Multiple clinical trials with HIV-infected patients have demonstrated the antiviral
activity, safety, and tolerability of ibalizumab treatment. A 9-week phase Ib study adding ibalizumab monotherapy to this website failing drug regimens led to transient reductions in HIV viral loads and the evolution of HIV-1 variants with reduced susceptibility to ibalizumab. This report characterizes these variants by comparing the phenotypic susceptibilities and envelope (env) sequences of (i) paired baseline and on-treatment virus populations, (ii) individual env clones from selected paired samples, and (iii) env clones containing site-directed mutations. Viruses with reduced susceptibility to ibalizumab Selleckchem P5091 were found to exhibit reduced susceptibility to the anti-CD4 antibody RPA-T4. Conversely, susceptibility to soluble CD4, which targets the HIV-1 gp120 envelope protein, was enhanced. No changes in susceptibility to the fusion inhibitor enfuvirtide or the CCR5 antagonist maraviroc were observed. Functionally, viruses with
reduced ibalizumab susceptibility also displayed high levels of infectivity relative to those of paired baseline viruses. Individual env clones exhibiting reduced ibalizumab susceptibility contained multiple amino acid changes in different regions relative to the paired baseline clones. In particular, clones with reduced susceptibility to ibalizumab contained fewer potential asparagine-linked glycosylation sites (PNGSs) in variable region 5 (V5) than did paired ibalizumab-susceptible clones. The reduction in ibalizumab susceptibility due to the loss of V5 PNGSs was confirmed Afatinib by site-directed mutagenesis.
Taken together, these findings provide important insights into resistance to this new class of antiretroviral drug.”
“Recognition without identification (RWI) refers to people’s ability to discriminate studied from unstudied items when the items themselves fail to be identified, as when people fail to identify words from fragments. We sought to identify the ERP correlates of word fragment RWI in an effort to better understand its underlying mechanisms; in so doing, we also examined the ERP correlates of word identification failure vs. success. We found the ERP correlate of the RWI effect to be the N300; greater negativity was shown for unidentified fragments of studied words than for unidentified fragments of unstudied words between 300-325 ms post test fragment onset. We further separated the ERPs according to whether subjects showed the behavioral RWI effect or not; the N300 effect emerged only among those subjects who showed the behavioral effect, suggesting that the N300 is related to the behavioral effect itself. With regard to the ERP correlates of word identification failure vs. success, we found very early indicators of later word identification success vs.