HIV-1 circulates within an infected host as a genetically heterogeneous viral population. Viral intrahost diversity is shaped by substitutional evolution and recombination. Although many studies have speculated that recombination could have a significant impact on viral phenotype, this has never been definitively demonstrated. We report here phylogenetic and subsequent phenotypic analyses of envelope genes obtained from HIV-1 populations present in different anatomical compartments. Assessment of env compartmentalization from immunologically discrete tissues was assessed utilizing a single genome amplification approach, minimizing in vitro-generated artifacts. Genetic compartmentalization of variants was frequently observed. In addition, multiple incidences of intercompartment recombination, presumably facilitated by low-level migration of virus or infected cells between different anatomic sites and coinfection of susceptible cells by genetically divergent strains, were identified. These analyses demonstrate that intercompartment recombination is a fundamental evolutionary mechanism that helps to shape HIV-1 env intrahost diversity in natural infection. Analysis of the phenotypic consequences of these recombination events showed that genetic compartmentalization often correlates with phenotypic compartmentalization and that intercompartment recombination results in phenotype modulation. This represents definitive proof that recombination can generate novel combinations of phenotypic traits which differ subtly from those of parental strains, an important phenomenon that may have an impact on antiviral therapy and contribute to HIV-1 persistence in vivo.
HIV-1 R5 viruses predominantly use CCR5 as a coreceptor to infect CD4 + T cells and macrophages. While R5 viruses generally infect CD4 + T cells, research over the past few years has demonstrated that they vary extensively in their capacity to infect macrophages. Thus, R5 variants that are highly macrophage tropic have been detected in late disease and are prominent in brain tissue of subjects with neurological complications. Other R5 variants that are less sensitive to CCR5 antagonists and use CCR5 differently have also been identified in late disease. These latter variants have faster replication kinetics and may contribute to CD4 T-cell depletion. In addition, R5 viruses are highly variable in many other properties, including sensitivity to neutralizing antibodies and inhibitors that block HIV-1 entry into cells. Here, we review what is currently known about how HIV-1 R5 viruses vary in cell tropism and other properties, and discuss the implications of this variation on transmission, pathogenesis, therapy and vaccines. Keywords CCR5; CD4; CD4 + T cell; envelope; HIV-1; macrophage; macrophage tropism; neuroAIDS; R5; receptor; tropism HIV-1 was first described in 1983 [1] and CD4 identified as its receptor in 1984 [2,3]. It was quickly apparent that CD4 alone was not sufficient for infection and that a putative second determinant was required for HIV-1 entry. The identification of CXCR4 in 1996 by Ed Berger's group as the coreceptor for T-tropic HIV-1 strains [4] thus heralded a new era for HIV-1 receptor and cell tropism research. Well before 1996, it was clear that there were two types of HIV-1 that infected primary T cells or macrophages with different efficiencies. The first type
Seven women and 3 men infected with hepatitis C virus, all of whom had failed to respond to therapy with either IFN-alpha or IFN and ribavirin, were treated with 200 mg/day of amantadine hydrochloride for 12 months. We found a significant decrease of serum ALT activity without any decrease in virus load. These results suggest that amantadine hydrochloride should not be used as monotherapy for patients who do not respond to treatment with IFN-alpha and/or ribavirin.
Background and Purpose. Osteoarthritis (OA) affects a large and growing proportion of the population. The purpose of this project was to create guidelines for the use of therapeutic exercises and manual therapy in the management of adult patients (Ͼ18 years of age) with a diagnosis of OA. All stages of the disease were included in the analysis, and studies of patients who had recent surgery or other rheumatologic, musculoskeletal, or spinal problems or of subjects without known pathology or impairments were excluded. Methods. The Ottawa Methods Group used Cochrane Collaboration methods to find and synthesize evidence from comparative controlled trials and then asked stakeholder groups to nominate representatives to serve on a panel of experts. The Ottawa Panel agreed on criteria for grading the strength of the recommendations and their supporting evidence. Of the 609 potential articles on therapeutic exercises for OA that were identified, 113 were considered potentially relevant, and 26 randomized controlled trials and controlled clinical trials were ultimately used. Results. Sixteen positive recommendations of clinical benefit were developed for therapeutic exercises, especially strengthening exercises and general physical activity, particularly for the management of pain and improvement of functional status. Manual therapy combined with exercises also is recommended in the management of patients with OA. Discussion and Conclusion. The Ottawa Panel recommends the use of therapeutic exercises alone, or combined with manual therapy, for managing patients with OA. There were a total of 16 positive recommendations: 13 grade A and 3 grade Cϩ. The Ottawa Panel recommends the use of therapeutic exercises because of the strong evidence (grades A, B, and Cϩ) Introduction Osteoarthritis (OA) affects a large proportion of the population. Its prevalence is increasing dramatically as the populations of industrialized countries age and the baby boomers enter older adulthood. 1 It has been estimated that the prevalence will increase in the United States from 43 million in 1997 to 60 million in 2020. 2 Similarly, in Canada, an increase from 2.9 in 1991 to 6.5 million in 2033 (a 124% increase) is expected. 3 Osteoarthritis is recognized as a substantial source of disability with significant social and financial costs due to surgical and medical interventions and frequent absenteeism from work. 1,4 In 1994, the total cost for arthritis and rheumatism in Canada was estimated to be between Can $4.3 billion and $7.3 billion, 5 and the estimated medical expenses (excluding cost of time lost from paid or unpaid work) were estimated to be between Can $1.7 billion and $2.5 billion. 6 Efficiency and efficacy of rehabilitation interventions in OA management have an obvious bearing on the direct and indirect costs of the disease. The development of evidence-based clinical practice guidelines (EBCPGs) will assist patients and clinicians in maximizing their rehabilitative efforts. Evidence-based clinical practice guidelines are sy...
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