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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sexual transmission is the most common pathway for HIV-1; nevertheless some individuals remain seronegative despite repeated high risk sexual exposure. These were grouped in cohorts of "highly exposed but persistently seronegative" individuals, mostly prostitutes and flailing couples. Three lines of defence were observed in these cohorts. The first one is the mucosal barrier, the determining factors of which are the type of epithelium (monolayer or multilayer), epithelial integrity, and the pre-existing microflora. The second one is linked to innate immunity directly related to the genetic and/or immune predispositions of the individual: mutations affecting the CCR5 chemokine receptor, secretion of protective soluble factors, and particular HLA alleles. The third one is acquired immunity via the mechanisms of humoral and/or specific cellular immunity. These studies suggest anti HIV-1 vaccinal strategies aiming at a local immunization combining the different types of responses observed in these individuals.
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PMID:[Mechanisms of resistance to sexual transmission of HIV-1]. 1625 54

The 32-bp deletion (CCR5del32 mutation) in the CCR5 (chemokine (C-C motif) receptor 5) gene, encoding CCR5 chemokine receptor, is one of the factors determining natural resistance to human immunodeficiency virus (HIV-1) infection. In the present study, the samples of Russians (n = 107), Tuvinians (n = 50), and HIV-infected individuals were examined for the presence of CCR5del32 mutation in the CCR5 gene. The CCR5del32 allele frequency in Russians and Tuvinians constituted 7.84 and 2%, respectively. Among HIV-1 infected individuals, two groups, of macrophage-tropic HIV-1 strain- and T-cell-tropic HIV-1 strain-infected were distinguished. The CCR5del32 allele frequency in the first group (6.45%) was lower than in the second one (8.73%). Statistical treatment of the HIV-1 infected individuals typing data showed that the difference in the CCR5del32 allele frequencies between the groups of sexually (macrophage-tropic) and parenterally (T-cell-tropic) infected individuals observed was within the limit of random deviation.
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PMID:[Comparison CCR5de132 mutation in the CCR5 gene frequencies in Russians, Tuvinians, and in different groups of HIV-infected individuals]. 1635 23

Since the discovery of the 32-base-pair deletion in the CCR5 chemokine receptor gene (CCR5-Delta32) and its effect on HIV-1 infection and AIDS progression, many genetic factors affecting AIDS have been identified. Here we quantify the impact of 13 of these factors on AIDS progression using a new statistic based on the mutual information between causal factors and disease, the explained fraction. The influence of causal factors on disease is commonly measured by the attributable fraction statistic, but the attributable fraction is a poor measure of the extent to which a factor explains disease because it considers only whether a factor is necessary, not whether it is sufficient. The definition of the explained fraction, which is analogous to R or the explained variation for regression models, extends naturally to multiple factor levels. Because the explained fraction is approximately additive, it can be used to estimate how much of epidemiological data is explained by known genetic or environmental factors, and conversely how much is yet to be explained by unknown factors. We show that 13 genetic factors can cumulatively explain 9% of slow progression to AIDS, an effect comparable to the effect of smoking on lung cancer.
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PMID:Using mutual information to measure the impact of multiple genetic factors on AIDS. 1676 24

Most human immunodeficiency virus type 1 (HIV-1) strains require either the CXCR4 or CCR5 chemokine receptor to efficiently enter cells. Blocking viral binding to these coreceptors is an attractive therapeutic target. Currently, several coreceptor antagonists are being evaluated in clinical trials that require characterization of coreceptor tropism for enrollment. In this report, we describe the development of an automated and accurate procedure for determining HIV-1 coreceptor tropism (Trofile) and its validation for routine laboratory testing. HIV-1 pseudoviruses are generated using full-length env genes derived from patient virus populations. Coreceptor tropism is determined by measuring the abilities of these pseudovirus populations to efficiently infect CD4+/U87 cells expressing either the CXCR4 or CCR5 coreceptor. Viruses exclusively and efficiently infecting CXCR4+/CD4+/U87 cells are designated X4-tropic. Conversely, viruses exclusively and efficiently infecting CCR5+/CD4+/U87 cells are designated R5-tropic. Viruses capable of infecting both CXCR4+/CD4+/U87 and CCR5+/CD4+/U87 cells are designated dual/mixed-tropic. Assay accuracy and reproducibility were established by evaluating the tropisms of well-characterized viruses and the variability among replicate results from samples tested repeatedly. The viral subtype, hepatitis B virus or hepatitis C virus coinfection, and the plasma viral load did not affect assay performance. Minority subpopulations with alternate tropisms were reliably detected when present at 5 to 10%. The plasma viral load above which samples can be amplified efficiently in the Trofile assay is 1,000 copies per ml of plasma. Trofile has been automated for high-throughput use; it can be used to identify patients most likely to benefit from treatment regimens that include a coreceptor inhibitor and to monitor patients on treatment for the emergence of resistant virus populations that switch coreceptor tropism.
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PMID:Development and characterization of a novel single-cycle recombinant-virus assay to determine human immunodeficiency virus type 1 coreceptor tropism. 1711 63

