Lack of detectable HIV-1 molecular evolution during suppressive antiretroviral therapy.

A better understanding of changes in HIV-1 population genetics with combination antiretroviral therapy (cART) is critical for designing eradication strategies. We therefore analyzed HIV-1 genetic variation and divergence in patients' plasma before cART, during suppression on cART, and after viral rebound. Single-genome sequences of plasma HIV-1 RNA were obtained from HIV-1 infected patients prior to cART (N = 14), during suppression on cART (N = 14) and/or after viral rebound following interruption of cART (N = 5). Intra-patient population diversity was measured by average pairwise difference (APD). Population structure was assessed by phylogenetic analyses and a test for panmixia. Measurements of intra-population diversity revealed no significant loss of overall genetic variation in patients treated for up to 15 years with cART. A test for panmixia, however, showed significant changes in population structure in 2/10 patients after short-term cART (<1 year) and in 7/10 patients after long-term cART (1-15 years). The changes consisted of diverse sets of viral variants prior to cART shifting to populations containing one or more genetically uniform subpopulations during cART. Despite these significant changes in population structure, rebound virus after long-term cART had little divergence from pretherapy virus, implicating long-lived cells infected before cART as the source for rebound virus. The appearance of genetically uniform virus populations and the lack of divergence after prolonged cART and cART interruption provide strong evidence that HIV-1 persists in long-lived cells infected before cART was initiated, that some of these infected cells may be capable of proliferation, and that on-going cycles of viral replication are not evident.

Patterns of Human Immunodeficiency Virus type 1 recombination ex vivo provide evidence for coadaptation of distant sites, resulting in purifying selection for intersubtype recombinants during replication.

High-frequency recombination is a hallmark of HIV-1 replication. Recombination can occur between two members of the same subtype or between viruses from two different subtypes, generating intra- or intersubtype recombinants, respectively. Many intersubtype recombinants have been shown to circulate in human populations. We hypothesize that sequence diversity affects the emergence of viable recombinants by decreasing recombination events and reducing the ability of the recombinants to replicate. To test our hypothesis, we compared recombination between two viruses containing subtype B pol genes (B/B) and between viruses with pol genes from subtype B or F (B/F). Recombination events generated during a single cycle of infection without selection pressure on pol gene function were analyzed by single-genome sequencing. We found that recombination occurred slightly ( approximately 30%) less frequently in B/F than in B/B viruses, and the overall distribution of crossover junctions in pol was similar for the two classes of recombinants. We then examined the emergence of recombinants in a multiple cycle assay, so that functional pol gene products were selected. We found that the emerging B/B recombinants had complex patterns, and the crossover junctions were distributed throughout the pol gene. In contrast, selected B/F recombinants had limited recombination patterns and restricted crossover junction distribution. These results provide evidence for the evolved coadapted sites in variants from different subtypes; these sites may be segregated by recombination events, causing the newly generated intersubtype recombinants to undergo purifying selection. Therefore, the ability of the recombinants to replicate is the major barrier for many of these viruses.

Percutaneous Needle Tenotomy for the Treatment of Lateral Epicondylitis: A Systematic Review of the Literature.

OBJECTIVE: To analyze the literature to determine whether controlled studies on percutaneous tenotomy have been published, and if so, to systematically assess the efficacy of percutaneous tenotomy for the treatment of tendinosis at the lateral epicondyle of the elbow. DESIGN: Systematic review of the available literature. METHODS: Cochrane Controlled Trials Register (CENTRAL), MEDLINE, EMBASE, CINAHL, and Web of Science databases were searched in November 2015, unrestricted by date. After the initial search, we excluded conference proceedings, theses, reviews, expert opinions, and publications written in languages other than English. Next, 2 independent reviewers screened all of the remaining records with regard to their titles and abstracts, and subsequently, the full texts of identified publications potentially relevant to the present study. RESULTS: Six articles focused on percutaneous tenotomy, none of which were controlled against a placebo or conservative treatment group. The absence of true randomized controlled trials created a great deal of heterogeneity between the studies; thus we could not include any of our studies in the intended final quantitative analysis with meta-analysis tools. We describe all 6 studies identified by this systematic review with a detailed analysis of the procedural methods, outcome measures, and conclusions of each study. CONCLUSIONS: Percutaneous tenotomy presents an alternative to surgical release of the common extensor tendon for the treatment of chronic tendinosis at the lateral epicondyle of the elbow. Current research supporting the efficacy of this procedure, however, is of low quality (level II to level IV). LEVEL OF EVIDENCE: III.

