Another possible weapon against HIV.

<p>An illustration of the principles of using a monoclonal antibody as passive immunization to prevent HIV infection, as compared with the more traditional vaccine approach of active immunization. <i>Created by Nolo Moima</i>, Sunday Times, <i>and Carina Kriel</i>, <i>NICD</i>.</p

Neutralisation Dose-Response Curves of the MAbs 2G12, 2F5, IgG1b12, and 4E10, Alone and in Combination

<p>The MAb concentrations in the triple and quadruple combination are represented as the concentration of each MAb in the equimolar mix starting at 50 μg/ml. Results are shown as the reduction of virus infectivity relative to the virus control (without MAbs) with 50% inhibition indicated by a dotted line. Note those viruses sensitive to IgG1b12 and 4E10 (A) and those viruses sensitive to 4E10 alone (B).</p

Effects of Darwinian Selection and Mutability on Rate of Broadly Neutralizing Antibody Evolution during HIV-1 Infection

<div><p>Accumulation of somatic mutations in antibody variable regions is critical for antibody affinity maturation, with HIV-1 broadly neutralizing antibodies (bnAbs) generally requiring years to develop. We recently found that the rate at which mutations accumulate decreases over time, but the mechanism governing this slowing is unclear. In this study, we investigated whether natural selection and/or mutability of the antibody variable region contributed significantly to observed decrease in rate. We used longitudinally sampled sequences of immunoglobulin transcripts of single lineages from each of 3 donors, as determined by next generation sequencing. We estimated the evolutionary rates of the complementarity determining regions (CDRs), which are most significant for functional selection, and found they evolved about 1.5- to 2- fold faster than the framework regions. We also analyzed the presence of AID hotspots and coldspots at different points in lineage development and observed an average decrease in mutability of less than 10 percent over time. Altogether, the correlation between Darwinian selection strength and evolutionary rate trended toward significance, especially for CDRs, but cannot fully explain the observed changes in evolutionary rate. The mutability modulated by AID hotspots and coldspots changes correlated only weakly with evolutionary rates. The combined effects of Darwinian selection and mutability contribute substantially to, but do not fully explain, evolutionary rate change for HIV-1-targeting bnAb lineages.</p></div

Selection pressure dynamics for all time points of the three lineages.

<p>(A) Selection pressure changes of the VRC26 lineage heavy (left) and light (right) chains. (B) Selection pressure changes of the CH103 lineage heavy (left) and light (right) chains. (C) Selection pressure changes of the VRC01 clade 03+06 heavy (left) and light (right) chains. (D) Selection pressure changes of the VRC01 clade 08 heavy (left) and light (right) chains. (E) Selection pressure changes of the VRC01 clade H3. (F) Selection pressure changes of the VRC01 clade L3. The selection strength for each time point of a lineage chain was measured using BASELINe. The same datasets used for evolutionary rate calculation were used to calculate selection strength. The mean and 95% HPD interval of selection strength for the CDRs (magenta) and FWRs (blue) were calculated separately. The statistical significance of the measured selection strength is shown on the bottom of the plot with ‘-’, ‘+’ and ‘n’ denoting negative selection, positive selection, and neutral selection, respectively.</p

Selection pressure dynamics for all time points of the three lineages.

<p>(A) Selection pressure changes of the VRC26 lineage heavy (left) and light (right) chains. (B) Selection pressure changes of the CH103 lineage heavy (left) and light (right) chains. (C) Selection pressure changes of the VRC01 clade 03+06 heavy (left) and light (right) chains. (D) Selection pressure changes of the VRC01 clade 08 heavy (left) and light (right) chains. (E) Selection pressure changes of the VRC01 clade H3. (F) Selection pressure changes of the VRC01 clade L3. The selection strength for each time point of a lineage chain was measured using BASELINe. The same datasets used for evolutionary rate calculation were used to calculate selection strength. The mean and 95% HPD interval of selection strength for the CDRs (magenta) and FWRs (blue) were calculated separately. The statistical significance of the measured selection strength is shown on the bottom of the plot with ‘-’, ‘+’ and ‘n’ denoting negative selection, positive selection, and neutral selection, respectively.</p

The longitudinal changes of the predicted mutability correlate weakly with evolutionary rate decrease.

