CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Results: We synthesized and tested 48 oleanolic acid derivatives and found a novel entry inhibitor OKS3-019, which could inhibit HIV-1 infection in IC 50 values of 1.6, 1.0, 40, 26 and 28 μM for HIV-1 NL4-3, 89.6, JR-FL, YU2, and KP-5mvcR strain (primary R5 isolate), respectively. Time-of-addition experiments indicated that OKS3-019 interfered viral infection in the entry step. To investigate synergistic effect of OKS3-019 and anti-HIV-1 NAbs, we calculated Combination Indexes (CIs) using the Chow and Talalay method in combinations of the OKS3-019 and each NAb. All combinations showed synergistic effect in CI values from 0.59 to 0.81. These results demonstrate that the novel oleanolic acid derivative OKS3-019 targeting non-CD4 binding site acts as bifunctional entry inhibitors similar to CD4 mimetics. Conclusion: In the present work, we found the novel bifunctional small molecule OKS3-019. Binding of such OKS compounds to HIV-1 envelope (Env) may affect the quaternary structure of the Env and the accessibility of NAbs to the epitopes. These findings indicate that OKS compounds might be useful in inhibiting HIV-1 infection not only by directly obstructing viral entry, but also enhancing sensitivity to neutralizing antibodies. 248 GP41 ANTIGENIC RECOGNITION AND RESPONSE IN HIV-NEGATIVE MEN WHO HAVE SEX WITH MEN Katie McFaul , Jia Guo, Elizabeth Atkins, Xiao-Ning Xu, Peter Kelleher, for the Centre for Immunology andVaccinology, Imperial College London Imperial Coll London, London, UK Background: Early HIV infection is characterised by polyclonal anti-HIV gp41 responses which do not control virus. This may be due to a previously educated B cell pool producing a response characteristic of a second exposure to a recognised antigen in a pre-primed host, or regular exposure to HIV antigens in individuals who remain seronegative but develop anti-HIV immune responses. Pre-existing anti-gp41 responses could divert developing mechanisms of protection in the case of future HIV acquisition. Seronegative men who have sex with men (MSM) engaging in unprotected sexual intercourse may be exposed to HIV antigens. We hypothesized seronegative MSM with either low (LR) or high risk (HR) HIV exposure history may develop varying anti-HIV responses accordingly. We sought to characterise the antigenic determinants and response to gp41 using a novel yeast surface display (YSD) mechanism. Methods: A YSD system encompassing the gp41 gene-region (Fig 1A) was induced to display HIV gp41 epitope fragments as surface proteins. We selected serum samples from 20 HIV-negative MSM and pooled these into four groups of 5 samples (H5, H9, L6, L10). HIV risk exposure was classified according to PROUD-UK criteria. Sera from healthy controls and known HIV positive samples were used as negative and positive controls respectively. Sera were used to select reactive yeast clones by flow cytometric analysis and sorting. Reactive yeast clones were enriched and sequenced. These were aligned to the original full length gp41 sequence, and characterised according to regions identified (Fig. 1B). Amino acid residues were calculated as a proportion of total fragments identified and mapped to major gp41 epitope regions (Fig. 1C). Results: We identified antibody responses to gp41 in both HR and LR MSM (Fig 1B and 1C). HRMSM displayed responses to all major gp41 epitopes, recognising 91.0% of gp41’s 343 amino acid residues, compared to 64.1% in LR (p<0.05, CI 20.7- 32.9). HRMSM had greater recognition of fusion protein (FP), N-helix (NH), transmembrane (TMD) and cytoplasmic tail (CT). LRMSM had greater recognition of the C-helix (CH) (p < 0.01). There was no difference in recognition of monoclonal antibody (MAb) sites. Conclusion: Serum responses to HIVgp41 epitopes vary according to exposure risk in seronegative MSM. High risk seronegative MSM have a greater breadth and magnitude of immunologic responses, which could be due to repeated viral exposure, and may influence viral dynamics in the case of future infection.

Poster and Themed Discussion Abstracts

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CROI 2017