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HIV Replication (hiv + replication)
Selected AbstractsSuppression of viral replication with highly active antiretroviral therapy has no impact on the functional profile of HIV-specific CD8+ T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 6 2008Mariola López Abstract A better control of viral replication in long-term non-progressors has been associated with polyfunctional CD8+ T cell responses. However, low levels of HIV replication could be the cause rather than the consequence of enhanced immune responses in long-term non-progressors. The functional profile and the expansion ability of HIV-Gag- and HIV-Nef-specific CD8 responses were analysed measuring the production of MIP-1,, IL-2, TNF-, and expression of CD107, using polychromatic flow cytometry, in 36,HIV-infected patients at baseline and after 12,months of highly active antiretroviral therapy (HAART) and complete viral suppression. Most patients presented detectable Gag and Nef responses both at baseline and after 1,year of HAART, with a significant decline after achieving viral suppression. At baseline, the majority of CD8+ response was due to cells producing only MIP-1, or simultaneously MIP-1, and CD107. The functional profile did not significantly change after achieving complete viral suppression with HAART. Therefore, control of HIV-1 replication after 1,year of HAART had no significant impact on the quality of HIV-1-specific CD8 response, but the effects of treatment in long-term, or of early HAART are not known. Thus, it is still uncertain whether multifunctional CD8 responses are the cause or consequence of low plasma viremia. [source] CD30 ligation differentially affects CXCR4-dependent HIV-1 replication and soluble CD30 secretion in non-Hodgkin cell lines and in ,,,,T,lymphocytesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2003Priscilla Biswas Abstract We studied whether signaling through CD30, a member of the TNF receptor family, affected acute infection with HIV-1, encompassing its entire replicative cycle. Several non-Hodgkin cell lines, targets of CXCR4-dependent (X4) HIV-1 infection, were positive for CD30 expression. CD30 ligation induced up-regulation of viral replication only in certain CD30+ cell lines. Enhancement ofX4 virus replication by CD30 engagement inversely correlated with both CD30 surface density and constitutive NF-,B activation. Conversely, expression of CD30, but not of other members of the TNF receptor family, was proportional to constitutive NF-,B binding. Concomitantly, secretion of soluble (s) CD30 increased in all cell lines by CD30 ligation. sCD30 release was enhanced by engagement of CD30 alone and, to a greater extent, by co-engagement of CD3 also in primary ,,,,T,lymphocytes, along with complementary modulations of their surface CD30 expression. sCD30-containing supernatant specifically inhibited HIV-1 expression induced by CD30 engagement in chronically infected ACH-2 T,cells; thus sCD30 may act as a negative feed-back molecule. In conclusion, we have delineated novel features of CD30 biology and underline the peculiar link of CD30 expression to constitutive NF-,B activation which is pivotal to both HIV replication and cell survival. [source] Clinical benefit of interventions driven by therapeutic drug monitoringHIV MEDICINE, Issue 5 2005AL Rendón Background Adequate plasma concentrations of antiretroviral drugs are key to achieving and maintaining long-term suppression of HIV replication. Multiple factors may influence drug levels, causing increases or reductions that may, respectively, result in toxicity or virological failure. Therapeutic drug monitoring (TDM) might help to detect and correct such abnormalities. Objective To evaluate the usefulness of TDM in the care of HIV-infected patients in an out-patient clinical setting. Methods All the requests for TDM of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients attending our HIV out-patient clinic from October 2000 to August 2003 were analysed. Blood samples were collected before the morning dose. Drug concentrations were measured by high performance liquid chromatography by ultraviolet waves (HPLC-UV). Results A total of 151 requests from 137 patients were assessed. The reasons for requesting TDM were drug toxicity (59%), virological failure (39%) and possible drug interactions (2%). NNRTI levels were more often requested because of toxicity, while PI levels were more often requested because of virological failure. Elevated drug levels were confirmed in 36% of patients with suspected drug toxicity, while subtherapeutic levels were found in 37% of patients failing virologically. Based on the results of TDM, dose modifications were made in 37% of patients, allowing correction of such abnormalities in 80% of cases. Moreover, adequate plasma concentrations were confirmed in 79% of patients whose levels were assessed again. Conclusions Therapeutic drug monitoring may be a useful tool to identify