CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

Results: We demonstrated that the gp41 mutations Env-A539V and A556T, which enhance viral cell-to-cell transmission, provide a replication advantage over WT in the presence of not only DTG but also other classes of ARVs targeting RT and PR. Moreover, Env-A539V compensated for viral fitness defects induced by drug resistance mutations in the viral enzymes and increased resistance to ARVs when coupled with these mutations, suggesting that the Env mutations may be a “stepping-stone” on the path to high-level drug resistance. Interestingly, Env mutations that show enhanced cell-to-cell transmission cluster in the gp120 C1 domain and gp41 heptad repeat 1, which are located at the gp120/gp41 interface and are crucial for stabilizing the gp120-gp41 interaction. Indeed, we observed that the Env mutations reduced gp120 shedding from virus particles. In addition, Env-A539V decreased the sensitivity of HIV-1 to NAbs that recognize the CD4-induced Env conformation, suggesting that this mutation decreases the efficiency with which Env transitions from the unliganded state. Sequencing of viruses from RTG-failure patients revealed the presence of several mutations in the highly conserved gp120/gp41 interface in the absence of resistance mutations in IN. Conclusion: These results demonstrate that mutations in Env can contribute to broad HIV drug resistance in vitro. Moreover, we established a relationship between Env stability, drug resistance, and the efficiency of viral cell-to-cell transmission. These findings offer mechanistic insights into Env-mediated drug resistance in culture, and suggest, preliminarily, that Env-mediated drug resistance may also occur in vivo. Sergio Ita 1 , Antoine Chaillon 1 , Maris Kamalu 1 , Jonny Baham 1 , Aimee Chen 1 , Magali Porrachia 1 , Caroline Ignacio 1 , Stephen A. Rawlings 1 , Gabriel A.Wagner 1 , Sara Gianella 1 , Davey M. Smith 1 1 University of California San Diego, La Jolla, CA, USA Background: HIV drug resistance can be an obstacle to successful antiretroviral therapy (ART), but the vast majority of studies on drug resistance have focused on studying blood. Here, we present evidence of drug resistance across multiple tissues in two persons with HIV. Methods: Last Gift study participant 3 (LG03) was a 72-year-old man with HIV and metastatic pancreatic cancer with no previous history of drug resistance. LG05 was a 57-year old man with HIV and amyotrophic lateral sclerosis with pre-existing resistance to nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI) identified by the GenoSure Archive NGS-based assay. Both had suppressed HIV RNA in blood plasma collected within 7 hours from death. Tissues were isolated via a rapid autopsy and HIV DNA was extracted from gut (ileum and duodenum), lymph nodes (axillary and aortic), kidney and spleen. 72 3.5-kb pol single genome amplicons were prepared in a single library and sequenced (Illumina MiSeq). Reads were mapped to HIV HXB2, and consensus sequences generated. Mutations at sites of drug resistance were determined (Stanford HIV Drug Resistance Database) and analyzed for each variant. Results: Despite no previous diagnosis of ART failure with drug resistance, in tissues LG03 had mutations associated to (NRTI) including D67N, K70R, T215F, and K219Q/E in 9 kidney, 3 aortic lymph node, and 3 axillary lymph nodes SGA variants, but not in his duodenum or ileum (Table 1). In tissues, LG05 had NRTI resistance associated mutations (D67N, K70R, T215F, and K219Q/E) in 1 duodenum, 1 ileum, and 3 spleen SGA variants. Nonpolymorphic mutations associated with PI included M46I, I54V, V82T, I84V, and L90M. These mutations matched those identified in the GenoSure Archive assay. Conclusion: This study found high rates of resistance associated mutations in proviruses across tissues in persons with HIV who were fully suppressed on ART. The pattern of HIV drug resistance associated mutations across PBMC and tissues was not consistent for either LG03 or LG05 (table 1). These discrepancies were pronounced between PBMC DNA (based on the GenoSure Archive assay) and non-circulating tissues. These findings highlight that HIV drug resistance might be present in various tissue reservoirs without prior diagnosis, and that just sampling in one compartment, like PBMC, is likely to miss the full repertoire of HIV drug resistance that is present.