<p>(A) Predicted mutability for the stages of the three lineages. (B) The correlations between predicted mutability and evolutionary rate of CDRs were estimated using linear regression. No statistically significant correlation between the selection strength and evolutionary rate was observed. (C) The linear correlations between predicted mutability and evolutionary rate of FWRs. No significant correlation was observed for the three lineages.</p

Selection pressure changes of the three lineages correlate with evolutionary rate decrease.

<p>(A) Estimated selection strength for the stages of the three lineages. For all three lineages, the negative selection strength of later stages is comparable or stronger than earlier stages. The statistical significance of the measured selection strength is shown on the bottom of the plot with ‘-’, ‘+’ and ‘n’ denoting negative selection, positive selection, and neutral selection, respectively. (B) The selection strength on CDRs showed trends of correlation with the slowing of the evolutionary rate. Only the linear correlation for the CDRs of the VRC01 lineage is statistically significant. (C) The correlations between selection strength and evolutionary rate of FWRs. There are trends of correlation but none is statistically significant.</p

The stage method is better than the time-bin method for estimating evolutionary rate dynamics.

<p>(A) The evolutionary rate for the constant-rate (CR) dataset was estimated using both restricted and relaxed log-normal clock models (labeled CR_restricted_clock and CR_lognormal_clock respectively). The estimated mean evolutionary rates from the two models are in good agreement. The mean evolutionary rates of the decreasing rate (DR) dataset estimated from the MCC tree and the 1000 time scaled Bayesian trees (labeled DR_MCC_tree and DR_1000_tree respectively) are highly consistent with the expected rates (red dots) derived from the calculated evolutionary rate of the CR dataset (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004940#sec012" target="_blank">Materials and Methods</a>). (B) The mean evolutionary rates for the eight time bins of the DR dataset were estimated from a single MCC tree (blue) and the mean and the 95% highest probability density (HPD) intervals estimated from 1000 time scaled Bayesian trees (green). The estimated evolutionary rates for each bin are significantly different from the expected rate (red). (C) The expected rates (red) of the three stages of the DR dataset are within the estimated 95% HPD of the mean evolutionary rates (purple), suggesting the stage method is reliable for characterizing evolutionary rate changes over time.</p

Dynamics of the predicted mutability for all time points of the three lineages.

<p>(A) Changes of predicted mutability of the VRC26 heavy (left) and light (right) chains. (B) Changes of predicted mutability of the CH103 heavy (left) and light (right) chains. (C) Changes of predicted mutability of the VRC01 clade 03+06 heavy (left) and light (right) chains. (D) Changes of predicted mutability of the VRC01 clade 08 heavy (left) and light (right) chains. (E) Changes of predicted mutability of the VRC01 clade H3. (F) Changes of predicted mutability of the VRC01 clade L3. Dashed line represents the mutability of UCA (VRC26 and CH103) or MRCA (VRC01 clades) of the lineages.</p

Novel Cyclopropyl-Indole Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors

The HIV pandemic represents one of the most serious diseases to face mankind in both a social and economic context, with many developing nations being the worst afflicted. Due to ongoing resistance issues associated with the disease, the design and synthesis of anti-HIV agents presents a constant challenge for medicinal chemists. Utilizing molecular modeling, we have designed a series of novel cyclopropyl indole derivatives as HIV non-nucleoside reverse transcriptase inhibitors and carried out their preparation. These compounds facilitate a double hydrogen bonding interaction to Lys101 and efficiently occupy the hydrophobic pockets in the regions of Tyr181/188 and Val179. Several of these compounds inhibited HIV replication as effectively as nevirapine when tested in a phenotypic assay