CROI 2015 Program and Abstracts

Abstract Listing

Oral Abstracts

52 Post-Treatment Controllers Have Particular NK Cells With High Anti-HIV Capacity: VISCONTI Study Daniel Scott-Algara 1 ; Céline Didier 1 ;Vincent Arnold 1 ; Jean-Saville Cummings 1 ; Faroudy Boufassa 2 ; Olivier Lambotte 5 ; Laurent Hocqueloux 4 ; Asier Sáez-Cirión 1 ; Christine Rouzioux 3 1 Institut Pasteur, Paris, France; 2 CESP U1018 Inserm, Le Kremlin-Bicêtre, France; 3 Laboratoire de Virologie, EA 3620–Université Paris Descartes Hôpital Necker, Paris, France; 4 Service des Maladies Infectieuses et Tropicales CHR d’Orléans–La Source, Orleans, France; 5 Hôpital Bicêtre, Le Kremilin-Bicêtre, France Background: The association of T-cells with the control of HIV infection has been well documented. In addition, several studies pointed out the role on innate immune responses in the resistance or delay to HIV disease progression. The recent description (VISCONTI study) of a group of patients, so-called post-treatment controllers (PTCs), who remains with undetectable viral load after treatment interruption despite poor CD8+T cell responses, led us to study NK cells and their relationship to HIV control. Methods: 14 patients enrolled in the French ANRS VISCONTI cohort were studied. PTCs’ results were compared to those of Viremic patients, (VIR), natural HIV controllers (HIC), patients on ARV since acute infection (ARV) and normal blood donors (controls). All phenotypic studies were done on fresh whole blood. CD107a expression on NK cells and the ICS- based assay were done on PBMC after stimulation. NK cells were tested for their capacity to inhibit HIV infection (measured by intracellular or supernatant p24) in autologous CD4 T cells. Results obtained were compared using Wilcoxon rank sum test or by the Fisher exact test Results: Visconti patients showed significantly higher expression of CD158a, CD158b (KIR2DL2/DL3), PTC showed significantly higher expression of CD158a, CD158b (KIR2DL2/ DL3), CD158b/DX9 (KIR3DL1/3DS1) and NKG2A receptors (p<0.002, p<0.001, p<0.0.01, p<0.001, respectively) with lower expression of CD160 and NKp46 (p<0.001, p<0.03, respectively) receptors compared to others groups. Activation of NK cells from PTC and ARV, measured by CD69 marker, was similar to normal donors but lower than in HIC (p<0.006) or VIR patients (p<0.001). Functional studies when NK cells were stimulated by K562 cell line showed normal levels of degranulation (CD107a marker) but higher IFN- γ production for PTC than for other groups (p<0.01). NK cells from PTCs, but not from other individuals (p<0.001), were able to reduce p24 levels when co-cultured with in vitro- infected autologous CD4 T cells. Conclusions: NK cells from PTC had a different NK cell repertoire and higher potential to produce IFN- γ compared to HIC, Viremic patients or normal donors, but similar to those treated since primary infection. More importantly, PTC NK cells showed high capacity to control in vitro HIV infection on autologous CD4 T cells. Our results suggest that preserving NK cell phenotype and function during acute infection is important to control HIV and identify NK cells as possible important agents in the durable remission of PTC. 53 Antiretroviral Therapy Preserves Polyfunctional HIV-1 – Specific CD8 T Cells With Stem-Cell –L ike Properties Selena Vigano 1 ; Jordi J. Negron 1 ; Eric S. Rosenberg 2 ; Bruce D.Walker 1 ; Mathias Lichterfeld 2 ; Xu G.Yu 1 1 The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, US; 2 Massachusetts General Hospital, Harvard Medical School, Boston, MA, US Background: CD8 stem-cell like memory T cells (T SCM cells) have been recently identified in humans, mice and non-human primates, and seem to represent the most immature memory CD8 T cell population with potent abilities to proliferate and repopulate the memory T cell pool. The presence and the function of CD8 T SCM cells in HIV-1 positive individuals are unknown. Methods: CD8 T SCM cells were analyzed in 61 HIV-1-positive patients (31 with HAART-suppressed HIV-1 infection, 14 with untreated progressive HIV-1 infection, and 16 untreated HIV-1 controllers (viremia < 1000 RNA copies/ml). Phenotype and function of CD8 T SCM cells were assessed by flow cytometry; virus-specific CD8 T cell populations (n=90 HIV-1- specific responses, n=24 CMV/EBV/Flu-specific responses) were identified by MHC class I multimer staining or intracellular cytokine staining. 