d has low nanomolar antiviral activity; (IC₅₀ = 30 nM, HIV-1) and (IC₅₀ = 36 nM, HIV-2) which is over tenfold more potent than d4T. Interestingly, ProTide 5d showed a significantly high selectivity indices with SI = 1753 (HIV-1) and 1461 (HIV-2) which is more than twice that of the d4T. All ProTides were screened in wild type as well as thymidine kinase deficient (TK^?) cells. Enzymatic activation of ProTide 5d using carboxypeptidase Y enzyme and monitored using both ³¹P and ¹⁹F NMR is presented.     

HIV-Associated Kaposi Sarcoma and Gender

Background: Cancer in individuals living with HIV and AIDS is a common source of morbidity and mortality, especially in the underdeveloped world. As antiretrovirals are distributed with greater equity across the globe, individuals with HIV and AIDS are living longer and developing malignancies, as opposed to other opportunistic infections.Objective: This article reviews the gender differences in studies of AIDS-associated cancers, examining factors related to transmission, treatment, and outcome.Methods: MEDLINE, PubMed, Ovid, conference proceedings, and abstract books were searched from 1983 onward for English-language publications and data on gender differences related to AIDS-associated cancers. Relevant trials were similarly reviewed. The search terms used were women or gender, cancer or tumor or malignancy, lymphoma or Kaposi, and HIV or AIDS.Results: We found that studies in established market economies have focused predominantly on men, although a wider view suggests that the rapidly growing rates of HIV infection among women should prompt specific oncologic challenges.Conclusion: Immunosuppression-induced malignancies in women, Kaposi sarcoma in particular, are likely to represent a global issue in the future. (Gend Med..     

Dual-Energy X-Ray Absorptiometry And Calculated Frax Risk Scores May Underestimate Osteoporotic Fracture Risk In Vitamin D-Deficient Veterans With Hiv Infection

Objective: We evaluated the utility of the Fracture Risk Assessment Tool (FRAX) in assessing fracture risk in patients with human immunodeficiency virus (HIV) and vitamin D deficiency.Methods: This was a retrospective study of HIV-infected patients with co-existing vitamin D deficiency at the Atlanta Veterans Affairs Medical Center. Bone mineral density (BMD) was assessed by dual-energy X-ray absorptiometry (DEXA), and the 10-year fracture risk was calculated by the FRAX algorithm. Two independent radiologists reviewed lateral chest radiographs for the presence of subclinical vertebral fractures.Results: We identified 232 patients with HIV and vitamin D deficiency. Overall, 15.5% of patients met diagnostic criteria for osteoporosis on DEXA, and 58% had low BMD (T-score between -1 and -2.5). The median risk of any major osteoporotic and hip fracture by FRAX score was 1.45 and 0.10%, respectively. Subclinical vertebral fractures were detected in 46.6% of patients. Compared to those without fractures, those with fractures had similar prevalence of osteoporosis (15.3% versus 15.7%; P>.999), low BMD (53.2% versus 59.3%; P = .419), and similar FRAX hip scores (0.10% versus 0.10%; P = .412). While the FRAX major score was lower in the nonfracture group versus fracture group (1.30% versus 1.60%; P = .025), this was not clinically significant.Conclusion: We found a high prevalence of subclinical vertebral fractures among vitamin D–deficient HIV patients; however, DEXA and FRAX failed to predict those with fractures. Our results suggest that traditional screening tools for fragility fractures may not be applicable to this high-risk patient population.Abbreviations:25(OH)D = 25-hydroxyvitamin DBMD = bone mineral densityBMI = body mass indexDEXA = dual-energy X-ray absorptiometryFRAX = Fracture Risk Assessment ToolHIV = human immunodeficiency virusIQR = interquartile rangePTH = parathyroid hormoneVA = Veterans AffairsWHO = World Health Organization     

Introduction of HIV-1 subtypes C,E and A into Austria

Background: Different subtypes of HIV-1 are prevalent in various geographical regions. Knowledge of their distribution is of importance with respect to possible differences in biological properties (such as reported for subtype E) as well as to diagnostic problems that may arise when specific subtypes are not recognized by standard serological assays.Objectives: The objectives of this study were to investigate the presence of the five major subtypes of HIV-1 (A–E) in the Austrian population and to estimate the prevalence of the individual subtypes in different risk groups.Study design: Serum samples from 88 HIV-1 positive patients were tested for the presence of subtype-specific antibodies using a peptide ELISA.Results: The majority of the patients were shown to be infected with HIV-1 subtype B, but infections with subtypes A, C, and E were also detected in the Austrian population, primarily in the heterosexual transmission group. While subtypes A and C were probably imported from different African countries, subtype E appears to have been introduced by sex tourists returning from Thailand.Conclusion: Introduction of HIV subtypes other than B from Africa and Asia into Austria has already occurred and will certainly increase within the next few years.