toxic levels of NNRTI and subtherapeutic concentrations of PI. Dose adjustments following TDM may ameliorate drug-related toxicities or improve virological response rates. [source] Dendritic cell-based human immunodeficiency virus vaccineJOURNAL OF INTERNAL MEDICINE, Issue 1 2009C. R. Rinaldo Abstract. Dendritic cells (DC) have profound abilities to induce and coordinate T-cell immunity. This makes them ideal biological agents for use in immunotherapeutic strategies to augment T-cell immunity to HIV infection. Current clinical trials are administering DC-HIV antigen preparations carried out ex vivo as proof of principle that DC immunotherapy is safe and efficacious in HIV-infected patients. These trials are largely dependent on preclinical studies that will provide knowledge and guidance about the types of DC, form of HIV antigen, method of DC maturation, route of DC administration, measures of anti-HIV immune function and ultimately control of HIV replication. Additionally, promising immunotherapy approaches are being developed based on targeting of DC with HIV antigens in vivo. The objective is to define a safe and effective strategy for enhancing control of HIV infection in patients undergoing antiretroviral therapy. [source] In vitro analysis of synergism and antagonism of different nucleoside/nucleotide analogue combinations on the inhibition of human immunodeficiency virus type 1 replication,JOURNAL OF MEDICAL VIROLOGY, Issue 2 2009M. Perez-Olmeda Abstract In this study we have developed an in vitro system to evaluate the combined effect of two NRTIs on HIV replication and to assess their antagonism or synergy. Synergy or antagonism effect was determined in peripheral blood mononuclear cells (PBMCs) to approach a more physiological model than T-cell lines. PBMCs were infected with a full-length HIV-1 clone carrying the luciferase gene as a reporter. The following combinations were investigated: zidovudine+stavudine (ZDV,+, d4T), lamivudine,+,abacavir (3TC,+,ABC), lamivudine,+,didanosine (3TC,+,ddI), lamivudine,+ stavudine (3TC,+,d4T), tenofovir,+,stavudine (TDF,+,d4T), tenofovir,+,didanosine (TDF,+,ddI), tenofovir,+,abacavir (TDF,+,ABC), tenofovir,+, lamivudine (TDF,+,3TC), tenofovir,+,zidovudine (TDF,+,ZDV), stavudine,+,didanosine (d4T,+,ddI), zidovudine,+,lamivudine (ZDV,+,3TC), abacavir,+, didanosine (ABC,+,ddI), zidovudine,+,didanosine (ZDV,+,ddI), and abacavir,+,stavudine (ABC,+, d4T). The effect of combining two drugs was evaluated with a quantitative method based on the median-effect principle of Chou and Talalay. A synergistic effect was observed with combinations containing TDF and ZDV or d4T, d4T and ddI and ZDV plus 3TC. In contrast, combinations including TDF,+,ddI, 3TC,+,ddI, ABC,+,ddI, and ZDV,+,ddI showed an antagonistic effect on the inhibition of viral replication at all levels of inhibition tested. Lower antagonistic effect was also found in drug combinations that included 3TC,+,ABC, 3TC,+,TDF, 3TC,+,d4T, and TDF,+, ABC. In conclusion, the method developed allows to measure in vitro the effect of different combinations of two NRTIs on HIV replication. The results suggest that combined therapy including TDF with thymidine analogues may be considered for future therapeutic options in contrast to clearly antagonistic combinations such us TDF plus ddI or 3TC plus ddI, that would explain virological failure in clinical studies when these combinations were used. J. Med. Virol. 81:211,216, 2009. © 2008 Wiley-Liss, Inc. [source] Virological characterization of patients treated early is able to control HIV-1 replication after multiple cycles of structured therapy interruptionJOURNAL OF MEDICAL VIROLOGY, Issue 8 2007G. Rozera Abstract This study aimed to define clinical and virological parameters associated with spontaneous control of HIV replication in patients having initiated HAART during primary HIV infection, who underwent structured therapy interruption by two protocols with either fixed or HIV viremia-guided scheme. At the end of the protocol all patients were changed to viremia-guided scheme and observed for 12 months (follow-up). Patients maintaining HIV viremia below the indications for resumption of HAART during the follow-up, were defined controllers, those who had to resume HAART were defined non-controllers. The following parameters were examined: pre-interruption therapy duration, CD4+, HIV RNA, proviral DNA, evolution of viral quasispecies. No specific advantage was conferred by either interruption of structured therapy in the proportion of controllers and non-controllers. Pre-HAART and zenith CD4+, pre-therapy interruption, HAART duration, but not pre-HAART HIV RNA, were significantly higher in controllers as compared to non-controllers. HIV RNA levels after the first interruption cycle of therapy were significantly lower in controllers than in non-controllers. Proviral DNA levels were also lower in controllers at this time point. HIV RNA and proviral DNA levels associated with the last interruption of therapy cycle were not different from those associated with the first cycle, and, in spite of multiple waves of virus rebound, very few gag quasispecies variants emerged in each patient. The data suggest that pre-treatment clinical parameters and virological events associated with the first viral rebound are crucial factors in determining the ability to control viral replication after multiple cycles of interruption of treatment. J. Med. Virol. 