CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

with coinfections may boost RANTES levels and thus CXCR4 use, potentially explaining the fast progression. We propose that CRF19 is evolutionary very fit and causing rapid progression to AIDS in many newly infected patients in Cuba.

TUESDAY, FEBRUARY 24, 2015 Session P-E1 Poster Session

Poster Hall

2:30 pm– 4:00 pm The Effect of HIV Infection on B Cells 339 Acute HIV-1 Infection Is AssociatedWith Rapid Changes in B-Cell Subsets and Levels of CXCL13 Jenniffer K. Maroa 1 ; Anne-Sophie Dugust 2 ; Zelda Euler 2 ;Yathisha Ramlakhan 1 ; Krista Dong 3 ; BruceWalker 2 ;Thumbi Ndung’u 4 ; Galit Alter 2 1 University of KwaZulu-Natal, Durban, South Africa; 2 Ragon Institute of MIT, MGH and Harvard, Boston, MA, US; 3 Massachusetts General Hospital, Harvard Medical School, Boston, MA, US; 4 HIV Pathogenesis Programme, Durban, South Africa Background: HIV chronic infection (CI) is characterized by perturbations in B cell homeostasis, phenotype and function. There are limited data describing B cell dynamics during HIV acute infection (AI). Characterizing B cell subsets during AI might help define signatures that shape the humoral response in HIV infection. Methods: Eleven women who became HIV-1 infected during a longitudinal follow-up study in Durban, South Africa were analyzed. Samples were analyzed at baseline (pre- infection) and weeks 1, 2, 4 and 12 post detection of HIV RNA. Multicolor flow cytometry was used to identify B cell subsets based on expression of CD21CD27 on live CD19+ lymphocytes and defined as follows; activated memory (AM) CD27+CD21-, resting memory (RM) CD27+ CD21+, naïve cells (N) CD27-CD21+, tissue-like memory (TLM) CD27-CD21- and plasmablasts (PBs) CD27+CD38+ cells. Evolution of HIV-specific antibodies and changes in CXCL13 levels were determined by ELISA Results: Compared to a baseline sample, we observed rapid and significant expansion of TLM cells post HIV infection (PI); 1week (p = 0.0003), 2 weeks (p = 0.0018), 1 month (p = 0.046) and 3 months (p= 0.043). In contrast, RM cells were significantly lower throughout AI compared to baseline; 1week (p = 0.0007), 2 weeks (p = 0.016), 1 month (p = 0.019) and 3 months (p= 0.018). We observed significant expansion of AM cells at 2 weeks and 1 month (p = 0.008, p= 0.009 respectively) followed by contraction by 3 months (p = 0.260) PI. Peripheral blood PBs peaked by a median of 17 days (range 7-32 days) PI. Changes in B cell subsets were driven by the increase in viral loads. Levels of CXCL13 a chemokine critical for B cell homing to the germinal centers also increased over time in the first 3 months. Conclusions: Perturbations in B cell subsets and CXCL13 levels occurs immediately following HIV-1 infection and this may therefore determine the subsequent development of anti-HIV antibodies. 340 Bone Marrow Plasma Cells Dictate SerumHIV-Specific Antibodies in Chronic Viremia Jairo Mauricio Montezuma-Rusca 1 ; Olivia R. Fankuchen 1 ; Lela Kardava 1 ; Clarisa M. Buckner 1 ; Aaron Louie 1 ;Yuxing Li 2 ;TaeWook Chun 1 ; Katherine R. Calvo 3 ; Susan Moir 1 ; Anthony S. Fauci 1 1 NIAID/NIH, Bethesda, MD, US; 2 University of Maryland, Rockville, MD, US; 3 NIH Clinical Center, Bethesda, MD, US Background: Screening for HIV-neutralizing antibody activity in the serum or plasma has been the starting point for the isolation of several potent and broadly neutralizing antibodies to HIV from peripheral blood B cells of infected individuals. Despite the success of this approach, little is known regarding the cells that produce the antibodies detected in the serum. To gain a better understanding of the cellular source of circulating antibodies, we investigated two possible sources, the bone marrow and peripheral blood, of chronically HIV-viremic individuals. Methods: Bone marrow biopsies and peripheral blood