CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

Conclusions: These data suggest that HIV-specific, ADCC-mediating passively acquired Abs may impact disease progression and survival among infected infants. In particular, IgG1 and not IgG3 Abs appear to be responsible for the effect and de novo responses do not explain the survival benefit. 163 AAV-Expressed eCD4-Ig Protects Rhesus Macaques FromMultiple SHIV-AD8 Challenges Michael Farzan The Scripps Research Institute, Jupiter, FL, US Background: Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional HIV-1 vaccine. Adeno-associated virus (AAV) vectors can stably express broadly neutralizing HIV-1 antibodies (bNAbs). However, more than a quarter of HIV-1 isolates are at least partially resistant (IC 80 > 5 m g/ml) to even the best bNAbs, suggesting that very high concentrations of these antibodies would be necessary to achieve general protection. Methods: Here we characterize eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, and assess AAV-delivery of eCD4-Ig as a means of stably protecting individuals from a new HIV-1 infection. Results: We show that eCD4-Ig binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean IC 50 < 0.05 m g/ ml). Because eCD4-Ig only binds conserved regions of the Env, it is also much broader than any bNAb. For example, eCD4-Ig neutralized 100% of a diverse panel of neutralization- resistant HIV-1, HIV-2, and SIV isolates with IC 80 s less than 5 m g/ml, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46, and 3BNC117. Rhesus macaques inoculated with an AAV vector expressed 16-84 m g/ml of fully functional rhesus eCD4-Ig over 32 weeks, and these macaques were protected from multiple challenges with SHIV-AD8 that efficiently infected control macaques. Moreover, eCD4-Ig was markedly less immunogenic than any of four well characterized bNAbs.

Conclusions: AAV-expressed eCD4-Ig can function as an effective HIV-1 vaccine alternative. 164LB HIV Neutralizing Antibodies Induced by Native-Like Envelope Trimers Rogier Sanders TheWCMC/Scripps/AMC HIVRAD team Academic Medical Center University of Amsterdam, Amsterdam, Netherlands

Oral Abstracts

Background: Inducing HIV-1 neutralizing antibodies against neutralization-resistant (Tier-2) virus strains has been a challenge. Methods: Our working hypothesis has been that stable native-like envelope trimers should induce neutralizing antibodies (NAbs).

Results: We show here that such trimers based on the pediatric founder virus BG505 (BG505 SOSIP.664 gp140), consistently induced neutralizing antibodies (NAbs) against the autologous, neutralization-resistant (Tier-2) BG505.T332N virus at high titers in rabbits and macaques. Cross-reactive NAbs against more sensitive (Tier-1) viruses were also induced. The Tier-1 and the autologous Tier-2 NAb responses were uncorrelated, implying that different pathways and B-cell subsets are involved. Tier-1 NAbs were depleted by linear V3 peptides, while Tier-2 NAbs recognized several conformational epitopes that differed between animals, that sometimes involved glycosylation sites and that were similar to some broadly active NAb epitopes. We have designed amino acid substitutions that further stabilize and antigenically improve BG505 SOSIP.664 trimers. The same substitutions also allowed the generation of stable native-like trimers based on virus isolates from clades B and C, including a clade B isolate from an elite neutralizer that developed broad neutralization within 9 months post seroconversion. Finally, we designed a stable native-like trimer that is able to interact with the germline versions of diverse bNAbs. Conclusions: These rationally designed trimers represent suitable starting points for lineage and/or polyvalent vaccines aimed at inducing NAbs able to counter diverse Tier-2 isolates. 165 Efficacy Loss of BnAbs During HIV-1 Cell-Cell Spread Is Strain- and Epitope-Dependent Lucia Reh ; Carsten Magnus; Merle Schanz; JacquelineWeber;Therese Uhr; Peter Rusert; AlexandraTrkola University of Zurich, Zurich, Switzerland Background: HIV-1 cell-cell transmission promotes high efficacy of infection, which inflicts a dramatic loss in neutralization potency even by broadly neutralizing antibodies (bnAbs) compared to free virus infection. A precise definition of inhibitory potentials during cell-cell transmission is therefore needed to select bnAbs that are capable of suppressing HIV irrespective of the transmission mode, securing in vivo activity and allowing for their use as vaccines and in passive immunization. Methods: We have compiled assay systems that allow for unambiguous discrimination between free virus and cell-cell transmission. For this, PBMC or CD4+ CCR5+ A3.01 T cells were co-cultured with producer cells (PBMC or 293-T cells), either infected with replication competent virus or transfected with env pseudotyped inGLuc reporter viruses to distinguish cell-cell transmission from fusion events. Inhibitory capacities of the bnAbs (b12, VRC01, NIH45-46, 3BNC117, PGV04, PGTs 121, 125, 128, 135, 145, PG9, PG16, 2G12, 10E8, 2F5, 4E10) during cell-cell transmission of HIV-1 strains from subtypes A, B and C were studied and their potency to block virus transmission pre and post CD4 engagement was assessed. Results: Across almost all bnAb-virus combinations tested, the potency to inhibit HIV-1 cell-cell transmission was strongly decreased compared to free virus transmission. However, loss of potency varied considerably between virus strains and strikingly, high potency against free virus did not ensure lower loss in activity during cell-cell transmission.

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CROI 2015