CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

replication to undetectable levels (HIC group), and compared them to treated patients with similarly low viral loads (ART group). Methods: HIV-specific cTfh (Tet+) were detected by Gag MHC-II tetramer labeling in the CD45RA- CXCR5+ CD4+ T cell population. The function of cTfh was analyzed by the capacity to promote IgG secretion in cocultures with autologous memory B cells. Results: HIV-specific cTfh (Tet+) proved more frequent in the controller group than in the treated patient group (P=0.002). The frequency of PD-1 expression in Tet+ cTfh was increased in both groups (median >75%) compared to total cTfh (<30%), but the intensity of PD-1 expression per cell remained higher in the ART group (P=0.02), pointing to the persistence of abnormal immune activation in treated patients. The function of cTfh, analyzed in coculture with memory B cells, did not showmajor differences between groups in terms of total IgG production, but proved significantly more efficient in the controller group when measuring HIV-specific IgG production. The frequency of Tet+ cTfh correlated with HIV-specific IgG production (R=0.71 for Gag-specific and R=0.79 for Env- specific IgG, respectively). Conclusion: Taken together, these findings indicate that key cTfh/B cell interactions are preserved in controlled HIV infection, resulting in potent memory B cell responses that may play an underappreciated role in HIV control. Genevieve L. Wojcik 1 , Michael A. Eller 2 , David Serwadda 3 , Kate Grabowski 4 , Fred Wabwire-Mangen 3 , Anthony Ndyanabo 5 , Merlin L. Robb 2 , Nelson L. Michael 2 , Leigh Anne Eller 2 , Ronald H. Gray 4 , Thomas C. Quinn 6 , Oliver Laeyendecker 6 1 Stanford University, Stanford, CA, USA, 2 Walter Reed Army Institute of Research, Silver Spring, MD, USA, 3 Makerere University, Kampala, Uganda, 4 The Johns Hopkins University, Baltimore, MD, USA, 5 Rakai Health Sciences Program, Kalisizo, Uganda, 6 NIAID, Baltimore, MD, USA Background: Viral and host genetic factors have been associated with beneficial and detrimental impacts on HIV disease progression. We assessed the impact of host genetics, after controlling for viral factors on disease progression in a Ugandan population where subtypes A and D circulate. Previous studies in this population have demonstrated that subtype D is much more pathogenic than subtype A. Methods: A total of 393 HIV seroconverters infected between 1997 and 2001 in Rakai Uganda were genotyped on Illumina’s Multi-Ethnic Global Array (MEGA). HIV subtype data was generated using the multi region hybridization assay using probes specific for subtypes A, C and D. Viral load was assessed with Roche Amplicor version 1.5. Set point viral load was defined as the median viral load for all time points tested after the initial HIV positive visit and prior to AIDS. AIDS was defined as a CD4 count <250 cells/ul or WHO stage 4. Rapid HIV progressors were defined as AIDS or death within 4 years of infection. SNP associations with set point viral load and CD4 slope were evaluated with linear regression. Logistic regression was used to identify SNPs associated with rapid progression, controlling for HIV subtype and set point viral load. Proportional hazards regression was used to estimate hazard ratios of years to death or AIDS, adjusted for subtype. Analyses were restricted to variation in the Major Histocompatability Complex (MHC) class I and II regions and adjusted for age at infection and sex. Results: The minor allele of rs2524119 was associated with decreased CD4 slope (P=3.04x10 -5 ; Beta=-9.3) and is located upstream of HLA-B and HLA-C. Set point viral load was associated with class I SNP variants rs60993483 (P=6.68x10 -5 ; Beta=-0.53) within HLA-H/HLA-G and rs1051488 (P=5.88x10 - 5 ; Beta=-0.26). Rapid progression was associated with a HLA-B within rs551116093 (OR=2.49; P=3.15x10 -5 ). HLA-B (rs2524084; HR= 0.57; P=3.75x10 - 4 ) was associated with years to death or AIDS among individuals with subtype D. Conclusion: CD4 slope, set point viral load, rapid progression, and years to death or AIDS were found to be associated with MHC class I variants, highlighting the importance of human genetic variation in HIV pathogenesis, independent of other known viral and host factors. 227 FC DEPENDENT ANTI-HIV-SPECIFIC ANTIBODY FUNCTIONALITY DISTINGUISHES HIV CONTROLLERS Sanket Kant 1 , Franck P. Dupuy 1 , Chris Leeks 1 , Alexandre Barbe 1 , Ningyu Zhang 1 , Cindy X. Zhang 1 , Jean-Pierre Routy 1 , Petronela Ancuta 2 , Cécile Tremblay 2 , Nicole Bernard 1 226 INTERACTION OF HOST AND VIRAL GENOMICS ON HIV DISEASE PROGRESSION IN RAKAI UGANDA

