CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

TUESDAY, FEBRUARY 24, 2015 Session P-E2 Poster Session

Poster Hall

2:30 pm– 4:00 pm The Envelope/Antibody Dynamic 343 Estimating and Visualizing HIV-1 Susceptibility to Broadly Neutralizing Antibodies Anna Feldmann ; Nico Pfeifer Max Planck Institute for Informatics, Saarbrücken, Germany

Background: In HIV-1 treatment, clinicians still have to face drug-resistant viral strains, while the amount of available drugs and drug targets remains limited. Recently, combination therapy with broadly neutralizing antibodies (bNAbs) was introduced as a potential HIV-1 treatment that is capable to reduce viral load under detectable levels for up to 60 days in humanized mice and primates. However, similarly to HAART, the emergence of resistant strains is a major problemwhen selecting an efficient combination therapy of bNAbs for an individual patient. Prior to the administration of a bNAb combination therapy to a patient, it has to be ensured that the patient’s viral strains are susceptible to the particular bNAb. Methods: For seven different bNAbs we trained a classifier for each using support vector machines. The prediction models are able to determine the neutralization susceptibility of unseen viral strains to the specific bNAb based on the viral envelope sequence (Env). Different string kernels as well as the polynomial kernel and the Gaussian RBF kernel were tested by 10 times nested cross-validation. In addition, we introduce new visualization techniques (e.g., motif of most important residues) to increase model interpretability of non-linear classifiers. Results: Among all considered kernels, the oligo string kernel performed best. High prediction performance could be traced back to learnt discriminant features that are supported by literature. State of the art performance of the classifiers can be seen in the table. For the V3-loop directed bNAbs the N-glycosylation site at position 332 was found as the most discriminant residue for neutralization susceptibility whereas position 334 confers neutralization resistance. The N-glycosylation site at position 160 was identified to be the most discriminant residue for the classifiers targeting the V1/V2 -loop indicating neutralization susceptibility. The classifiers for the CD4 binding site-directed bNAbs recognized different known binding sites to the CD4 molecule on the gp120 Env subunit to be associated with neutralization susceptibility of the viral strains. In addition to the already known epitopes, we also found other discriminant residues that might be interesting for follow-up structural studies.

AUC (area under the curve) performance of each classifier assessed by 10 times 5-fold nested cross-validation. Conclusions: The good classfier performances motivate their use in the selection of bNAb combination therapy. The robustness of the models implies that models with similar accuracy and interpretability can also be learnt for additional bNAbs. 344 Sequential SHIV-Env Clones With Neutralization Sensitivity for Breadth Development Manxue Jia ; Cecilia Cheng-Mayer; XuelingWu Aaron Diamond AIDS Research Center, New York, NY, US Background: Neutralizing antibodies gradually increase in breadth in selected SHIV-infected rhesus macaques (RMs) and HIV-1-infected humans. However, the envelope (Env) clones that are responsible for the development of neutralization breadth have not been identified. Methods: Because the SHIV-RM is the best available animal model for HIV-1 antibody studies, we screened 13 viremic RMs that were intra-rectally infected with the R5 clade B SHIV SF162P3N for neutralization activity against eight HIV-1 heterologous strains. Two animals, GB40 and FF69, were identified as containing the best neutralization breadths and titers. Using plasmas collected longitudinally from these animals, we tested four homologous Env clones derived from the SHIV SF162P3N inoculum and identified two sequential homologous neutralization activities (waves) prior to a third wave that cross-neutralized the tested HIV-1 strains. Based on the time when each wave appears, we selected time points for Env isolation. Full-length env sequences were obtained by single genome amplification, and representative env clones were tested for neutralization. Results: From GB40, we obtained 116 env sequences and cloned 11 fromweek 2 (w2), w19 and w35 plasmas, and from the genomic DNA of w13 PBMC. The Env clone w2_1 is sensitive to plasmas from the wave 1 time points (w13 – w19). The Env clone w13_d13 is sensitive to time points between waves 1 and 2, and thus defined a new neutralization activity – wave 1b (w17 – w35). The other isolated GB40 Env clones are not particularly sensitive to wave 2 time points (~w45); therefore, the search for the specific Envs responsible for wave 2 continues. The isolated GB40 Env clones are sensitive to wave 3 time points (w54 and after) when heterologous neutralization is evident. From FF69, we thus far obtained 21 env sequences from the peak viremia (w2 plasma) and cloned two major variants, w2_17 and w2_27. Both variants are sensitive to wave 1 time points (w8 – w12) in this animal. Conclusions: From two SHIV SF162P3N -infected RMs, we identified 2-3 sequential waves of homologous responses before the appearance of the heterologous neutralization activity. Examination of sequential Env clones from these animals identified specific Envs with neutralization sensitivity to temporal plasmas in which neutralization specificity gradually broadens. The identification of these Env clones is highly relevant for HIV-1 Env immunogen design.

Poster Abstracts

267

CROI 2015