Prediction of HIV-1 sensitivity to broadly neutralizing antibodies shows a trend towards resistance over time

<div><p>Treatment with broadly neutralizing antibodies (bNAbs) has proven effective against HIV-1 infections in humanized mice, non-human primates, and humans. Due to the high mutation rate of HIV-1, resistance testing of the patient’s viral strains to the bNAbs is still inevitable. So far, bNAb resistance can only be tested in expensive and time-consuming neutralization experiments. Here, we introduce well-performing computational models that predict the neutralization response of HIV-1 to bNAbs given only the envelope sequence of the virus. Using non-linear support vector machines based on a string kernel, the models learnt even the important binding sites of bNAbs with more complex epitopes, i.e., the CD4 binding site targeting bNAbs, proving thereby the biological relevance of the models. To increase the interpretability of the models, we additionally provide a new kind of motif logo for each query sequence, visualizing those residues of the test sequence that influenced the prediction outcome the most. Moreover, we predicted the neutralization sensitivity of around 34,000 HIV-1 samples from different time points to a broad range of bNAbs, enabling the first analysis of HIV resistance to bNAbs on a global scale. The analysis showed for many of the bNAbs a trend towards antibody resistance over time, which had previously only been discovered for a small non-representative subset of the global HIV-1 population.</p></div

Genetic characterization of viral blips in patients following suppressive HIV ART.

Masters Degree. University of KwaZulu-Natal, Durban.Antiretroviral therapy (ART) has resulted in the decline of HIV-related mortality worldwide. On initiating treatment, most patients can suppress plasma viral RNA to undetectable levels (2,000 copies/mL). Gag and env genes were amplified by single genome amplification followed by sequencing. The protease and reverse transcriptase region of the pol gene were also amplified and bulk sequenced. Phylogenetic relatedness and genetic differences were visualized using Maximum-likelihood trees and Highlighter plots respectively (Los Alamos HIV-1 database). The gag and env blip sequences of the acute-treated participants were similar to those of the T/F, while those of the chronic-treated participants were genetically distinct from the T/F but similar to the pre-treatment initiation virus (PreART). In the acute-treated participants, all transmitted HLA-associated gag cytotoxic CD8+ T lymphocyte (CTL) escape identified was retained in the blip-derived sequences, however the chronic-treated participants experienced an increase of ~0.8% CTL escape at the blip time point. This increase coupled with development of a reduced replication capacity mutation (HLA-B*57:01/58:01 T242N), may be indicative of immune pressure prior to ART initiation. Mutations associated with bnAb escape in the CD4 binding, gp120/gp41 and V1V2 sites were identified only in the PreART and blip sequences of the chronic-treated participants, whereas the acute-treated retained the same amino acid residues at T/F and blip. With the exception of one chronic-treated participant who developed mutations associated with resistance to efavirenz, the viral blips were not associated with mutations linked to drug resistance. This data suggests that those who initiate treatment late are less likely to benefit from an immune response-inducing vaccine or bnAb therapy