This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ http://www.aidsrestherapy.commostviewed/ Most viewed articles in last 30 days from AIDS Research and Therapy (ISSN 1742-6405) published by BioMed Central Human T-cell leukemia virus type-1 (HTLV-1) induces adult T-cell leukemia/lymphoma (ATL/L), a fatal lymphoproliferative disorder, and HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP), a chronic progressive disease of the central nervous system after a long period of latent infection. Although the mechanism of transformation and leukemogenesis is not fully elucidated, there is evidence to suggest that the viral oncoprotein Tax plays a crucial role in these processes through the regulation of several pathways including NF-kappaB and the cell cycle pathways. The observation that NF-kappaB, which is strongly induced by Tax, is indispensable for the maintenance of the malignant phenotype of HTLV-1 by regulating the expression of various genes involved in cell cycle regulation and inhibition of apoptosis provides a possible molecular target for these infected cells. To develop potential new therapeutic strategies for HTLV-1 infected cells, in this present study, we initially screened a battery of NF-kappaB and CDK inhibitors (total of 35 compounds) to examine their effects on the growth and survival of infected T-cell lines. Two drugs namely BMS-345541 and Purvalanol A exhibited higher levels of growth inhibition and apoptosis in infected cell as compared to uninfected cells. BMS-345541 inhibited IKKbeta kinase activity from HTLV-1 infected cells with an IC50 (the 50% of inhibitory concentration) value of 50 nM compared to 500 nM from control cells as measured by in vitro kinase assays. The effects of Purvalanol A were associated with suppression of CDK2/cyclin E complex activity as previously shown by us. Combination of both BMS-345541 and Purvalanol A showed a reduced level of HTLV-1 p19 Gag production in cell culture. The apparent apoptosis in these infected cells were associated with increased caspase-3 activity and PARP cleavage. The potent and selective apoptotic effects of these drugs suggest that both BMS-345541 and Purvalanol A, which target both NF-kappaB and CDK complex and the G1/S border, might be promising new agents in the treatment of these infected patients. http://www.aidsrestherapy.com/content/5/1/12 Emmanuel Agbottah, Wen-I Yeh, Reem Berro, Zachary Klase, Caitlin Pedati, Kylene Kehn-Hall, Weilin Wu and Fatah Kashanchi AIDS Research and Therapy 2008, 5:12 Number of accesses: 696 2008-06-10 doi:10.1186/1742-6405-5-12 AIDS Research and Therapy 1742-6405 5 12 2008-06-10 Background: Access to antiretroviral drugs for HIV-1 infection has increased in sub-Saharan Africa (SSA) during the past few years. Mutations in the HIV-1 genome are often associated with treatment failure as indicated by viral replication and elevated levels of virus in the blood. Mutations conferring resistance to antiretroviral drugs are based on comparing gene sequences with corresponding consensus sequences of HIV-1 subtype B that represents only 10% of the AIDS pandemic. The HIV pandemic in SSA is characterized by high viral genetic diversity. Before antiretroviral drugs become more widely available, it is important to characterize baseline naturally occurring genetic mutations and polymorphisms associated with antiretroviral drug resistance among circulating HIV-1 subtypes. Methods: The prevalence of mutations associated with antiretroviral drug resistance in protease (PR) and reverse transcriptase (RT) regions among antiretroviral treatment-naïve HIV-1 infected pregnant women was investigated in Bukoba (Kagera) and Moshi (Kilimanjaro) municipalities, Tanzania, between September and December 2005. The HIV-1 pol gene was amplified using primers recognizing conserved viral sequences and sequenced employing BigDye chemistry from 100 HIV-1 seropositive treatment-naïve pregnant women and 61 HIV-1 seropositive women who had received a single dose of Nevirapine (sdNVP). Positions 1–350 of the RT and 1–99 of the PR genes were analyzed for mutations based on the Stanford University HIV Drug Resistance Database. Results: HIV-1 subtypes A, C, D, CRF10_CD and Unique Recombinant Forms (URF) were detected. Primary mutations associated with NRTI and NNRTI resistance were detected among 3% and 4% of treatment-naïve strains, respectively. Primary mutations associated with NRTI and NNRTI resistance were detected in 1.6% and 11.5% of women who had received sdNVP, respectively. None of the primary mutations associated with PI resistance was found. Polymorphisms detected in RT and PR sequences were mainly mutations that are found in the consensus sequences of non-B subtypes Conclusion: Based on the WHO HIV Drug Resistance Research Network Threshold of less than 5%, the baseline prevalence of primary mutations among treatment-naïve HIV-1 infected pregnant women in Kagera and Kilimanjaro regions was