Combinatorial therapies for the treatment of HIV infection have changed the course of the AIDS epidemic in developed nations where the antiviral drug combinations are readily available. Despite this progress, there are many problems associated with chemotherapy for AIDS including toxicities and emergence of viral mutants resistant to the drugs. Our goal has been the development of a hematopoietic gene therapy treatment for HIV infection. Like chemotherapy, gene therapy for treatment of HIV infection should be used combinatorially. We have thus combined three different inhibitory genes for treatment of HIV infection into a single lentiviral vector backbone. The inhibitory agents engage RNAi via a short hairpin RNA targeting HIV tat/rev mRNAs, a nucleolar localizing decoy that binds and sequesters the HIV Tat protein, and a ribozyme that cleaves and downregulates the CCR5 chemokine receptor used by HIV for cellular entry. This triple combination has proven to be highly effective for inhibiting HIV replication in primary hematopoietic cells, and is currently on track for human clinical application.
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PMID:RNAi in combination with a ribozyme and TAR decoy for treatment of HIV infection in hematopoietic cell gene therapy. 1714 37

The CCR5 chemokine receptor plays a pivotal role in human immunodeficiency virus type 1 (HIV-1) infection. Several studies have suggested that CCR5 density levels in individuals are rate limiting for infection. In addition, CCR5 density levels influence the antiviral activity of the HIV-1 fusion inhibitor enfuvirtide (T-20) against R5 strains. In the present study we demonstrate that rapamycin (RAPA), a drug approved for the treatment of renal transplantation rejection, reduces CCR5 density levels on CD4 T cells and inhibits R5 HIV-1 replication. In addition, RAPA increased the antiviral activity of T-20 against R5 strains of the virus in a cell-cell fusion assay and as shown by quantification of early products of viral reverse transcription. Median-effect analysis of drug interaction between RAPA and T-20 in infectivity assays using donor peripheral blood mononuclear cells demonstrated that the RAPA-T-20 combination is synergistic against R5 strains of HIV-1 and this synergy translates into T-20 dose reductions of up to approximately 33-fold. Importantly, RAPA effects on replication levels and T-20 susceptibility of R5 strains of HIV-1 were observed at drug concentrations that did not inhibit cell proliferation. These results suggest that low concentrations of RAPA may potentiate the antiviral activity of T-20 against R5 strains of HIV-1, which are generally present throughout the course of infection and are less sensitive to T-20 inhibition than are X4 strains.
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PMID:Rapamycin reduces CCR5 density levels on CD4 T cells, and this effect results in potentiation of enfuvirtide (T-20) against R5 strains of human immunodeficiency virus type 1 in vitro. 1748 1

Maraviroc is a specific, slowly reversible, noncompetitive, small-molecule antagonist of the CCR5 chemokine receptor, which also serves as an HIV-1 coreceptor. By acting as an antagonist at the CCR5 coreceptor, maraviroc inhibits HIV-1 from entering host cells. Clinical data for maraviroc are available from two large, well designed, ongoing phase IIb/III trials (MOTIVATE-1 and MOTIVATE-2) conducted in patients infected with R5-tropic HIV-1 who had previously received at least one agent from three of the four classes of antiretroviral drugs and/or were triple-class resistant. According to 24-week interim results of the MOTIVATE-1 and -2 trials, a significantly greater reduction in viral load occurred in patients receiving maraviroc 150 or 300mg (depending on optimised background therapy [OBT]) twice daily plus OBT compared with placebo plus OBT. This significant difference was maintained at 48 weeks in MOTIVATE-1. In the MOTIVATE-1 and -2 trials, a significantly greater proportion of patients receiving maraviroc plus OBT achieved an HIV-1 RNA level <400 and <50 copies/mL compared with those receiving placebo plus OBT. In addition, the CD4+ cell count was increased to a significantly greater extent with maraviroc plus OBT compared with placebo plus OBT. The 48-week results of MOTIVATE-1 also report a significant difference in favour of maraviroc for all these endpoints. In general, maraviroc at dosages of up to 300mg twice daily was well tolerated in treatment-experienced patients infected with R5-tropic HIV-1.
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PMID:Maraviroc. 1792 88