1 Research Institute of McGill University Health Centre, Montreal, QC, Canada, 2 Centre de Research du Centre Hospitalier de l’Université de Montreal, Montreal, QC, Canada Background: Antibodies (Ab) bridge antigen expressing cells with Fc receptor (FcR)+ innate effector cells mediating multiple functions. Engagement of FcRs on monocytes triggers phagocytosis. Ab-antigen complexes can also initiate the complement (C’) cascade. Elite Controllers (EC) are HIV infected individuals with viral loads (VL) <50 copies/ml plasma (c/mlp) without treatment. We hypothesized that if Fc-mediated functions play a role in HIV control, EC would differ from HIV+ untreated progressors (UTP, VL > 2000c/mlp), antiretroviral therapy (ART) treated individuals (TP, VL < 50c/mlp), and viremic controllers (VC, VL < 2000c/mlp) in terms of anti-HIV envelope (gp120)-specific IgG functionality. Here, we compared Ab-dependent (AD) complement deposition (ADCD) and AD cellular phagocytosis (ADCP) assays in these groups. Methods: Plasma samples from 18 UTP, 24 TP, 36 EC and 16 VC were quantified for total IgG and anti-gp120-specific IgG concentrations by ELISA. The ADCD assay assessed the frequency of gp120-coated and HIV-infected CEM.NKr. CCR5 target cells (T) positive for the complement component C3b on their cell surface. The ADCP assay measured the phagocytosis of gp120-functionalized fluorescent beads by THP-1 (E) monocyte-like cells. Activity was measured as the area under the curve (AUC) of the ADCD and ADCP score (% fluorescent T/E x the mean fluorescence intensity (MFI) of T/E), respectively for 2 plasma IgG concentrations. Positive and negative controls for these assays were pooled plasma from HIV+ and HIV- individuals Results: UTP and EC had significantly higher concentrations of anti-gp120 specific Ab than TP (p<0.0001, Kruskal-Wallis test with Dunn’s post tests). ADCD and ADCP activity levels in plasma from UTP, EC and VC did not differ from each other significantly but was higher than in plasma from TP (p<0.0001 for all, Dunn’s). When ADCD and ADCP results were normalized to the concentration of each sample’s anti-gp120 Ab, between group differences disappeared. Conclusion: The higher levels of ADCD and ADCP activity in plasma from EC, VC and UTP than in TP were due to differences in anti-gp120 specific Ab concentrations present in these samples and could not be attributed to between-group differences in the ability of the anti-gp120 specific Abs to support these functions. Future research should address how EC and VC maintain high concentrations of anti- gp120 specific Abs in a setting of HIV VL suppression. 228 TEMPORAL VARIATION OF IgG SUBCLASSES DIFFERENTIATES HIV CONTROLLERS AND PROGRESSORS Jishnu Das 1 , Saheli Sadanand 1 , Amy Chung 2 , Todd J. Suscovich 1 , Hendrik Streeck 3 , Davey M. Smith 4 , Susan J. Little 4 , Douglas Lauffenburger 5 , Douglas D. Richman 4 , Galit Alter 1 1 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 2 University of Melbourne, Melbourne, VIC, Australia, 3 Institute for HIV Research, Essen, Germany, 4 University of California San Diego, San Diego, CA, USA, 5 MIT, Cambridge, MA, USA Background: Given the emerging appreciation for the role of antibody(Ab)- dependent effector functions and IgG subclass distributions among spontaneous controllers of HIV, we sought to examine whether Ab-associated features diverged in early HIV infection between subjects who ultimately became controllers versus those who became progressors. Methods: IgG was purified from plasma from nine acutely infected subjects who subsequently controlled HIV spontaneously (controllers) and ten acutely infected individuals who did not control viremia (progressors). Ab profiles were compared at weeks 4, 12, 24 and 48 post-infection. Levels of clade B gp120-, gp140-and gp41-specific IgG Ab subclasses were measured. Additionally, gp120- specific Ab-dependent cellular phagocytosis (ADCP), cellular cytotoxicity (ADCC), cellular viral inhibition (ADCVI) and NK activation (ADNKA) were assessed. Results: We found that no individual Ab-dependent effector function or subclass level at any timepoint was significantly associated with long- term HIV control. However, a multivariate LASSO/PLS model that used the overall temporal variation of Ab-associated variables, was able to accurately differentiate controllers and progressors (median classification accuracy measured in a 5-fold cross-validation framework = 0.75, P < 0.001 compared to null models). In contrast to controllers, progressors showed greater dynamic changes in gp120-specific subclass selection profiles, with increasing levels of Env-specific IgG2 Abs and losses in Env-specific IgG3 Abs. Moreover, progressors, but not controllers, lost ADCVI function over time. These results demonstrate that maintaining functional Abs such as IgG3, and not gaining less functional Abs, such as IgG2, together play a role in controlling viremia.

Poster Abstracts

80

CROI 2018