CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

THURSDAY, FEBRUARY 26, 2015 Session P-T9 Poster Session

Poster Hall

2:30 pm– 4:00 pm Mechanisms of MTCT and Maternal/Infant Health 897 HIV Target Cells and Altered Microbiome AssociatedWith Mixed Feeding in South Africa Lianna F. Wood 1 ; Cosette LeCiel 2 ; Heather Jaspan 3 ; Donald Sodora 2 1 University of Washington, Seattle, WA, US; 2 Seattle BioMed, Seattle, WA, US; 3 Seattle Children’s Hospital, Seattle, WA, US

Background: In many South African informal settlements, 25% of newmothers are HIV-infected, and 40% of HIV-infected infants acquire HIV through breast milk. The common practice of feeding infants both breast milk and non-breast milk foods, known as mixed-feeding, increases an infant’s susceptibility to HIV by up to 11 fold compared to exclusively breast feeding. We hypothesized that the increase in HIV susceptibility seen in mixed-fed infants is due to an increase in HIV target cells at the oral mucosal, the mucosal surface first encountered by HIV in breast milk, and that systemic immune activation and altered gut microbiome influence this increase in target cells. Methods: Blood (analyzed by flow cytometry), stool (analyzed by 16S rRNA sequencing) and oral mucosa cytobrush samples (analyzed by flow cytometer, Nanostring and qPCR) were collected from 156 HIV-unexposed infants (either exclusively breast fed or mixed-fed) in Khayelitsha, South Africa at 6 and 14 weeks of age. Results: Although at 6 weeks of age mixed and exclusively breastfed infants showed few differences in blood, oral mucosa or stool, at 14 weeks of age we observed several key differences. At 14 weeks of age, the oral mucosa of mixed-fed infants had a significantly higher percentage of HIV target cells compared to infants that were exclusively breastfed (p=0.01). In addition, transcript levels of 16 immune factors, including IL7R, KRT5 and CCL22, showed increased expression and 3 genes, IL18, IL12A and CASP3, showed decreased expression in the oral mucosa of mixed-fed infants. Interestingly, CCL5 (RANTES) expression was elevated in the oral mucosa of mixed-fed infants, suggesting recruitment of CCR5+ HIV target cells to the oral mucosa. In the blood, mixed fed infants also showed higher levels of activation (% HLA-DR+) in CD4+ T cells, with a specific increase in Treg (CD25hiCD39+) activation. In addition, mixed fed infants had an increased proportion of Ruminococcus in their stool microbiome. Conclusions: These data suggest that the increased HIV susceptibility of mixed-fed infants may be mediated by an increase in HIV-susceptible cells at the first site of viral exposure, the oral mucosa, and the systemic circulation. Understanding the mechanism and the role of the gut microbiome in the increased HIV susceptibility of mixed-fed infants may inform interventions to prevent HIV transmission across mucosal surfaces. 898 Role of Type 1 IFNs in the Control of HIV-1 Infection at the Feto-Maternal Interface Erica L. Johnson ; Sahithi Boggavarapu; Elan S. Johnson; Asim A. Lal; Siddhartha Bhaumik; Murali-Krishna Kaja; Rana Chakraborty Emory University School of Medicine, Atlanta, GA, US Background: Low rates of in utero transmission of HIV-1 may reflect high endogenous placental and fetal production of type 1 interferons (IFNs). Type 1 IFNs are important for placental development, and are implicated in fetal protection against various pathogens, potentially via transcription of IFN-stimulated genes (ISGs). Type 1 IFN treatment of myeloid cells potently induces a block to HIV-1 replication at the level of viral DNA accumulation, possibly through IFN-induced host restriction factors. Although the antiviral role of IFNs is well established, it remains unclear whether placental IFNs prevent fetal viral infection in vivo . Methods: With written informed consent, placentae and cord blood were collected from 15 HIV-1 and Hep. B seronegative women (>18 years) at Emory Midtown Hospital in Atlanta, GA. Peripheral blood was