79: 1047,1054, 2007. © 2007 Wiley-Liss, Inc. [source] HIV-associated neuropathies: role of HIV-1, CMV, and other virusesJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2001Dennis L. Kolson Abstract The role of the human immunodeficiency virus (HIV) and other viruses in the development of neuropathies associated with HIV infection is controversial. Distal symmetric polyneuropathy (DSP), the most common subtype of HIV-associated neuropathy, is characterized by an abundance of reactive macrophages within the peripheral nerve, but HIV replication is limited to a small percentage of the macrophages. Thus, the pathological destruction may be mediated by pro-inflammatory signals amplified by activated glial elements within the nerve, similar to the proposed mechanism of damage caused by HIV within the central nervous system. In contrast, in mononeuropathy multiplex (MM) and progressive polyneuropathy (PP), cytomegalovirus (CMV) replication in the peripheral nerve is consistently demonstrable, and this replication likely results in direct damage to the infected cells (neurons and glia). The rarest form of HIV-associated neuropathy, the diffuse infiltrative lymphocytosis syndrome (DILS), is characterized by an intense CD8+ T lymphocyte infiltration into the nerve and abundant HIV infection of macrophages. Finally, while other viruses (varicella zoster, herpes simplex) are associated with myelitis in HIV-infected individuals, there is little support for a role for these viruses in HIV-associated neuropathy. [source] Recent progress in the development of coumarin derivatives as potent anti-HIV agents,MEDICINAL RESEARCH REVIEWS, Issue 3 2003Donglei Yu Abstract Numerous plant-derived compounds have been evaluated for inhibitory effects against HIV replication, and some coumarins have been found to inhibit different stages in the HIV replication cycle. This review article describes recent progress in the discovery, structure modification, and structure,activity relationship studies of potent anti-HIV coumarin derivatives. A dicamphanoyl-khellactone (DCK) analog, which was discovered and developed in our laboratory, and calanolide A are currently in preclinical studies and clinical trials, respectively. © 2003 Wiley Periodicals, Inc. Med Res Rev, 23, No. 3, 322-345, 2003 [source] Oral infectious diseases: a potential risk factor for HIV virus recrudescence?ORAL DISEASES, Issue 5 2009OA González As the highly active antiretroviral therapy (HAART) has transitioned human immunodeficiency virus (HIV) infection into a ,chronic disease' management strategy, there is growing evidence that infection with non-HIV pathogens in HIV+ patients may have important public health implications in undermining HAART success and acquired immunodeficiency syndrome progression. Several bacterial and host cell products during infections with non-HIV pathogens have shown the capacity to regulate HIV replication in latently infected cells. A high prevalence of oral infections caused by bacteria, viruses and fungi has been described in HIV+ patients, including periodontal disease. The oral cavity appears to be a site of HIV pathogenesis and potential reservoir for the disease as HIV RNA and DNA forms are present in saliva as well as in gingival crevicular fluid, and oral epithelial cells are susceptible to either cell free or cell-associated HIV infection. The clinical and biological bases of potential associations between chronic oral inflammatory disorders, such as periodontal disease, and exacerbation of HIV viraemia have received little attention. This review attempts to evaluate the current understanding of HIV reactivation as a result of co-infection and/or inflammation induced by non-HIV pathogens in HIV-infected patients, and presents a hypothetic model about the potential role of periodontitis as a global oral infection that potentially contributes to HIV recrudescence. [source] Development and characterization of a triple combination gene therapy vector inhibiting HIV-1 multiplicationTHE JOURNAL OF GENE MEDICINE, Issue 10 2008Maria B. Asparuhova Abstract Background RNA-based approaches are promising for long-term gene therapy against HIV-1. They can target virtually any step of the viral replication cycle. It is also possible to combine anti-HIV-1 transgenes targeting different facets of HIV replication to compensate for limitations of any individual construct, maximizing efficacy and decreasing chances of escape mutations. We have previously developed two strategies to inhibit