CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

301 Oral PrEP Enhances Genital HIV-Neutralizing IgA in HIV-1 Exposed SeronegativeWomen Jennifer M. Lund 1 ; Kristina Broliden 2 ; Maria N. Pyra 3 ; Katherine K.Thomas 3 ; Deborah Donnell 4 ; Elizabeth Irungu 5 ;Timothy R. Muwonge 6 ; Nelly R. Mugo 5 ; Jared M. Baeten 3 ; Jairam R. Lingappa 3 1 Fred Hutchinson Cancer Rsr Cntr, Seattle, WA, USA; 2 Karolinska Univ, Stockholm, Sweden; 3 Univ of Washington, Seattle, WA, USA; 4 SCHARP, Fred Hutchinson Cancer Rsr Cntr, Seattle, WA, USA; 5 Kenya Med Rsr Inst, Thika, Kenya; 6 Makerere Univ Coll of Hlth Scis, Kampala, Uganda Background: Several clinical trials have reported efficacy of pre-exposure prophylaxis (PrEP) with antiretroviral drugs against sexual HIV-1 transmission. Non-human primate studies have found that SIV-1 exposure during PrEP can induce adaptive immunity in the absence of productive infection. We evaluated cervicovaginal IgA in female study participants on PrEP and placebo, and examined whether responses persist or wane after discontinuation of PrEP. Methods: Cervicovaginal swab samples were collected from a subset of 99 HIV-1 uninfected women participating in the Partners PrEP Study (a clinical trial of tenofovir-DF based oral PrEP versus placebo in HIV-1 uninfected East Africans). An HIV-1 exposure risk score was calculated from longitudinal data including unprotected sex frequency and plasma HIV-1 RNA level of the HIV-infected stable partner; a 1-unit increase in exposure score indicates a 2.7-fold increased risk of infection. Total IgA1 was extracted from swabs, and tested for anti-HIV-1 functional activity in a PBMC-based HIV-1 neutralizing assay. Positive IgA neutralization was defined as neutralization at >90% in duplicate wells. Results: Among 99 samples processed, 40 were fromwomen on PrEP, 45 at 2 months post-PrEP (32 of these paired with on treatment), and 14 on placebo. PrEP and placebo recipients were comparable by age and HIV-1 exposure. Twenty percent of women on PrEP had HIV-1-neutralizing IgA, versus 9% in the post-treatment group, and 0% in the placebo group. Women on PrEP had a 29%-point increase in level of neutralization compared to those on placebo (p=0.006). Women off-PrEP also had a significant though smaller increase of 22%-point compared to placebo (p=0.03). We also examined the effect of HIV-1 exposure on the level and presence of HIV-neutralizing IgA: each unit increase in the HIV-1 exposure risk score was associated with a 5% increase in level of HIV-neutralization (p=0.04), or with 47% higher odds of neutralizing both wells at >90% (OR = 1.47 (95% CI: 1.01-2.13), p=0.04). Conclusions: We found an enhanced IgA-mediated HIV-1 neutralizing activity in genital samples of women on PrEP compared to placebo. These observations are reminiscent of data from studies on HIV-exposed uninfected individuals who can harbor mucosal HIV-1 specific immune responses in the absence of productive HIV-1 infection. Further studies in humans and non-human primate models are needed to elucidate whether induced mucosal immune responses could contribute to PrEP efficacy. 302 Potent Broadly Neutralising Antibody Responses in Slow-Progressing Pediatric HIV Emily Adland 1 ; Maximilian Muenchhoff 1 ; Anna Csala 1 ;Thumbi P. Ndungu 2 ; Pieter Jooste 3 ; Owen Karimanzira 4 ; Carol Crowther 4 ; Penny Moore 4 ; Lynn Morris 4 ; Philip Goulder 1 1 Univ of Oxford, Oxford, UK; 2 Univ of KwaZulu-Natal, Durban, South Africa; 3 Kimberley Hosp, Kimberley, South Africa; 4 NCID, Johannesburg, South Africa Background: In the absence of anti-retroviral therapy (ART), ~50% of HIV-infected children have died by 2yrs. However, ~5% of ART-naïve HIV-infected children maintain normal CD4 counts through childhood. Unlike non-progressing adults, where high CD4 counts are associated with low viremia and protective HLA class I allele expression, non-progressing pediatric infection features high viral loads and a minimal role for HLA I. We here tested the hypothesis that non-progressing children present a similar phenotype to that observed in natural SIV infection; and make broadly neutralising antibody (bNAb) responses in association with persistent high viremia. Methods: We studied 276 ART-naïve HIV-infected children aged >5yrs recruited in South Africa. Phenotypic characterisation of T-cells was undertaken using mAbs specific for CD3, CD4, CD8, HLA-DR, CD38, CD45RA, CCR7, PD-1, CCR5, IL-2, IFNg, and TNFa. Plasma sCD14 and iFABP levels were quantified via Luminex and ELISA. Antibody neutralization was measured in TZM-bl cells using a multi-subtype panel of 16 Env-pseudotyped viruses, with breadth defined as neutralization of >50% of heterologous viruses. Results: Low immune activation was strongly associated with high absolute CD4 count in ART-naive children. Low levels of plasma sCD14 and iFABP were consistent with limited microbial translocation in slow-progressing children. Immune factors associated with non-progression included high naïve CD4 T cells, low effector