Neural Tube Defects in Pregnancies Among Women With Diagnosed HIV Infection - 15 Jurisdictions, 2013-2017.

In May 2018, a study of birth defects in infants born to women with diagnosed human immunodeficiency virus (HIV) infection in Botswana reported an eightfold increased risk for neural tube defects (NTDs) among births with periconceptional exposure to antiretroviral therapy (ART) that included the integrase inhibitor dolutegravir (DTG) compared with other ART regimens (1). The World Health Organization* (WHO) and the U.S. Department of Health and Human Services† (HHS) promptly issued interim guidance limiting the initiation of DTG during early pregnancy and in women of childbearing age with HIV who desire pregnancy or are sexually active and not using effective contraception. On the basis of additional data, WHO now recommends DTG as a preferred treatment option for all populations, including women of childbearing age and pregnant women. Similarly, the U.S. recommendations currently state that DTG is a preferred antiretroviral drug throughout pregnancy (with provider-patient counseling) and as an alternative antiretroviral drug in women who are trying to conceive.§ Since 1981 and 1994, CDC has supported separate surveillance programs for HIV/acquired immunodeficiency syndrome (AIDS) (2) and birth defects (3) in state health departments. These two surveillance programs can inform public health programs and policy, linkage to care, and research activities. Because birth defects surveillance programs do not collect HIV status, and HIV surveillance programs do not routinely collect data on occurrence of birth defects, the related data have not been used by CDC to characterize birth defects in births to women with HIV. Data from these two programs were linked to estimate overall prevalence of NTDs and prevalence of NTDs in HIV-exposed pregnancies during 2013-2017 for 15 participating jurisdictions. Prevalence of NTDs in pregnancies among women with diagnosed HIV infection was 7.0 per 10,000 live births, similar to that among the general population in these 15 jurisdictions, and the U.S. estimate based on data from 24 states. Successful linking of data from birth defects and HIV/AIDS surveillance programs for pregnancies among women with diagnosed HIV infection suggests that similar data linkages might be used to characterize possible associations between maternal diseases or maternal use of medications, such as integrase strand transfer inhibitors used to manage HIV, and pregnancy outcomes. Although no difference in NTD prevalence in HIV-exposed pregnancies was found, data on the use of integrase strand transfer inhibitors in pregnancy are needed to understand the safety and risks of these drugs during pregnancy.

Impaired IL-4 phosphorylation of STAT6 in EBV transformed B-cells.

BACKGROUND: The Interleukin-4 signal transducer and activator of transcription 6 (IL-4-STAT6) signaling pathway plays a pivotal role in regulation of gene transcription. We have previously identified a defective STAT6 activational phenotype in response to IL-4 in patients from our familial Inflammatory Bowel Disease registry. This has been termed Stat6(null) and Stat6(high) is the normal phenotype. The purpose of this study was to investigate the defect in Stat6 activation in Stat6(null) cells. METHODS: Stat6(null) and Stat6(high) Epstein Barr virus transformed cell lines were stimulated with 10 ng/mL of IL-4 for 0, 10, 30, or 60 min and cytoplasmic and nuclear proteins harvested. Western blot for STAT6, phosphorylated STAT6 (pSTAT6), Janus Kinase (Jak)1 and Jak3 was performed. Cells were also cultured for 48 h and interferon gamma (IFNgamma) measured in the supernatant. Additional cells were cultured with 20 ng/mL of IFNgamma for 90 min or 5 ug of antibody to IFNgamma for 48 h, and then stimulated with IL-4. RESULTS: There were no differences in cytoplasmic STAT6 in Stat6(null)versus Stat6(high) cells. In Stat6(high) cells, STAT6 was rapidly phosphorylated and translocated to the nucleus. In Stat6(null) cells there was minimal phosphorylation and translocation of pSTAT6 to the nucleus. Spontaneous secretion of IFNgamma by Stat6(null) cells was significantly higher than Stat6(null) cells. Addition of IFNgamma decreased pSTAT6 in Stat6(high) cells to Stat6(null) levels while blocking IFNgamma increased baseline pSTAT6 in Stat6(null) cells to levels similar to Stat6(high) cells. CONCLUSION: This suggests that the spontaneously produced IFNgamma in the Stat6(null) cell lines suppresses STAT6 function and creates the Stat6(null) phenotype.

Hepatitis B virus reverse transcriptase and epsilon RNA sequences required for specific interaction in vitro.

Initiation of reverse transcription and nucleocapsid assembly in hepatitis B virus (HBV) depends on the specific recognition of an RNA signal (the packaging signal, epsilon) on the pregenomic RNA by the viral reverse transcriptase (RT). Using an in vitro reconstitution system whereby the cellular heat shock protein 90 chaperone system activates recombinant HBV RT for specific epsilon binding, we have defined the protein and RNA sequences required for specific HBV RT-epsilon interaction in vitro. Our results indicated that approximately 150 amino acid residues from the terminal protein domain and 230 from the RT domain were necessary and sufficient for epsilon binding. With respect to the epsilon RNA sequence, its internal bulge and, in particular, the first nucleotide (C) of the bulge were specifically required for RT binding. Sequences from the upper portion of the lower stem and the lower portion of the upper stem also contributed to RT binding, as did the base pairing of the upper portion and the single unpaired U residue of the upper stem. Surprisingly, the apical loop of epsilon, known to be required for RNA packaging, was entirely dispensable for RT binding. A comparison of the requirements for in vitro RT-epsilon interaction with those for in vivo pregenomic RNA (pgRNA) packaging clearly indicated that RT-epsilon interaction was necessary but not sufficient for pgRNA packaging. In addition, our results suggest that recognition of some epsilon sequences by the RT may be required specifically for viral DNA synthesis.