The Activity of Breast Milk and Monoclonal HIV-specific Antibodies in Mother-to-Child Transmission

Mother-to-child transmission of HIV is a unique setting that allows us to explore both the correlates of protective immunity and the characteristics of transmitted variants. This thesis first describes the levels and functional capacity of breast milk HIV-specific antibodies in 19 women with high plasma viral loads. Neutralizing antibodies (Nabs) were detected in breast milk supernatant (BMS) of 4 of 19 women examined, were of low potency and were not associated with infant infection. The low NAb activity in BMS was reflected in binding antibody levels with HIV envelope specific IgG titers being 2.2 log10 lower in BMS versus plasma. In contrast, non- neutralizing antibodies (nNAbs) capable of antibody dependent cell-mediated cytotoxicity (ADCC) were detected in the BMS from all 19 women. BMS ADCC activity was associated with envelope-specific IgG titers (p = 0.014) and was inversely associated with infant infection risk (p = 0.039). Our data indicate that BMS has limited HIV neutralizing activity, however, BMS ADCC activity is a correlate of transmission that may impact infant infection risk. In the second part of this thesis the neutralization sensitivity of 111 variants of diverse subtypes obtained from mothers and infants was determined against 7 HIVspecific broadly neutralizing monoclonal antibodies (mAbs) (NIH45-46w, VRC01, PGT128, PGT121, PG9 PGT145 and b12). Maternal and infant variants did not differ in their neutralization sensitivity to these mAbs and neither did variants from transmitting versus those from non-transmitting women. However, subtype A viruses were iii significantly more sensitive to neutralization by NIH45-46w and VRC01 (p= 0.0001 in both cases) and PGT145 (p=0.03) compared to non-subtype A viruses. Together, NIH45- 46w and PGT128 neutralization profiles resulted in 100% coverage of the variants tested. These data suggest that the epitopes targeted by these mAbs are present and accessible in both circulating and transmitted variants and that a combination of antibodies would provide maximum coverage against diverse subtypes commonly found in HIV endemic regions. Overall, this data suggest that an antibody based HIV vaccine capable of eliciting antibodies of multiple specificities that can mediate ADCC and/or neutralizing activity can provide protection and conquer the genetic diversity displayed by HIV.

A Rare Complication of Tracheal Intubation: Tongue Perforation

Aim. To describe the subsequent treatment of airway trauma sustained during laryngoscopy and endotracheal intubation. Methods. A rare injury occurring during laryngoscopy and endotracheal intubation that resulted in perforation of the tongue by an endotracheal tube and the subsequent management of this unusual complication are discussed. A 65-year-old female with intraparenchymal brain hemorrhage with rapidly progressive neurologic deterioration had the airway secured prior to arrival at the referral institution. The endotracheal tube (ETT) was noted to have pierced through the base of the tongue and entered the trachea, and the patient underwent operative laryngoscopy to inspect the injury and the ETT was replaced by tracheostomy. Results. Laryngoscopy demonstrated the ETT to perforate the base of the tongue. The airway was secured with tracheostomy and the ETT was removed. Conclusions. A wide variety of complications resulting from direct and video-assisted laryngoscopy and tracheal intubation have been reported. Direct perforation of the tongue with an ETT and ability to ventilate and oxygenate subsequently is a rare injury.

Workforce Patterns and the Prevention of Mother-to-Child Transmission of HIV Option B Cascade in Côte d'Ivoire

Thesis (Master's)--University of Washington, 2016-08