low. The significance of HIV-1 subtype B polymorphic positions with respect to antiretroviral resistance identified among the prevalent HIV-1 subtypes is unknown. More studies addressing the correlation between polymorphic mutations, antiretroviral resistance and clinical outcome are warranted in regions where non-B subtypes are prevalent. http://www.aidsrestherapy.com/content/5/1/13 Balthazar M Nyombi, Carol Holm-Hansen, Knut I Kristiansen, Gunnar Bjune and Fredrik Müller AIDS Research and Therapy 2008, 5:13 Number of accesses: 524 2008-06-21 doi:10.1186/1742-6405-5-13 AIDS Research and Therapy 1742-6405 5 13 2008-06-21 Background: Terpenoid derivatives originating from many plants species, are interesting compounds with numerous biological effects, such as anti-HIV-1 activity. The zinc tetra-ascorbo-camphorate complex (or "C14"), a new monoterpenoid derivative was evaluated in vitro for its anti-HIV-1 activity on both R5- and X4-HIV-1 infection of primary target cells (macrophages, dendritic cells and T cells) and on HIV-1 transfer from dendritic cells to T cells. Results: The toxicity study was carried out in vitro and also with the New Zealand White rabbit vaginal irritation model. C14 was found to be no cytotoxic at high concentrations (CC50 > 10 μM) and showed to be a potential HIV-1 inhibitor of infection of all the primary cells tested (EC50 = 1 μM). No significant changes could be observed in cervicovaginal tissue of rabbit exposed during 10 consecutive days to formulations containing up to 20 μM of C14. Conclusion: Overall, these preclinical studies suggest that zinc tetra-ascorbo-camphorate derivative is suitable for further testing as a candidate microbicide to prevent male-to-female heterosexual acquisition of HIV-1. http://www.aidsrestherapy.com/content/5/1/10 Héla Saïdi, Mohammad-Ali Jenabian, Bernard Gombert, Charlotte Charpentier, Aurèle Mannarini and Laurent Bélec AIDS Research and Therapy 2008, 5:10 Number of accesses: 455 2008-06-03 doi:10.1186/1742-6405-5-10 AIDS Research and Therapy 1742-6405 5 10 2008-06-03 The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients initiating antiretroviral therapy (ART) results from restored immunity to specific infectious or non-infectious antigens. A paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating therapy characterizes the syndrome. Potential mechanisms for the syndrome include a partial recovery of the immune system or exuberant host immunological responses to antigenic stimuli. The overall incidence of IRIS is unknown, but is dependent on the population studied and its underlying opportunistic infectious burden. The infectious pathogens most frequently implicated in the syndrome are mycobacteria, varicella zoster, herpesviruses, and cytomegalovirus (CMV). No single treatment option exists and depends on the underlying infectious agent and its clinical presentation. Prospective cohort studies addressing the optimal screening and treatment of opportunistic infections in patients eligible for ART are currently being conducted. These studies will provide evidence for the development of treatment guidelines in order to reduce the burden of IRIS. We review the available literature on the pathogenesis and epidemiology of IRIS, and present treatment options for the more common infectious manifestations of this diverse syndrome and for manifestations associated with a high morbidity. http://www.aidsrestherapy.com/content/4/1/9 David M Murdoch, Willem DF Venter, Annelies Van Rie and Charles Feldman AIDS Research and Therapy 2007, 4:9 Number of accesses: 447 2007-05-08 doi:10.1186/1742-6405-4-9 AIDS Research and Therapy 1742-6405 4 9 2007-05-08 Background: Human immunodeficiency virus type 1 (HIV-1)-based gene delivery systems are popular due to their superior efficiency of transduction of primary cells. However, these systems cannot be readily used for delivery of anti-HIV-1 genes that target constituents of the packaging system itself due to inimical effects on vector titer. Here we describe HIV-1-based packaging systems containing the Rev-response element (RRE), of simian immunodeficiency virus (SIV) in place of the HIV-1 RRE. The SIV RRE-containing packaging systems were used to deliver the anti-Rev gene, Rev M10, into HIV-1 susceptible target cells. Results: An HIV-1 based packaging system was created using either a 272- or 1045-nucleotide long RRE derived from the molecular clone SIVmac239. The 1045-nucleotide SIV RRE-containing HIV-1 packaging system provided titers comparable to that of the HIV-1 RRE-based one. Moreover, despite the use of HIV-1 Rev for production of vector stocks, this packaging system was found to be relatively refractory to the inhibitory effects of Rev M10. Correspondingly, the SIV RRE-based packaging system provided 34- to 130-fold higher titers than the HIV-1 RRE one when used for packaging a gene transfer vector encoding Rev-M10. Jurkat T-cells, gene modified with Rev M10 encoding