CROI 2016 Abstract eBook

Abstract Listing

Poster Abstracts

Conclusions: Expanding ART for prevention of MTCT is not expected to also improve excess mortality among HEU infants. New strategies are urgently needed to mitigate mortality among this large vulnerable group.

806 Recombination Elevates HIV-1 Evolution Following Mother-to-Child Transmission Mohan Somasundaran 1 ; Keri Sanborn 1 ; Katherine Luzuriaga 1 ;Thomas Leitner 2 1 Univ of Massachusetts Med Sch, Worcester, MA, USA; 2 Los Alamos Natl Lab, Los Alamos, NM, USA

Background: Available data suggest that single HIV-1 variants are transmitted through mother-to-child transmission (MTCT); such analyses have often used samples from a single time point, which may detect only the most replication competent variant at that time point, even when other forms may have been transmitted. Such forms may have a replication advantage later in infection, and may thus be detected in follow-up samples. Because HIV-1 frequently recombines, however, phylogenetic analyses that ignore recombination may miss transmission of multiple forms if they recombine after transmission. The effect of recombination on viral evolution in HIV-1-infected children has not been well defined and warrants analysis of longitudinal samples. Methods: We analyzed full-length env sequences after single genome amplification from the plasma of 4 subtype B HIV-1 infected women (11—67 env clones from 1 time point within a month prior to delivery) and their non-breastfed intrapartum infected children (3-6 longitudinal time points per child starting at the time of HIV-1 diagnosis). To address the potential effects of recombination, we used a recently developed hierarchical recombination detection method based on the pairwise homoplasy index (PHI)-test. Results: Recombination was widespread, occurring in 9—67% of the maternal sequences and in 25—60% of the child sequences. In the child, recombination only occurred between variants that had evolved after transmission; there was no evidence for the recombination of multiple transmitted forms, even in one case where 2 maternal HIV-1 forms were transmitted. We also found evidence for changing effective evolutionary rates of HIV-1 following MTCT, with the highest rates measured in the early years following transmission. Recombination generally inflated the early evolutionary rates, suggesting that it may facilitate adaptation following transmission. Conclusions: Following a transmission bottleneck, the establishment of HIV-1 infection in newborns involves evolutionary dynamics with abundant recombination that elevates the early effective evolutionary rates. Early evolutionary effects of recombination and other selective pressures may facilitate adaptation. 807 Infant CD4+ T Cells Have a Distinct Immunophenotype by Single Cell Analysis Pamela Lincez ; Fan Li; Kyle J. Nakamura; David Lee; Nicole H.Tobin; Grace M. Aldrovandi Children’s Hosp of Los Angeles, Los Angeles, CA, USA Background: The establishment and persistence of HIV reservoirs in memory CD4+ T cell subsets (central memory (T CM ), transitional memory (T TM ), effector memory (T EM ) and ) limits the effectiveness of antiretroviral therapy (ART) and the potential for an HIV cure. Compared to adults, infants harbor a greater number of circulating CD4+ T cells with a markedly different T-cell subset distribution. Discrepancies in T-cell activation, differentiation propensity and HIV permissibility have also been described for infant cells. Determining the relative proportion of memory T cell subsets and their transcriptional activity at the single cell level may help uncover potential mechanisms driving HIV pathogenesis. Methods: Memory and naive CD4+ T-cell subsets (T CM , T TM , T EM , T SCM and T N ) were isolated from single cell suspensions of unstimulated, HIV-unexposed cord blood mononuclear cells (CBMCs) and peripheral blood mononuclear cells (PBMCs), stained with classical activation markers and sorted by flow cytometry. Differential gene expression was compared stem cell memory (T SCM )) and to a lesser extent in naïve T-cells (T N Principal component analysis showed the segregation of T N from CBMC versus those from PBMC. 302 genes were differentially expressed (using ‘monocle’ software package (v1.2.0, R version 3.2.1, p-value cutoff of 0.1), including several genes involved in T cell activation and characteristic of fetal CD4+ T cells (RGS1, CD69, TNFAIP3, JUND, KLF6). Notably, changes in genes that influence the propensity of CD4+ T cells to differentiate into Th17 or regulatory T cells (IL-23R, RGS1, TNFAIP3) and genes that influence HIV pathogenesis (IL-32, PLCG1) were observed. Conclusions: Infant immune cells have a distinct immunophenotype at the transcriptome and cellular level. Understanding the transcriptional and immune mechanisms that support the seeding and proliferation of infected cell types in which viral reservoirs reside, may help determine potential targets and provide insight into both an infant and adult HIV cure. 808 Duration of Tenofovir Exposure in Utero and Linear Growth in the First Year of Life Stanzi M. le Roux 1 ; Jennifer Jao 2 ; Kirsty Brittain 3 ;Tamsin Phillips 3 ; Agnes Ronan 3 ; Olawaseun A. Olatunbosun 3 ; Allison Zerbe 4 ; Elaine J. Abrams 5 ; Landon Myer 3 1 Sch of PH & Family Med, Univ of Cape Town, Cape Town, South Africa; 2 Icahn Sch of Med at Mount Sinai, New York, NY, USA; 3 Univ of Cape Town, Cape Town, South Africa; 4 ICAP at Columbia Univ, New York, NY, USA; 5 ICAP, Columbia Univ Mailman Sch of PH, New York, NY, USA Background: Tenofovir disoproxil fumarate (TDF) is widely used as part of first-line antiretroviral therapy (ART) in pregnancy globally, but there are concerns that TDF may impair bone growth in children. Data on the effect of TDF exposure in utero on growth are mixed, with few insights from sub-Saharan Africa. We examined the association between duration of TDF exposure in utero and linear growth in HIV-exposed infants. Methods: We recruited pregnant women initiating TDF (+emtricitabine +efavirenz) at primary care services in Cape Town, South Africa and followed breastfeeding mother- infant pairs through 12 months postpartum. Timing of antenatal ART initiation and birth length were abstracted from clinical records. Infant length was measured at 6, 12, 24, 36 and 48 weeks (wks) of age with a recumbent stadiometer. Analyses used length-for-age z-scores (LAZ) based on Intergrowth-21 and World Health Organization reference on flow cytometry sorted naïve CD4+ CD45RA+ CCR7+ CD27+ T cells from CBMCs and PBMCs using single cell RNA sequencing. Results: The distribution of CD4+ T-cell subsets from CBMCs compared to PBMCs was consistent with previous observations, where T N dominate CD4+ T cells in CBMCs (T N, 90%, T CM , 1.1%) but are decreased (T N, 40%, T CM , 22%) in PBMCs. At the single cell level, RNA sequencing on T N from CBMCs and PBMCs revealed distinct transcriptional phenotypes.

Poster Abstracts

337

CROI 2016