Comparing Percutaneous Vertebroplasty and Conservative Therapy for Treating Osteoporotic Compression Fractures in the Thoracic and Lumbar Spine: A Systematic Review and Meta-Analysis.

BACKGROUND: Vertebral compression fractures are a common complication of osteoporosis and are often treated by percutaneous vertebroplasty (PVP). The ability of this procedure to relieve pain better than conservative treatment is still debated. The purpose of this study was to compare the degree and duration of pain relief following PVP with that following conservative treatment for osteoporotic compression fractures by means of meta-analysis of randomized controlled trials. METHODS: The CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and Web of Science databases were queried for randomized controlled trials comparing PVP with conservative treatment or placebo/sham. The methodological quality was assessed according to the Cochrane Collaboration's domain-based evaluation framework. Random-effects meta-analysis of the raw mean difference between groups in change in pain level was performed, with sensitivity analyses and the Egger test for potential publication bias. RESULTS: Of 209 records found, 11 were considered relevant, involving 1,048 participants. The risk of bias was considered low in 10 studies and high in 1. The 531 patients treated with PVP had a significantly lower pain level compared with the control group at 1 to 2 weeks, 2 to 3 months, and 12 months. The 95% CI (confidence interval) of the pooled effect size at every time interval included the score of 1.5, considered to be the minimal clinically important difference. The largest pooled effect size of -1.4 (95% CI, -2.3 to -0.5) was found during the first 1 to 2 weeks. The heterogeneity was high at all 3 time points (I(2), 71% to 96%). No significant publication bias was detected. CONCLUSIONS: Up to 1 year postoperatively, the effect of PVP exceeded the effect of conservative therapy with respect to pain relief in patients with osteoporotic compression fractures. The effect size was significant and close to the minimal clinically important difference.

Effect of epitope position on neutralization by anti-human immunodeficiency virus monoclonal antibody 2F5.

The membrane-proximal region of the human immunodeficiency virus type 1 (HIV-1) transmembrane protein (TM) is critical for envelope (Env)-mediated membrane fusion and contains the target for broadly reactive neutralizing antibody 2F5. It has been proposed that 2F5 neutralization might involve interaction of its long, hydrophobic, complementarity-determining region (CDR) H3, with adjacent viral membrane. Using Moloney murine leukemia virus (MLV) as a tool, we examined the effect of epitope position on 2F5 neutralization. When the 2F5 epitope was inserted in the proline-rich region of MLV Env surface protein (SU), 2F5 blocked cell fusion and virus infection, whereas MLV with a hemagglutinin (HA) epitope at the same position was not neutralized by anti-HA, even though the antibodies bound their respective Envs on the surface of infected cells and viruses equally well. When the 2F5 epitope was inserted in the MLV Env TM at a position comparable to its natural position in HIV-1 TM, 2F5 antibody blocked Env-mediated cell fusion. Epitope position had subtle effects on neutralization by 2F5: the antibody concentration for 50% inhibition of cell fusion was more than 10-fold lower when the 2F5 epitope was in SU than in TM, and inhibition was less complete at high concentrations of antibody; we discuss possible explanations for these effects of epitope position. Since membrane proximity was not required for neutralization by 2F5 antibody, we speculate that the CDR H3 of 2F5 contributes to neutralization by destabilizing an adjacent protein rather than by inserting into an adjacent membrane.