HIV-1 vectors, upon challenge with replication defective HIV-1 in single-round infection experiments, showed diminished production of virus particles. Conclusion: A simple modification of an HIV-1 gene delivery system, namely, replacement of HIV-1 RRE with that of SIV, allowed efficient delivery of Rev M10 transgene into T-cell lines for intracellular immunization against HIV-1 replication. http://www.aidsrestherapy.com/content/5/1/11 Narasimhachar Srinivasakumar AIDS Research and Therapy 2008, 5:11 Number of accesses: 311 2008-06-05 doi:10.1186/1742-6405-5-11 AIDS Research and Therapy 1742-6405 5 11 2008-06-05 Background: Kaposi Sarcoma (KS) is a multifocal angioproliferative neoplasm characterized by inflammation, oedema, neoangiogenesis and spindle cell proliferation. The pathogenesis of human immunodeficiency virus (HIV)-associated KS (HIV-KS) is multifactorial. HHV-8 is an essential factor but not in itself sufficient to cause HIV-KS, the development of which is influenced by HIV, by increased production of cytokines and by growth factors. Whether HIV-KS is a true malignancy or a reactive hyperplastic inflammatory condition is debatable.Results and ConclusionOedema of the face, legs and hands is a prominent feature of HIV-KS and is probably caused by lymphoedema related to the HIV-KS lesions. The cases of two HIV-seropositive subjects with KS-associated facial lymphoedema are reported. Extensive oral HIV-KS in association with facial oedema in the absence of anti-retroviral treatment appears to be an indication of a poor prognosis. http://www.aidsrestherapy.com/content/5/1/2 L Feller, JN Masipa, NH Wood, EJ Raubenheimer and J Lemmer AIDS Research and Therapy 2008, 5:2 Number of accesses: 301 2008-01-29 doi:10.1186/1742-6405-5-2 AIDS Research and Therapy 1742-6405 5 2 2008-01-29 Background: HIV disease itself is associated with increased healthcare utilization and healthcare expenditures. HIV-infected persons with lipodystrophy have been shown to have poor self-perceptions of health. We evaluated whether lipodystrophy in the HIV-infected population was associated with increased utilization of healthcare services and increased healthcare costs.ObjectiveTo examine utilization of healthcare services and associated costs with respect to presence of lipodystrophy among HIV-infected patients. Methods: Healthcare utilization and cost of healthcare services were collected from computerized accounting records for participants in a body image study among HIV-infected patients treated at a tertiary care medical center. Lipodystrophy was assessed by physical examination, and effects of lipodystrophy were assessed via body image surveys. Demographic and clinical characteristics were also ascertained. Analysis of healthcare utilization and cost outcomes was performed via between-group analyses. Multivariate modeling was used to determine predictors of healthcare utilization and associated costs. Results: Of the 181 HIV-infected participants evaluated in the study, 92 (51%) had clinical evidence of HIV-associated lipodystrophy according to physician examination. Total healthcare utilization, as measured by the number of medical center visits over the study period, was notably increased among HIV-infected subjects with lipodystrophy as compared to HIV-infected subjects without lipodystrophy. Similarly, total healthcare expenditures over the study period were $1,718 more for HIV-infected subjects with lipodystrophy than for HIV-infected subjects without lipodystrophy. Multivariate modeling demonstrated strong associations between healthcare utilization and associated costs, and lipodystrophy score as assessed by a clinician. Healthcare utilization and associated costs were not related to body image survey scores among HIV-infected patients with lipodystrophy. Conclusions: Patients with HIV-associated lipodystrophy demonstrate an increased utilization of healthcare services with associated increased healthcare costs as compared to HIV-infected patients without lipodystrophy. The economic and healthcare service burdens of HIV-associated lipodystrophy are significant and yet remain inadequately addressed by the medical community. http://www.aidsrestherapy.com/content/5/1/14 Jeannie S Huang, Karen Becerra, Susan Fernandez, Daniel Lee and W C Mathews AIDS Research and Therapy 2008, 5:14 Number of accesses: 288 2008-07-01 doi:10.1186/1742-6405-5-14 AIDS Research and Therapy 1742-6405 5 14 2008-07-01 Gut immune components are severely compromised among persons with AIDS, which allows increased translocation of bacterial lipopolysaccharides (LPS) into the systemic circulation. These microbial LPS are reportedly increased in chronically HIV-infected individuals and findings have correlated convincingly with measures of immune activation. Immune reconstitution inflammatory syndrome (IRIS) is an adverse consequence of the restoration of pathogen-specific immune responses in a subset of HIV-infected