CROI 2016 Abstract eBook

Abstract Listing

Oral Abstracts

55 Perception of Infectiousness in HIV-Infected Persons After Initiating ART: ACTG A5257 Raphael J. Landovitz 1 ;ThuyT.Tran 2 ; Susan E. Cohn 3 ; Ighovwerha Ofotokun 4 ; George A. Bishopric 5 ; Jeffrey L. Lennox 4 ; Judith S. Currier 1 ; Heather J. Ribaudo 2 1 David Geffen Sch of Med at Univ of California Los Angeles, Los Angeles, CA, USA; 2 Harvard Sch of PH, Boston, MA, USA; 3 Northwestern Univ, Chicago, IL, USA; 4 Emory Univ Sch of Med, Atlanta, GA, USA; 5 Univ of Miami, Miami, FL, USA

Background: Antiretroviral therapy (ART)-induced viral suppression has been shown to reduce sexual transmission of HIV. Data for prevention of HIV transmission are strongest for heterosexual transmission. ART does not produce immediate or universal viral suppression, and perception of infectiousness (POI) may impact sexual risk taking. Changes in POI as a result of ART may have implications for transmission and population incidence. Methods: A5257 followed 1809 ART-naïve participants in a randomized open-label ART study for up to 192 weeks(W). Self-report of POI was assessed at baseline and annually via a visual analog scale (0-100). Pre- defined infectiousness categories were high (67-100), medium (34-66), low (1-33), not infectious (0). We evaluated a decline in POI defined as ≥10 unit absolute decrease with a change in POI category at W48 relative to baseline; a decline to not infectious POI was evaluated as a secondary outcome. Multivariable binary Poisson regression was used to evaluate factors associated with these outcomes. Results: At baseline (pre-ART), 58%, 26%, 10%, 6% participants self-categorized as high, medium, low , or not infectious , respectively. At W48, 38%, 20%, 32%, and 10% self-categorized as high, medium, low, or not-infectious ; 91% had HIV RNA<50 c/mL. 49% reported a reduction in POI from baseline to W48. In multivariable analysis, higher baseline POI, younger age and higher education were associated with greater risk of a decline in POI; non-Hispanic Black race and pre-ART CD4<50 cells was associated with lower risk (Figure). Factors associated with a decline to not infectious POI (n=99) were baseline POI, female sex, and absence of stimulant drug use. Associations with RNA suppression were not apparent for either outcome (p=0.94 and 0.87, respectively). Only 8 of 99 participants who perceived themselves as not infectious on ART at W48 had RNA >50 c/mL. Conclusions: Nearly half of participants reported a reduction in POI 48W after initiating ART. Those who were younger and more educated were more likely to report a reduction in POI, whereas those of black race or with advanced disease were less likely to report a reduction. Overall, relatively few participants perceived themselves non-infectious – a salutary finding for prevention. Interestingly, actual viral suppression was not associated with POI. Understanding how POI changes due to therapy, and how it relates to condomless sex, will be critical for designing interventions to maximize the benefits of treatment as prevention. Structure of the HIV-1 RNA Packaging Signal Michael F. Summers , Howard Hughes Med Inst, Minneapolis, MN, USA

Oral Abstracts

56

The 5´-leader of the HIV-1 genome contains conserved elements that direct selective packaging of the unspliced, dimeric viral RNA into assembling particles. Using a novel 2 H- edited NMR approach, including a fragmentation-based approach that employs differential 2H labeling/editing, we determined the structure of a 155-nucleotide region of the leader that is independently capable of directing RNA packaging (Core Encapsidation Signal; Ψ CES ). The RNA adopts an unexpected tandem three-way junction structure, in which residues of the major splice donor and translation initiation sites are sequestered by long-range base pairing, and guanosines essential for both packaging and high-affinity binding to the cognate Gag protein are exposed in helical junctions. Mutation of these “junction guanosines” inhibits binding by the cognate NC protein in vitro and leads to severe attenuation of competitive RNA packaging in cell assays. The structure reveals how translation is attenuated, Gag binding promoted, and unspliced dimeric genomes selected, by the RNA conformer that directs packaging. 57 The Antiretroviral Activity of the SERINC Gene Family Massimo Pizzato , Univ of Trento, Trento, Italy SERINC genes represent a highly conserved family encoding homologous multipass transmembrane proteins, which in humans includes five members. SERINC5, and to a lesser extent SERINC3, were recently found to inhibit HIV and MLV virion particle infectivity. Both SERINC proteins are efficiently incorporated into virions and inhibit an early step of the infection process with a mechanismwhich remains to be elucidated. Nef from primate lentiviruses and glycoGag fromMoMLV are capable of counteracting SERINC5 and SERINC3 antiviral activity by causing their relocalization into the late endosomal compartment. The host factors are therefore removed from the cell surface and prevented from being incorporated into virus particles. In addition to glycoGag and Nef, we now identified the accessory protein S2, from equine infectious anemia virus (EIAV), as yet another retroviral factor capable of antagonizing SERINC5 and SERINC3. Reminescent of Nef, the counteracting activity of S2 requires myristoylation and clathrin-mediated endocytosis, indicating a common mechanism of action. Remarkably, Nef, GlycoGag and S2 share no sequence homology and are derived from distinct regions in the retrovirus genome, suggesting that the anti-SERINC activity was acquired independently by the three retroviruses. In light of these results, we are now expanding our investigation in order to assess how general the ability of SERINC genes to inhibit retroviruses is, and how frequently SERINC-counteracting factors have arisen during retrovirus speciation. For being restriction factors, SERINC5 and SERINC3 have unusual features, since they are highly conserved (from yeast to mammals) and their expression is not altered by treatment with interferon-beta. In addition, our analyses indicate that SERINC5 evolution is not driven by positive selection, an observation which would suggest the absence of selective pressure derived from a direct interaction with antagonizing factors. However, purified HIV-1 Nef and SERINC5 efficiently interact in vitro , demonstrating the ability of the two proteins to associate directly, in the absence of additional co-factors. SERINC proteins are therefore a unique and novel class of host factors with broad anti-retroviral activity. Mapping studies are currently under way to identify the molecular determinants crucial for the interaction with Nef and for the antiviral activity.

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CROI 2016