CROI 2020 Abstract eBook

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Poster Abstracts

525 SUSCEPTIBILITY TO bNAbs OF TRANSMITTED HIV VARIANTS AMONG RECENT INFECTIONS IN FRANCE Karl Stefic 1 , Mélanie Bouvin-Pley 1 , Asma Essat 2 , Clara Visdeloup 1 , Alain Moreau 1 , Cécile Goujard 2 , Marie-Laure Chaix Baudier 3 , Martine Braibant 1 , Laurence Meyer 2 , Francis Barin 1 , for the ANRS PRIMO Cohort Study Group 1 INSERM, Tours, France, 2 Hôpital Bicêtre, Le Kremlin-Bicetre, France, 3 Hôpital Saint-Louis, Paris, France Background: Pre-existing resistance to broadly neutralizing antibodies (bNAbs) restrains their use for prevention and treatment of HIV infection. In addition, an increasing resistance of HIV to neutralization over time has been observed arguing for a prospective monitoring of the sensitivity to bnAbs of all prevalent HIV subtypes. Here, we analyzed the susceptibility to bNAbs of HIV transmitted variants among recently infected individuals in France with a focus on evolution over time. Methods: We assessed the sensitivity to seven bnAbs against a panel of 73 early-transmitted subtype B and CRF02_AG viruses (the most prevalent subtypes in Europe) over a 25-year period of the French epidemic (1987- 2012). Samples were obtained during acute/recent infection from individuals included in the ANRS PRIMO cohort. Env pseudoviruses were constructed and neutralization assays on TZM-bl cells were performed using bnAbs targeting the CD4-binding site (CD4bs; VRC01, 3BNC117), the V1/V2-glycan region (PG9, PGT145), the V3-glycan region (PGT121, 10-1074), and the gp41 membrane proximal external region (MPER; 10E8). Results: Participants' median CD4 count was 506 cells/mm 3 , median viral load was 5.1 log 10 copies/mL and the estimated time from infection was 41 days. bNAbs targeting the CD4bs and 108E were the most potent and broadly neutralizing. VRC01 neutralized 92.5% of all variants at the target concentration of 10 µg/mL. 3BNC117 IC 50 s were the lowest of all bNAbs (respectively 0.01 et 0.25 µg/mL for B and CRF02_AG variants; Mann-Whitney P<0.05). CRF02_AG were more resistant than B viruses regarding bNAbs targeting V3 (64-67% of the strains neutralized at 10 µg/mL vs 78-88%, respectively). This resistance was associated with the absence of the glycosylation site N332 (p<0.01). Both subtypes were more resistant to bNAbs targeting V2 (55-65% of the strains neutralized at 10 µg/mL). Finally, we observed an increased resistance to several bNAbs over the course of the epidemic - especially those targeting the CD4bs – which correlated with the continuous diversification of Env sequences over time (Spearman P<0.05). Conclusion: Of the bNAbs in clinical development tested here, none neutralized 100% of T/F variants, indicating that combinations will be required to achieve a full coverage for prevention and treatment. As in other countries, we confirmed the natural drift of HIV towards higher resistance to bNAbs for the most prevalent subtypes spreading in France, arguing for a continuous surveillance of HIV transmitted variants around the globe.

526 INVESTIGATION OF INTEGRASE-INHIBITOR RESISTANCE MUTATIONS IN gp41 IN CLINICAL SAMPLES Hanwei Sudderuddin 1 , Anh Le 1 , Tetyana Kalynyak 1 , Rob Hollebakken 1 , Kyle Cobarrubias 1 , Jinny Choi 1 , Weiyan Dong 1 , Winnie W. Dong 1 , Walter Scott 1 , Kate Laird 1 , Paul Sereda 1 , Eric O. Freed 2 , Zabrina Brumme 1 , Chanson J. Brumme 1 1 British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada, 2 National Cancer Institute, Frederick, MD, USA Background: In vitro studies have suggested that resistance to HIV Integrase strand transfer inhibitors (INSTI) can occur outside the integrase gene, including in env, but it remains unclear whether such mutations arise in vivo. Using a large database of clinically-derived HIV-1 sequences, we sought to identify mutations in gp41 that were associated with exposure to INSTI in vivo. Methods: We identified 146 consenting participants of the BC-CfE Drug Treatment Program (DTP), infected with HIV-1 subtype B, whose physicians had ordered a genotypic INSTI resistance test following ≥3 months of INSTI exposure and whose genotype was susceptible to all INSTI (HIVdb v8.8 score <15). We then performed gp41 genotyping on these same samples. For comparison, we assembled reference datasets of subtype B Integrase (INT) and gp41 sequences from INSTI-naïve DTP participants collected during routine clinical drug resistance testing. Amino acids (AA) significantly over- or under-represented among INSTI-treated and -naïve participants at all INT and gp41 codons were identified by Fisher's exact test. Analyses were restricted to AA observed ≥5 times and multiple comparisons were addressed using the Benjamini-Hochberg method (q-values). Results: INT and gp41 sequences from participants treated with raltegravir (79; 54%), elvitegravir (27; 18%) or dolutegravir (40; 27%) were collected after a median of 32 (Q1-Q3: 13-56) months of INSTI exposure. Overall, 16% of INSTI- experienced participants were antiretroviral-naïve at the time of their first INSTI prescription, while 84% had prior NNRTI- and/or PI-based cART. INT sequences from 146 INSTI-treated and 2472 INSTI-naïve individuals were compared. Gp41 genotyping was successful for 115 (79%) INSTI-treated individuals; these were compared to sequences from 1222 INSTI-naïve individuals. Lower frequencies of the gp41 polymorphisms I182V (OR=0.40, p=9.1x10-6, q=0.0085) and H209R (OR=0.47, p=1.9x10-4, q=0.086) were observed in INSTI-experienced individuals at these positions. No significant differences in AA frequencies were observed in INT sequences (all q>0.2). Conclusion: Differences in gp41 amino acid frequencies in INSTI-experienced vs. -naïve individuals were observed only at highly polymorphic positions. No substitutions in gp41 previously associated with INSTI resistance in vitro were identified, suggesting that these may arise rarely in vivo. 527 MAPPING RESISTANCE OF POTENT HIV-1 ENTRY INHIBITORS TARGETING PREFUSION CONFORMATION Yen-Ting Lai 1 , Megan Demouth 1 , Adam Dingens 2 , Amarendra Pegu 1 , Jesse Bloom 2 , John R. Mascola 1 , Peter D. Kwong 1 1 Vaccine Research Center, NIAID, Bethesda, MD, USA, 2 Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Poster Abstracts

CROI 2020 188