subjects with underlying latent infections during the initial months of highly active antiretroviral treatment (HAART). Whether IRIS is the result of a response to a high antigen burden, an excessive response by the recovering immune system, exacerbated production of pro-inflammatory cytokines or a lack of immune regulation due to inability to produce regulatory cytokines remains to be determined. We theorize that those who develop IRIS have a high burden of proinflammatory cytokines produced also in response to systemic bacterial LPS that nonspecifically act on latent mycobacterial antigens. We also hypothesize that subjects that do not develop IRIS could have developed either tolerance (anergy) to persistent LPS/tubercle antigens or could have normal FOXP3+ gene and that those with defective FOXP3+ gene or those with enormous plasma LPS could be vulnerable to IRIS. The measure of microbial LPS, anti-LPS antibodies and nonspecific plasma cytokines in subjects on HAART shall predict the role of these components in IRIS. http://www.aidsrestherapy.com/content/4/1/29 Esaki Muthu Shankar, Ramachandran Vignesh, Kailapuri G Murugavel, Pachamuthu Balakrishnan, Ramalingam Sekar, Charmaine AC Lloyd, Suniti Solomon and Nagalingeswaran Kumarasamy AIDS Research and Therapy 2007, 4:29 Number of accesses: 237 2007-11-30 doi:10.1186/1742-6405-4-29 AIDS Research and Therapy 1742-6405 4 29 2007-11-30 Background: According to Vietnamese policy, HIV-infected women should have access at least to HIV testing and Nevirapine prophylaxis, or where available, to adequate counselling, HIV infection staging, ARV prophylaxis, and infant formula. Many studies in high HIV prevalence settings have reported low coverage of PMTCT services, but there have been few reports from low HIV prevalence settings, such as Asian countries. We investigated the access of HIV-infected pregnant women to PMTCT services in the well-resourced setting of the capital city, Hanoi. Methods: Fifty-two HIV positive women enrolled in a self-help group in Hanoi were consulted, through in-depth interviews and bi-weekly meetings, about their experiences in accessing PMTCT services. Results: Only 44% and 20% of the women had received minimal and comprehensive PMTCT services, respectively. Nine women did not receive any services. Twenty-two women received no counselling. The women reported being limited by lack of knowledge and information due to poor counselling, gaps in PMTCT services, and fear of stigma and discrimination. HIV testing was done too late for optimal interventions and poor quality of care by health staff was frequently mentioned. Conclusion: In a setting where PMTCT is available, HIV-infected women and children did not receive adequate care because of barriers to accessing those services. The results suggest key improvements would be improving quality of counselling and making PMTCT guidelines available to health services. Women should receive early HIV testing with adequate counselling, safe care and prophylaxis in a positive atmosphere towards HIV-infected women. http://www.aidsrestherapy.com/content/5/1/7 Thu Anh Nguyen, Pauline Oosterhoff, Yen Pham Ngoc, Pamela Wright and Anita Hardon AIDS Research and Therapy 2008, 5:7 Number of accesses: 232 2008-04-17 doi:10.1186/1742-6405-5-7 AIDS Research and Therapy 1742-6405 5 7 2008-04-17 Background: Immune restoration disease (IRD) is an adverse consequence of antiretroviral therapy, where the restored pathogen-specific response causes immunopathology. Mycobacteria are the pathogens that most frequently provoke IRD and mycobacterial IRD is a common cause of morbidity in HIV-infected patients co-infected with mycobacteria. We hypothesised that the excessive effector immune response in mycobacterial IRD reflects impaired regulation by IL-10. Results: We studied two patients who experienced mycobacterial IRD during ART. One patient developed a second episode of IRD with distinct clinical characteristics. Findings were compared with patients 'at risk' of developing IRD who had uneventful immune recovery. Peripheral blood mononuclear cells (PBMC) from all subjects were stimulated with mycobacterial antigens in the form of purified protein derivative (PPD). Supernatants were assayed for IFNγ and IL-10. In response to PPD, PBMC from IRD patients generated IFNγ during the first IRD episode, whilst cells from non-IRD controls produced more IL-10. Conclusion: We present preliminary data from two HIV-infected patients showing an imbalance between IFNγ and IL-10 responses to mycobacterial antigens during mycobacterial IRD. Our findings suggest that imbalanced effector and regulatory cytokine responses should be investigated as a cause of IRD. http://www.aidsrestherapy.com/content/5/1/9 Andrew Lim, Lloyd D'Orsogna, Patricia Price and Martyn A French AIDS Research and Therapy 2008, 5:9 Number of accesses: 214 2008-04-29 doi:10.1186/1742-6405-5-9 AIDS Research and Therapy 1742-6405 5 9 2008-04-29