HIV-1 multiplication. One was a short hairpin RNA targeting the host factor cyclophilin A implicated in HIV-1 replication. Additionally, an antisense derivative of U7 small nuclear RNA was designed to induce the skipping of the HIV-1 Tat and Rev internal exons. Results In the present study, we have established an additional tRNAval promoter-driven shRNA against the coding sequence of viral infectivity factor. When human T-cell lines or primary CD4+ T cells are transduced with a triple lentiviral vector encoding these three therapeutic RNAs, HIV-1 multiplication is very efficiently suppressed. Moreover, all three therapeutic RNAs exhibit antiviral effects at early stages of the viral replication cycle (i.e. prior to viral cDNA integration or gene expression). Conclusions These findings make this triple lentiviral vector an attractive candidate for a gene therapy against HIV/AIDS. Copyright © 2008 John Wiley & Sons, Ltd. [source] Gene therapy for HIV/AIDS: the potential for a new therapeutic regimenTHE JOURNAL OF GENE MEDICINE, Issue 8 2003Greg Fanning Abstract Human Immunodeficiency Virus (HIV) is the etiologic agent of Acquired Immunodeficiency Syndrome (AIDS). HIV/AIDS is a disease that, compared with the not so distant past, is now better held in check by current antiretroviral drugs. However, it remains a disease not solved. Highly active antiretroviral therapy (HAART) generally uses two non-nucleoside and one nucleoside reverse transcriptase (RT) inhibitor or two non-nucleoside RT and one protease inhibitor. HAART is far more effective than the mono- or duo-therapy of the past, which used compounds like the nucleoside reverse transcriptase inhibitor AZT or two nucleoside reverse transcriptase inhibitors. However, even with the relatively potent drug cocktails that comprise HAART, there are the issues of (i) HIV escape mutants, (ii) an apparent need to take the drugs in an ongoing manner, and (iii) the drugs' side effects that are often severe. This review speaks to the potential addition to these potent regimens of another regimen, namely the genetic modification of target hematopoietic cells. Such a new treatment paradigm is conceptually attractive as it may yield the constant intracellular expression of an anti-HIV gene that acts to inhibit HIV replication and pathogenicity. A body of preclinical work exists showing the inhibition of HIV replication and decreased HIV pathogenicity by anti-HIV genetic agents. This preclinical work used hematopoietic cell lines and primary cells as the target tissue. More recently, several clinical trials have sought to test this concept in vivo. Copyright © 2003 John Wiley & Sons, Ltd. [source] Astrocyte Activation and Apoptosis: Their Roles in the Neuropathology of HIV InfectionBRAIN PATHOLOGY, Issue 1 2003Farideh Sabri Astrogliosis is a common neuropathological finding in the brains of HIV infected individuals; both activation and apoptosis of astrocytes are seen. This review aims to discuss the Fas pathway in the context of proliferation and apoptosis of astrocytes during HIV infection, and as a result of astrogliosis, the dysregulation of astrocyte-neuron networks. The presence of molecules reflecting astrocyte activation, which are derived from the sol-ubilization of receptor/ligand from the surface of proliferating astrocytes, in the cerebrospinal fluid may be used to evaluate the degree of brain cell activation during HAART therapy. A better understanding of the molecular pathway(s) leading to increase activation and apoptosis of astrocytes, in parallel with studies conducted to unravel the molecules involved in T-cell apoptosis during HIV infection, may lead to the development of new therapeutic strategies for controlling HIV replication and tissue damage. [source] The ins and outs of HIV replicationCELLULAR MICROBIOLOGY, Issue 5 2005Candace Gomez Summary The life cycle of HIV-1 involves a series of steps necessary for the successful infection of human target cells. First the RNA genome enters the cytoplasm after the fusion of the viral membrane and that of the target cell. The RNA genome is then converted to DNA form through the process of reverse transcription. The DNA genome is then integrated into the host cell DNA. Next, viral proteins and more copies of the viral genome are produced. These components assemble to form new virions that are then able to propagate. The cellular proteins involved in HIV-1 entry have been known for more than a decade now and the study of the cellular and viral components involved in HIV-1 entry has led to the development of many therapeutic strategies and drugs designed to block viral replication. Recently, there have been significant advances in the understanding of HIV-1 assembly as a consequence of the identification of the cellular factors that mediate this process. This review will provide a basic outline of the current understanding of HIV-1 entry and exit. [source] New Inhibitors of the Tat,TAR RNA Interaction Found with a "Fuzzy" Pharmacophore ModelCHEMBIOCHEM, Issue 6 2005Steffen Renner Dipl.