memory CD4 cells; upon antigen stimulation, high IL-2 and low IFNg production; and low expression of T-cell exhaustion markers. LASSO and generalized linear models identified CD4 T-cell immune activation as the primary driver of CD4 decline among 16 parameters analyzed; notably, viral load had no significant impact. bNAbs were detected in 70% of slow-progressing pediatric subjects (n=89) compared to 15% of C clade infected adults (n=48) (p=1x10-12). The NAb titres were unusually high in the children often exceeding 1:10,000. Conclusions: Slow-progressing pediatric HIV infection shows features in common with natural SIV infection. HIV-specific immune responses in these children included high frequency bNAb responses in 85% of subjects. Further evaluation of this non-progressing pediatric group may be of value both in defining mechanisms limiting immune activation in the face of persistent viremia, and also in isolating highly potent bNAbs to facilitate future HIV prevention and cure strategies. 303 Broadly Reactive Neutralizing Activity Within the First 6 Months of HIV-1 Infection Amanda Fabra García 1 ; Nuria Gonzalez 2 ; Alberto Merino-Mansilla 3 ; Juan Ambrosioni 4 ; Anke Schultz 5 ; Jose M. Gatell 6 ; José Alcamí 2 ; José M. Miro 4 ; EloisaYuste 3 ;Victor Sanchez-Merino 3 1 IDIBAPS, Barcelona, Spain; 2 Inst de Salud Carlos III, Madrid, Spain; 3 Inst d`Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; 4 Hosp Clinic-IDIBAPS, Univ de Barcelona, Barcelona, Spain; 5 Fraunhofer Inst for Biomed Engineering, St Ingbert, Germany; 6 Hosp Clinic of Barcelona, Barcelona, Spain Background: According to the present knowledge, a fraction of HIV-1 infected individuals are able to generate broadly reactive neutralizing activity (brNA) after 2-4 years of infection and, in very rare occasions, close to the first year post-seroconversion. However, brNA has not been described in acute/recent HIV-1 infection. Methods: In this study, serum samples from 157 antiretroviral-naïve individuals within the first year of documented HIV-1 infection were tested in triplicate at a 1/200 dilution against a minipanel of 6 recombinant viruses from 5 different subtypes and different tropisms. The epitopes recognized by the antibodies present in these sera have been characterized by ELISAs, neutralization and competition assays. Samples with cross-reactive neutralization profile, within the first 6 months of infection, were then tested against an extended panel of 20 pseudoviruses (2 tier 3, 14 tier 2 and 4 tier 1) from 4 different subtypes and recombinant forms to confirm brNA. Results: Detectable brNA was observed in sera from 21 patients (13%) with less than one year of infection with no significant neutralization of the vesicular stomatitis virus (VSV) pseudotyped control. In these patients, neutralization breadth was positively associated with time post-infection (p=0.0001) but, contrary to what has been reported for chronic HIV-1 infection, no association with the level of viremia was observed. The characterization of the epitopes recognized by sera from patients with brNA in recent infection showed a predominant targeting of envelope epitopes within the V2 glycan dependent region. Remarkably, we were able to identify 5 individuals, within the first six months of infection (2 as early as 77 and 96 days post-infection), capable to neutralize viruses from 4 different subtypes and 2 circulating recombinant forms with a geometric mean ID50 titer between 100 and 800. Conclusions: These results indicate that the induction of broadly reactivity neutralizing responses, despite being rare, is feasible in recently HIV-1 infected individuals. This data should encourage the search for immunogens able to elicit this kind of responses in a preventive HIV-1 vaccine. 304 New Family of Neutralizing Antibodies in HIV Asymptomatic Long-TermNonprogressors Background: Through a large serie of studies, we previously characterized the pathogenic effect of the highly conserved 3S epitope of gp41 during HIV infection. By analyzing the humoral immune response induced in asymptomatic long-term non-progressor (ALT) patients, we recently observed that up to 25% patients elicited efficient neutralizing responses directed against a point-mutated form of 3S (W614A-3S). Here we extensively characterized the neutralizing profile of this new family of neutralizing Abs. Methods: Abs binding to 3S-WT (wild-type) or W614A-3S mutants were isolated from the sera of ALT patients. Abs were purified from heat-inactivated plasma of ALT patients by immunoprecipitation with synthetic W614A-3S peptides immobilized onto an amine-reactive agarose support, concentrated with Centicon filter, and dialyzed against PBS. The Patrice Debre 1 ;VincentVieillard 2 ; Olivier Lucar 2 ; Bin Su 3 ;Valérie Potard 4 ; Assia Samri 2 ; Christiane Moog 3 ; for the ANRS CO15 ALT Study Group 1 INSERM, Paris, France; 2 INSERM U1135, Paris, France; 3 INSERM UMR S-1109, Strasbourg, France; 4 INSERM UMR-S 1136, Paris, France

Poster Abstracts

117

CROI 2016