CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

Conclusions: Even when there is little or no predicted activity due to resistance, NRTIs make a major contribution to efficacy of PI/NRTI second-line therapy with clear added activity over the PI alone, equivalent to adding a drug from a new class. No difference between 0 and 1 active NRTIs suggests this contribution is not due to direct drug activity (possibly represents a viral fitness effect). The paradoxical trend to worse outcome with 2 active NRTIs may reflect a small group of patients with very poor adherence on first-line, continued during second-line. Algorithmic NRTI drug selection and attention to adherence are likely to achieve optimal outcomes in standardised PI/NRTI second-line therapy in resource-limited settings with resistance testing to select NRTIs of little added value. 120 Fitness Effects of Drug-Resistant Strains Across the United States HIV-1 Transmission Network Joel O. Wertheim 1 ; Alexandra M. Oster 2 ; Neeraja Saduvala 2 ;Walid Heneine 2 ; Jeffery A. Johnson 2 ;WilliamM. Switzer 2 ; Angela L. Hernandez 2 ; H. Irene Hall 2 1 University of California San Diego, San Diego, CA, US; 2 US Centers for Disease Control and Prevention (CDC), Atlanta, GA, US Background: Drug resistance associated mutations (DRAMs) can reduce the effectiveness of antiretrovirals (ARVs). DRAMs frommultiple drug classes can have deleterious effects on intrahost viral fitness (replication) and may reduce transmissibility. We used genetic transmission network analysis to assess the effect of DRAMs on interhost viral fitness (transmission, or network links). Methods: We analyzed 66,235 HIV-1 pol sequences reported to the US National HIV Surveillance System for persons diagnosed through 2012; 30,200 were collected within 3 months of diagnosis in ARV-naïve persons. We aligned all sequences to a reference sequence (HXB2), removed DRAM-associated codons, and constructed a transmission network by linking sequences with ≤ 1.5% Tamura-Nei genetic distance, indicating potential transmission between two persons. Among ARV-naïve persons, we determined the percentage that clustered with ≥ 1 sequence, by presence of DRAMs, overall and by drug class, and conducted multivariable analysis to account for potential confounders. Results: Of 30,200 ARV-naïve persons, 12,539 (42%) clustered. Protease and non-nucleoside reverse transcriptase inhibitor DRAMs were not associated with clustering. However, nucleoside reverse transcriptase inhibitor (NRTI) DRAMs were associated with reduced clustering (33%with NRTI DRAMs clustered vs. 42%without NRTI DRAMs, p <0.0001). After adjusting for age, race/ethnicity, transmission category, geographic region, and diagnosis year, having NRTI DRAMs was still associated with reduced clustering. No single mutation appears responsible for the reduced clustering. M184V, which has known deleterious intrahost fitness consequences, was associated with a lower prevalence of clustering (18%) and was present in only 8% of persons with an NRTI DRAM. Persons in the 7 largest DRAM clusters ( ≥ 30 person, ≥ 90% sharing a mutation) did not differ significantly from those in the 26 largest non-DRAM clusters ( ≥ 30 person) with respect to sex, race/ethnicity, or transmission category. However, persons in DRAM clusters were significantly more likely to be diagnosed in the last 3 years of the analysis period. These DRAM clusters contained mutations from all three drug classes. Conclusions: With the exception of NRTI mutations, DRAMs did not have deleterious effects on interhost transmission. Our findings likely reflect compensatory mechanisms that improve fitness or insignificant impact of DRAMs on transmissibility and highlight the propensity for drug-resistant HIV-1 to spread. 121 Dolutegravir Resistance Requires Multiple Primary Mutations in HIV-1 Integrase Background: HIV-1 integrase sequences containing mutations at positions 143, 148 and 155 represent major resistance pathways to integrase inhibitors (INI). These genetic pathways are generally distinct for raltegravir and elvitegravir; the emergence of more than one primary mutation in a single virus genome is rarely observed. In a clinical trial, the viruses of four of seven virologic failure cases treated with a dolutegravir (DTG) based regimen contained combinations of mutations at positions 143, 148 and 155. To understand how the combined effects of primary mutations enable HIV to escape DTG drug pressure, we examined the impact of combinations of primary mutations on DTG susceptibility and replication capacity, with and without additional secondary mutations. Methods: A series of laboratory viruses containing site directed mutations at HIV-1 integrase positions 143, 148 and 155 alone, in combination, or with secondary mutations T97A or G140S, were constructed. INI susceptibility and replication capacity (RC) were determined using a pseudovirus luciferase reporter assay. Results: Single mutations at positions 143, 148 or 155 alone did not confer reductions in DTG susceptibility. Double mutations Y143R+N155H and Q148H+N155H produced modest reductions in DTG susceptibility (FC=3.1, 4.2, respectively), whereas the Y143R+Q148H double mutations did not (FC=0.7). The addition of G140S, a Q148 pathway mutation, to the double mutants Y143R+Q148H and Q148H+N155H further reduced DTG susceptibility (FC=6.2, 35, respectively) and fully restored the RC of the Y143R+Q148H and Q148H+N155H viruses (RC=17%, 3%, respectively). In contrast, the addition of G140S dramatically decreased the RC of the Y143R+N155H mutant from 60% to 5%. The addition of T97A, a Y143 or N155 pathway mutation, to the Y143R+N155H mutant did not confer a further reduction in DTG susceptibility, but did reduce RC. Conclusions: This study demonstrates that HIV-1 variants containing combinations of INI resistance mutations at positions 143, 148 and 155 exhibit reduced susceptibility to DTG. Viruses that harbor mutations belonging to the 148+155 escape pathway are less susceptible to DTG and exhibit similar or greater RC than viruses harboring mutations belonging to the 143+148 or 143+155 pathways. Thus, in the face of DTG pressure, HIV-1 variants with 148 and 155 mutations likely possess a replication advantage over variants with 143 and 148 mutations or 143 and 155 mutations. Arne Frantzell; Christos J Petropoulos; Wei Huang Monogram Biosciences, South San Francisco, CA, US

