CROI 2018 Abstract eBook

Abstract eBook

Poster Abstracts

866 HIV SPECIFIC IGM MEMORY B CELLS DOMINATE IN SERONEGATIVE EARLY-TREATED CHILDREN Nicola Cotugno 1 , Elena Morrocchi 2 , Ilaria Pepponi 1 , Salvatore Rocca 2 , Mark Cameron 3 , Stefano Rinaldi 4 , Silvia Di Cesare 2 , Suresh Pallikkuth 4 , Stefania Bernardi 1 , Nigel Klein 5 , Jintanat Ananworanich 6 , Paolo Rossi 1 , Savita Pahwa 4 , Paolo Palma 1 1 Bambino Gesu Children’s Hospitalital, Rome, Italy, 2 University of Rome Tor Vergata, Rome, Italy, 3 Case Western Reserve University, Cleveland, OH, USA, 4 University of Miami, Miami, FL, USA, 5 London School of Hygiene & Tropical Medicine, London, UK, 6 US Military HIV Research Program, Silver Spring, MD, USA Background: Previous reports have shown that early initiation of ART (eART) in HIV+ vertically-infected infants results in loss of HIV antibodies (Ab) presumably due to rapid viral control resulting in short antigenic exposure. Whether HIV-specific memory responses are present in eART seronegative patients is still unknown. The present study investigated frequency and immune characteristics of gp140 specific B cells in seronegative (SN) and seropositive (SP) early-treated (ET) HIV+ children. Methods: 22 ET vertically-infected children, who initiated ART at a mean age of 4.8±3.7 mo. with durable viral control (mean 7.25±5.2 years, plasma HIV-RNA<50cp/mL) were enrolled at Bambino Gesù Children’s Hospital. Plasma samples, tested by Abbott Architect HIV Ag/Ab Combo Assay, defined SN or SP status. Cryopreserved PBMC were stimulated O/N with Envelope (Env) peptides and sCD40L or left unstimulated. PBMCs were then stained for analysis by flow cytometry (gating strategy in panel A). B cells were classified as total memory (CD27+IgD-), naïve (CD27-IgD+), unswitched memory (CD27+IgD+), activated memory (CD27+, IgD-, CD21-) and resting memory (CD27+, IgD-, CD21+). B-cell Fluorospot was performed to simultaneously detect IgM and IgG responses to gp160 and gp120. Results: 6 out of 22 (27.3%) children resulted SN. No differences in B cell subsets were observed between the SN and SP group (panel B). Although frequencies of antigen specific CD19+ gp140+ B cells resulted similar in both groups, SN children presented a higher frequency of HIV-specific IgMmemory (CD27+,IgD+) B cells (p=0.016) compared to SP in the peripheral blood (panel C). These data were further confirmed by Fluorospot assay where IgM response to Env-Ags gp160 (p= 0.008) and gp120 (p=0.024) was found higher in SN compared to SP group. Moreover, in vitro stimulation revealed a predominant IgMmemory HIV-specific B cell response in SN (p=0.034), while the IgG total memory (gp140+, CD27+, IgD-) response was found higher in SP (p=0.015; panel D). Conclusion: These data suggest that HIV-specific responses in seronegative patients resides in IgMmemory B cells. IgMmemory responses were recently reported to be rapid and functional in the context of other infectious diseases (Krishnamurty et al., 2016, Immunity). It is still unknown whether such responses could be targeted by new disease modifying strategies in order to achieve viral remission in HIV+ early treated children.

865 EARLY CMV AND EBV ACQUISITION PREDICTS HIV DNA LEVELS IN INFANTS ON SUPPRESSIVE ART

Jennifer Slyker 1 , Brandon Guthrie 1 , Mark D. Pankau 1 , Dalton Wamalwa 2 , Sarah Benki-Nugent 1 , Meei-Li Huang 1 , Grace John-Stewart 1 , Julie Overbaugh 3 , Dara Lehman 1 1 University of Washington, Seattle, WA, USA, 2 University of Nairobi, Nairobi, Kenya, 3 Fred Hutchinson Cancer Research Center, Seattle, WA, USA Background: Defining modifiable factors associated with HIV reservoir size may inform novel interventions to enable post-treatment control of HIV infection. HIV-infected infants in Africa often acquire cytomegalovirus (CMV) and Epstein-Barr virus (EBV) within a few weeks of HIV; primary infection with each of these initiates dramatic changes in immune activation and could impact HIV reservoir formation. We assessed the association between the timing of CMV and EBV infection and levels of plasma viremia with cell-associated HIV DNA (ca-DNA) in children with HIV RNA suppression after 2 years of ART. Methods: The study was nested into the Optimizing HIV Treatment (OPH) study (NCT00428116). All children started ART at HIV diagnosis, at <6 months of age, and had no prior ART. CMV and EBV DNA were measured in plasma using quantitative real time PCR at enrollment and quarterly thereafter; EBV serology was conducted in EBV-negatives at 24 months. HIV ca-DNA was measured using digital droplet PCR from PBMC at 24 months post-ART in children with at least 6 months of HIV RNA suppression. Linear regression was used to determine the association of the timing of CMV and EBV infection, and cumulative CMV and EBV viremia (area-under-the-curve, AUC over the first 21 months of ART) with the level of HIV ca-DNA at 24 months post ART. Results: A total of 23 infants were evaluated; 21 (91%) had CMV and 21 (91%) had EBV infection, only 1 child remained both CMV and EBV-uninfected. CMV detection at enrollment (p=0.01), duration of EBV infection (p=0.02) and EBV AUC (p=0.006) were associated with log 10 HIV ca-DNA at 24 months. Pre-ART CD4% and HIV RNA level were not associated with HIV ca-DNA level, but there was a trend association between later ART initiation and higher HIV ca-DNA level (p=0.1). Adjusting for age at ART, CMV infection at enrollment (p=0.02), longer duration of EBV infection (p=0.02), and higher EBV AUC (p=0.01) were independently associated with higher HIV ca-DNA level. Baseline HIV RNA level was not associated with CMV or EBV AUCs (p>0.05 for each), but lower baseline CD4%was associated with higher EBV AUC (coeff=-7.6 [-12, -2.7], p=0.004). CMV and EBV AUCs were not significantly correlated (coeff=0.020, p=0.9). Conclusion: Early acquisition of CMV and EBV, and higher cumulative exposure to systemic EBV DNA replication are associated with higher HIV DNA levels in early-treated infants with HIV RNA suppression. Understanding the basis of this association may reveal novel paths to limit the HIV reservoir.

Poster Abstracts

CROI 2018 328