537 HIV DRUG RESISTANCE IN FEMALE SEX WORKERS FROM THE DOMINICAN REPUBLIC AND TANZANIA Wendy Greenawalt 1 , Jessica M. Fogel 1 , William Clarke 1 , Autumn Breaud 1 , Jessie Mbwambo 2 , Samuel Likindikoki 2 , Said Aboud 2 , Yeycy Donastorg 3 , Martha Perez 3 , Clare Barrington 4 , Wendy Davis 5 , Mark A. Marzinke 1 , Noya Galai 6 , Deanna Kerrigan 5 , Susan H. Eshleman 1 1 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania, United Republic of, 3 Instituto Dermatologico y Cirugia de la Piel, Santo Domingo, Dominican Republic, 4 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 5 American University, Washington, DC, USA, 6 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Background: Female sex workers (FSW) are at high risk of HIV infection and sex work is known to play an important role in HIV transmission dynamics across settings. Low socioeconomic status, gender discrimination, and stigma associated with HIV and sex work may limit access to HIV care for FSW. We analyzed HIV drug resistance among HIV-infected FSW in the Dominican Republic (DR) and Tanzania who are enrolled in a longitudinal study of the social determinants of HIV outcomes. Methods: Plasma samples were collected at study entry. Samples with viral loads >1,000 c/mL were retrospectively tested for HIV drug resistance and antiretroviral (ARV) drugs. HIV genotyping was performed using the ViroSeq HIV-1 Genotyping System. ARV drug testing was performed using a qualitative assay that detects 22 ARV drugs in five drug classes. Chi-square tests were used to evaluate factors associated with drug resistance. Results: Among 410 enrolled FSW, 144 (35.1%) had a viral load >1,000 c/mL (50 from the DR, 94 from Tanzania). Genotyping results were obtained for 138 (95.8%) of 144 participants. Major drug resistance mutations were detected in 54 (39.1%) of the 138 samples (22 [15.9%] had non-nucleoside reverse transcriptase inhibitor resistance, 3 [2.2%] had nucleoside/nucleotide reverse transcriptase inhibitor resistance, 29 [21.0%] had multi-class resistance). ARV drugs were detected in 36 (25.0%) of the 144 cases; 19 (52.8%) of the 36 samples had only one or two drugs detected. The frequency of resistance was higher in the DR than Tanzania (27/50 [54.0%] vs. 27/88 [30.7%], p=0.011) and was higher among those with ≥1 ARV drug detected (31/35 [88.6%] vs. 23/103 [22.3%] with no drugs detected, p<0.0001). Seven participants with ≥1 ARV drug detected lacked corresponding resistance mutations; those individuals were at risk of acquiring additional drug resistance. K103N was the most common mutation detected among all 138 cases; M184V was the most common mutation detected among the 35 cases with ≥1 ARV drug detected. Conclusion: In this cohort of FSW, nearly 40% of participants with viral loads >1,000 c/mL had HIV drug resistance and >20% had multi-class resistance. Drug resistance was associated with study site and ARV drug use. ARV drugs were detected in 25% of the participants who had a viral load >1,000 c/mL; in more than half of those cases, only one or two drugs were detected. These findings highlight the need for improved HIV care and treatment among FSW. 538 RESISTANCE TO INTEGRASE STRAND TRANSFER INHIBITORS AMONG MSM IN THE US: HPTN 078 Jessica M. Fogel 1 , Vanessa Cummings 1 , Ethan A. Wilson 2 , Christophe Fraser 3 , David Bonsall 3 , Theresa Gamble 4 , Carlos Del Rio 5 , D. Scott Batey 6 , Kenneth H. Mayer 7 , Jason Farley 8 , James Hughes 9 , Robert H. Remien 10 , Chris Beyrer 11 , Susan H. Eshleman 1 , for the HPTN 078 Study Team 1 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Fred Hutchinson Cancer Research Center, Seattle, WA, USA, 3 University of Oxford, Oxford, UK, 4 FHI 360, Durham, NC, USA, 5 Emory University, Atlanta, GA, USA, 6 University of Alabama at Birmingham, Birmingham, AL, USA, 7 Harvard Medical School, Boston, MA, USA, 8 Johns Hopkins University School of Nursing, Baltimore, MD, USA, 9 University of Washington, Seattle, WA, USA, 10 Columbia University, New York, NY, USA, 11 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA Background: Increasing viral suppression with antiretroviral therapy (ART) is a critical step in curbing the HIV epidemic. Integrase strand transfer inhibitor (INSTI)-based ART regimens are now recommended for first-line ART in the United States (US), but pre-treatment resistance testing does not routinely include testing for INSTI resistance. The HIV Prevention Trials Network (HPTN) 078 study evaluated an HIV prevention strategy in men who have sex with men (MSM) in four US cities. We analyzed INSTI resistance in MSM recruited for participation in HPTN 078.

536 HIV DRUG RESISTANCE ACROSS ANATOMICAL TISSUES

Poster Abstracts

CROI 2020 192