obtained from healthy adult volunteer donors. In this study, uninfected or HIV-1BaL-infected fetal and adult myeloid subsets were treated IFN- α or IFN- β . Viral replication was determined by HIV-1 p24 ELISA. qPCR and Western blot analysis determined the expression of ISGs and restriction factors. Transfection of SAMHD1 siRNA into myeloid subsets was performed with the N-TER Nanoparticle System. Data were analyzed by using Student’s t -test and Mann-Whitney test. Results: IFN- α and IFN- β potently limit HIV-1 BaL replication in HCs in vitro. In addition, these IFNs induce significant increases in expression of ISGs in fetal myeloid cells, compared to adult subset. In fetal HCs and cord blood monocytes (CBMs), treatment with IFN- α and IFN- β upregulated mRNA expression of IFN-inducible host restriction factors, APOBEC3G and Tetherin. However, SAMHD1 expression was upregulated at the mRNA level and the IFNs had no effect on protein expression. Knockdown of SAMHD1 in HC enhanced HIV-1 replication. Interestingly, the antiviral activity of type 1 IFNs was SAMHD1-indepenent. Conclusions: The presence of type 1 IFNs at the feto-maternal interface may offset MTCT of HIV-1 through up-regulation of antiviral ISGs and interferon-inducible restriction factors with SAMHD1 having a significant role in antiviral defense. Identifying these mechanisms will provide groundbreaking information on protective correlates during repeated HIV-1 exposure and may contribute to the development of effective immunotherapies and vaccines. 899 Immune Activation During Pregnancy and Postpartum Period in Treated HIV+ Ugandans Peter W. Hunt 1 ; Helen Byakwaga 2 ;Yap Boum 2 ; LynnT. Matthews 3 ;Tricia H. Burdo 4 ;Yong Huang 1 ; Annet Kembabazi 2 ; Angela Kaida 5 ; David R. Bangsberg 3 ; Jeffrey Martin 1 1 University of California San Francisco, San Francisco, CA, US; 2 Mbarara University of Science and Technology, Mbarara, Uganda; 3 Massachusetts General Hospital, Harvard Medical School, Boston, MA, US; 4 Boston College, Boston, MA, US; 5 Simon Fraser University, Vancouver, Canada Background: We previously observed increased maternal mortality in the postpartum period (mostly from opportunistic infections) in HIV-infected women starting ART at low CD4+ T cell counts. We sought to understand whether pregnancy-related immunologic changes might explain these findings. Methods: We sampled HIV-infected Ugandan women starting their first ART regimen from the UARTO cohort who had live births during observation and assessed plasma markers of immune activation at 3-month intervals before, during, and in the year after pregnancy, excluding those with plasma HIV RNA levels >400 copies/ml after month 6 of ART. Pregnancy-related changes in activity of the immunoregulatory enzyme indoleamine 2,3-dioxygenase-1 (IDO, KT ratio), monocyte activation (sCD14 and sCD163), inflammation (IL-6), and coagulation (D-dimer) were assessed with linear mixed models adjusted for ART duration. Results: Among 54 women, median pre-ART values were: age, 29 years; CD4 count, 134 cells/mm 3 ; plasma HIV RNA level, 5.0 log 10 copies/ml; and 16/54 (30%) were pregnant at ART initiation. Pregnancies began at a median of 11 (IQR: -3 to 24) months after ART initiation and 7 women contributed >1 pregnancy to the analysis. During the 1st trimester of pregnancy, there was a consistent significant decline in IDO activity, monocyte activation, and IL-6 levels. In the 3 rd trimester, IDO activity increased to pre-pregnancy levels while sCD14 levels remained low. In the early postpartum period, IDO activity increased 35% and remained significantly higher than pre-pregnancy baseline for 6-9 months postpartum, while other markers of monocyte activation and inflammation remained low. The coagulation marker D-dimer increased throughout pregnancy, peaking in the 3 rd trimester, then steadily declined to pre-pregnancy baseline in the postpartum period.

Poster Abstracts

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CROI 2015