-Biol. Abstract TAR RNA is a potential target for AIDS therapy. Ligand-based virtual screening was performed to retrieve novel scaffolds for RNA-binding molecules capable of inhibiting the Tat,TAR interaction, which is essential for HIV replication. We used a "fuzzy" pharmacophore approach (SQUID) and an alignment-free pharmacophore method (CATS3D) to carry out virtual screening of a vendor database of small molecules and to perform "scaffold-hopping". A small subset of 19 candidate molecules were experimentally tested for TAR RNA binding in a fluorescence resonance energy transfer (FRET) assay. Both methods retrieved molecules that exhibited activities comparable to those of the reference molecules acetylpromazine and chlorpromazine, with the best molecule showing ten times better binding behavior (IC50=46 ,M). The hits had molecular scaffolds different from those of the reference molecules. [source] Gene Therapy in HIV-Infected Cells to Decrease Viral Impact by Using an Alternative Delivery MethodCHEMMEDCHEM, Issue 6 2010Teresa Gonzalo Dr. Abstract The ability of dendrimer 2G-[Si{O(CH2)2N(Me)2+(CH2)2NMe3+(I,)2}]8 (NN16) to transfect a wide range of cell types, as well as the possible biomedical application in direct or indirect inhibition of HIV replication, was investigated. Cells implicated in HIV infection such as primary peripheral blood mononuclear cells (PBMC) and immortalized suspension cells (lymphocytes), primary macrophages and dendritic cells, and immortalized adherent cells (astrocytes and trophoblasts) were analyzed. Dendrimer toxicity was evaluated by mitochondrial activity, cell membrane rupture, release of lactate dehydrogenase, erythrocyte hemolysis, and the effect on global gene expression profiles using whole-genome human microarrays. Cellular uptake of genetic material was determined using flow cytometry and confocal microscopy. Transfection efficiency and gene knockdown was investigated using dendrimer-delivered antisense oligonucleotides and small interfering RNA (siRNA). Very little cytotoxicity was detected in a variety of cells relevant to HIV infection and erythrocytes after NN16 dendrimer treatment. Imaging of cellular uptake showed high transfection efficiency of genetic material in all cells tested. Interestingly, NN16 further enhanced the reduction of HIV protein 24 antigen release by antisense oligonucleotides due to improved transfection efficiency. Finally, the dendrimer complexed with siRNA exhibited therapeutic potential by specifically inhibiting cyclooxygenase-2 gene expression in HIV-infected nervous system cells. NN16 dendrimers demonstrated the ability to transfect genetic material into a vast array of cells relevant to HIV pathology, combining high efficacy with low toxicity. These results suggest that NN16 dendrimers have the potential to be used as a versatile non-viral vector for gene therapy against HIV infection. [source] Absence of favourable changes in circulating levels of interleukin-16 or ,-chemokine concentration following structured intermittent interruption treatment of chronic human immunodeficiency virus infectionCLINICAL MICROBIOLOGY AND INFECTION, Issue 1 2005M. Montes de Oca Arjona Abstract Changes in virological and immunological parameters were analysed following structured intermittent interruption of highly active anti-retroviral therapy (HAART) of patients with chronic human immunodeficiency virus (HIV) infection. Parameters analysed were serum levels of the CD8+ T-cell-derived inhibitory molecules interleukin-16 (IL-16), monocyte inhibitory protein-1, (MIP-1,) and RANTES (,regulated upon activation, normal T-cell expressed and presumably secreted'), and the enhancer of HIV replication, monocyte chemotactic protein-1 (MCP-1). Twenty-five patients with chronic HIV infection were evaluated during three cycles of intermittent interruptions of therapy (8 weeks on/4 weeks off) in comparison with 20 healthy sex- and age-matched controls. At enrolment, HIV-infected patients showed significantly higher serum concentrations of IL-16 and RANTES, and significantly lower concentrations of MCP-1, than did healthy controls. Levels of MIP-1, were similar in both groups. Only the serum levels of IL-16 increased significantly in HIV-infected patients after every treatment interruption. However, differences between the CD4+ or CD8+ T-cell counts/µL, HIV loads and serum concentrations of each cytokine at baseline and at the end of the three cycles of intermittent interruptions of therapy were not significant. It was concluded that structured intermittent interruption of HAART for patients with chronic HIV infection did not modify the immunological parameters, including serum levels of CD8+ T-cell-derived inhibitory molecules, or the virus parameters studied. Thus, the findings do not support the use of this treatment modality for the management of HIV-infected patients. [source] | ||||||||||||||||