12 HIV-1 negative study subjects were cell frequency was directly associated with years of treatment ( p <0.0001, r=0.66) and inversely associated with immune activation ( p =0.007, r=-0.3) and apoptosis ( p =0.03, r=-0.27) levels. Moreover, HIV-1-specific CD8 T SCM cells from HAART-treated patients showed the highest degree of polyfunctionality in comparison to the other groups of patients (p <0.005). Conclusions: Polyfunctional HIV-1-specific CD8 T SCM cells are able to persist long-term and show a relative accumulation during antiretroviral therapy when viral antigen is pharmacologically suppressed. Due to their apparent antigen-independent persistence in HAART-treated patients, these cells may play an important role in targeting the reservoir of HIV-1-infected cells after pharmacological reversion of viral latency. 54LB In Vitro Replication and Interferon-Alpha Resistance of Transmitted HIV-1 Variants Background: Despite the diverse quasispecies of HIV-1 in the transmitting partner, a bottleneck occurs during transmission whereby, in general, a single genetic variant from that quasispecies establishes infection in the new host. The current working model explaining the transmission bottleneck suggests that transmitted/founder (TF) variants have a higher in vivo fitness and are preferentially resistant to the innate antiviral effects of interferon alpha (IFN α ), enabling escape from the early innate immune response. However, variants derived from HIV-1 transmission pairs with the full complement of HIV proteins have yet to be tested for IFN α resistance or in vitro replication. In this study, we assess replication and IFN α resistance of infectious molecular clones derived from both partners from six transmission pairs to compare the TF to non-transmitted (NT) variants that were present near the time of transmission. Methods: Using a novel cloning strategy, we generated 44 HIV-1 subtype-C full-length infectious molecular clones (6 TF & 38 non-transmitted (NT) variants) from plasma of 6 linked transmission pairs near the time of transmission from the Zambia-Emory HIV Research Project (ZEHRP). The NT variants were selected to represent the sequence diversity of the transmitting partner. We measured virus growth in stimulated PBMC and compared the levels of replication in the presence and absence of IFN α to determine IFN α resistance of the TF and NT variants. Results: We found no evidence of selection for IFN α resistance during heterosexual transmission (p=0.7813), when comparing the TF to matched NT variants. We also did not observe selection for TF varaints with higher in vitro replicative capacity than the median of the matched NT variants (p=0.7118). Notably, the in vitro replicative capacity of each variant correlated with the ability to replicate in the face of IFN α (p<0.0001) and replicative capacity correlated negatively with IFN α resistance (p<0.0001). Conclusions: Our results emphasize the importance of comparing TF variants to NT controls near the time of transmission and suggest that IFN α resistance and in vitro replicative capacity are not necessarily selected for during transmission of subtype C HIV-1 variants. Further characterization of TF variants is necessary to fully understand the viral properties selected for during the HIV-1 transmission bottleneck and to optimize protection through vaccines or other prevention modalities. analyzed as controls. Results: Levels of T SCM in total CD8 T cells were significantly decreased in untreated HIV-1-infected patients ( p <0.007), but not different between HAART-treated HIV-1 patients and HIIV-1-negative subjects. Among all HIV-1 patients, total and HIV-1-specific CD8 T SCM cells were most frequent in HAART-treated patients (p <0.0001). CD8 T SCM Zachary Ende 1 ; Martin Deymier 1 ; Angharad Fenton-May 2 ; DanielT. Claiborne 1 ;William Kilembe 3 ; Susan Allen 1 ; Persephone Borrow 2 ; Eric Hunter 1 1 Emory University, Atlanta, GA, US; 2 Oxford University, Oxfordshire, United Kingdom; 3 Zambia Emory HIV Research Project, Lusaka, Zambia

Oral Abstracts

103

CROI 2015