In the context of emerging resistance to antiretroviral agents in HIV medicine, the development of new drugs classes with a novel mechanism of action remains essential. The CCR5 co-receptor antagonists inhibit fusion of HIV with the host cell by blocking the interaction between the gp-120 viral glycoprotein and the CCR5 chemokine receptor. So far, four CCR5 antagonists have entered clinical evaluation, of which three are currently still in different stages of clinical assessment. In this review we compare the clinical efficacy in phase I and II as well as the long-term tolerability, pharmacokinetics and interactions of these new antiretroviral drugs entering HIV practice. Being the first CCR5 antagonist to be investigated in clinical trials, aplaviroc showed initial potent antiviral activity. However, after the occurrence of severe hepatotoxicity in several patients, its development had to be stopped in October 2005. The second CCR5 antagonist, maraviroc, has displayed promising results in phase I, II and III studies, showing a significantly greater decline in HIV RNA and CD4 cell increase compared to placebo, with no clinically relevant differences in safety profile and tolerability. The expanded access program for maraviroc was opened in June 2007 in several European countries. The FDA approved the use of maraviroc for antiretroviral therapy of HIV on the 7th of august, 2007. Finally, the third CCR5 antagonist vicriviroc also showed long-term potent viral activity in phase II studies as long as it was boosted with low-dose ritonavir, with no significant differences in grade 3 and grade 4 adverse effects compared to placebo. The phase II clinical trial amongst ART experienced individuals who received Ritonavir-boosted vicriviroc 10-15 mg qd was unblinded early because of the unexpected occurrence of malignant lymphoma and adenoma. However, no further malignancies occurred in the extended follow-up evaluation of this drug until today. Vicriviroc is currently entering phase III evaluation. Pharmacokinetics of maraviroc and vicriviroc may be influenced by coadministration of CYP3A4-inhibitors and -inducers, since both substances are metabolised primarily by the CYP3A4 system. This requires dose adjustments when combined with for instance protease inhibitors (with the exception of tipranavir/r), efavirenz, ketoconazole or rifampin. Concerns have risen about possible class-specific long-term adverse effects of CCR5 antagonists, particularly with regard to hepatotoxicity or malignancy. The pooled data from phase II and III however, so far show no new or added toxicity risk for maraviroc or vicriviroc compared to the respective placebo arms of the trials. Extended follow-up of the vicriviroc trials showed no further case of malignancy, reassuring the overall good tolerability profile of the drug so far.
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PMID:CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions--review of the literature. 1793 22

Drug development in the field of HIV treatment is rapid. New nucleoside analogues (NRTI), non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI) are currently being investigated in human trials. Furthermore, inhibitors of HIV attachment, fusion and integrase with novel modes of action are being developed, which offer new perspectives for the goal of a normalization of life-expectancy in HIV-infected individuals. The most advanced compounds likely to become licensed soon include the NNRTIs rilpivirine and etravirine, the integrase inhibitors raltegravir and elvitegravir, and maraviroc and vicriviroc, novel inhibitors of the CCR5 chemokine receptor, which functions as the major coreceptor for HIV-1.
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PMID:Antiviral drugs in the treatment of AIDS: what is in the pipeline ? 1793 30

HIV-infected patients have a higher risk of developing cutaneous reactions than the general population, which has a significant impact on patients' current and future care options. The severity of cutaneous adverse reactions varies greatly, and some may be difficult to manage. HIV-infected patients just at the beginning of antiretroviral treatment can frequently show a wide variety of adverse drug effects such as drug rashes, hyperpigmentation, hair loss, hypersensitivity reactions, injection site reaction, urticarial reaction, erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson syndrome. The early detection and treatment of cutaneous adverse drug reactions, plus identification of the causative agent, are essential to prevent the progression of the reaction, preventing additional exposures and ensuring the appropriate use of medications for the current condition and keeping in mind others, such as patient age. This article emphasizes the most common features of an antiretroviral drug-induced cutaneous reaction from protease inhibitors, non-nucleoside analogue reverse transcriptase inhibitors, fusion inhibitors, nucleoside reverse transcriptase inhibitors, integrase inhibitors and inhibitors of the CCR5 chemokine receptor, paying special attention to the newest drugs approved for the treatment of HIV infection, such as tipranavir, darunavir, etravirine, enfuvirtide, raltegravir and maraviroc.
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PMID:Adverse cutaneous reactions associated with the newest antiretroviral drugs in patients with human immunodeficiency virus infection. 1865 88


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