samples were obtained from eight chronically HIV-viremic individuals and bone marrow cells were obtained from eight healthy HIV-negative controls. Written informed consent was provided. Immunophenotyping was performed on cell suspensions using B-cell subset-defining markers. A biotinylated HIV envelope gp140 probe was used to measure HIV-specific antibodies in serum (via ELISA), HIV-specific plasmablasts (via ELISPOT) or memory B cells (via flow cytometry) in blood, and HIV-specific plasma cells in bone marrow (via ELISPOT). Results: Compared to HIV-negative counterparts, the bone marrow aspirates of the HIV-infected participants contained increased frequencies of plasma cells and B cell precursors (namely preB-I and preB-II), and decreased frequencies of mature B cells. Levels of HIV-specific antibodies measured in serumwere compared to corresponding frequencies of antibody-secreting or -binding cells measured in the bone marrow (plasma cells) and the blood (plasmablasts and memory B cells). A strong correlation was observed between HIV-specific antibodies in serum and the HIV-specific bone marrow-derived plasma cells, but not the plasmablasts or memory B cells from blood. Conclusions: Increased frequencies of plasma cells in the bone marrow are consistent with known hallmarks of HIV infection, namely hypergammaglobulinemia and increased frequencies of peripheral blood plasmablasts. These findings demonstrate that despite HIV-induced phenotypic and functional B-cell dysregulation in the peripheral blood and secondary lymphoid tissues, bone marrow plasma cells remain a primary source for circulating HIV-specific antibodies in HIV-infected individuals. 341 Reduced Expression of Blimp-1 on Memory B Cells in Patients with HIV-1 Infection Claudia Beisel ; IlonaToth; Jan van Lunzen; Julian Schulze zurWiesch University Hospital Hamburg-Eppendorf, Hamburg, Germany Background: Blimp-1 has long been recognized as master regulator for B cell development and has additionally been recognized as important rheostat, balancing effector function and T cell exhaustion. Although several studies described Blimp-1 in the context of T cell exhaustion in viral infections, the role of Blimp-1 was first and primarily defined as a “master regulator” of terminal B cell development. Blimp-1 attenuates the expression of many transcription factors, thereby inhibiting B cell proliferation and B cell receptor mediated activation while promoting immunoglobulin secretion and plasma cell differentiation. Here, we present novel data describing the expression pattern of Blimp-1 in different B cell memory subsets in a cohort of viremic and treated HIV-1 patients. Methods: The expression of Blimp-1 in different B cell memory subsets was analyzed by flow cytometry in a cohort of 26 individuals, classified as healthy donors (n = 7), treatment naïve HIV-1 infected patients (n = 9) and HIV-1 infected patients under antiretroviral therapy (cART) (n = 10). B cell memory subsets were defined as activated memory B cells (CD20 + /CD21 lo /CD27 int ), tissue like memory B cells (CD20 + /CD21 lo /CD27 - ), resting memory B cells CD20 + /CD21 hi /CD27 int ) and naïve memory B cells (CD20 + /CD21 lo /CD27 lo ). Results: The expression of Blimp-1 on activated memory B cells was significantly down-regulated in patients with HIV-1 infection compared to healthy donors. Viremic, treatment naïve patients showed an even lower expression of Blimp-1 than patients on cART. The relative frequency of Ki67 on activated memory B cells directly correlated with HIV viral load (p = 0.005, r 2 = 0.30). Additionally, the relative frequency of Blimp-1 on activated memory B cells inversely correlated with HIV-1 viral loads and the relative frequency of Ki67+ activated memory B cells (p = 0.026, r 2 = 0.62; p = 0.033, r 2 = 0.51) (Figure 1).

Poster Abstracts

265

CROI 2015