Oral Abstracts

Session S-4 Symposium

Room 613

4:00 pm– 6:00 pm Making Sense of Sensing: Innate Immunity and HIV Infection 122 Role of Tetherin in the Evolution and Spread of HIV-1 Daniel Sauter Ulm University Medical Center, Ulm, Germany

The interferon-inducible protein tetherin (also known as BST-2 or CD317) has emerged as a key component of the intrinsic immunity against retroviruses. Initially, tetherin was shown to restrict HIV-1 in the absence of the viral protein U (Vpu) by inhibiting the release of budding virions from infected cells. More recently, it has become clear that tetherin also acts as a pattern recognition receptor inducing NF- κ B-dependent expression of antiviral and proinflammatory genes in HIV infected cells. Notably, tetherin does not only restrict retrovirus release but has activity against diverse enveloped viruses including Arena-, Filo- and Herpesvirues. Whereas the ability to restrict virion release is highly conserved among mammalian tetherin orthologs and probably an ancient function of this protein, innate sensing seems to be unique to the human and chimpanzee orthologs and thus an evolutionarily recent activity. The potent and broad antiviral activity of tetherin has driven the evolution of antagonists in many viruses. Simian (SIV) and human immunodeficiency viruses, for example, use at least three different proteins (Nef, Vpu or Env) to antagonize tetherin. The continuous arms race of tetherin with viral antagonists is probably also the reason for a unique deletion in the cytoplasmic tail of human tetherin that renders it resistant against SIV Nef. Since most SIVs - including the direct precursors of HIV-1 - use Nef to antagonize tetherin in their respective hosts, human tetherin poses a significant barrier to successful cross-species transmissions to humans. Interestingly, the four groups of HIV-1 (M, N, O and P) which arose from independent cross-species transmissions, have evolved different mechanisms to overcome this hurdle. Whereas pandemic HIV1 group M viruses switched from Nef to Vpu to counteract human tetherin, rare group P and N Vpus do not or only poorly antagonize this restriciton factor. In contrast, Nef

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CROI 2015