ABSTRACT
A major goal of HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bnAbs). Although success has been achieved in initiating bnAb B cell lineages, design of boosting immunogens that select for bnAb B cell receptors with improbable mutations required for bnAb affinity maturation remains difficult. Here, we demonstrate a process for designing boosting immunogens for a V3-glycan bnAb B cell lineage. The immunogens induced affinity-matured antibodies by selecting for functional improbable mutations in bnAb precursor knockin mice. Moreover, we show similar success in prime and boosting with nucleoside-modified mRNA-encoded HIV-1 envelope trimer immunogens, with improved selection by mRNA immunogens of improbable mutations required for bnAb binding to key envelope glycans. These results demonstrate the ability of both protein and mRNA prime-boost immunogens for selection of rare B cell lineage intermediates with neutralizing breadth after bnAb precursor expansion, a key proof of concept and milestone toward development of an HIV-1 vaccine.
Subject(s)
AIDS Vaccines , Antibodies, Neutralizing , B-Lymphocytes , HIV Antibodies , HIV-1 , AIDS Vaccines/immunology , AIDS Vaccines/genetics , Animals , HIV Antibodies/immunology , HIV-1/immunology , HIV-1/genetics , Mice , Antibodies, Neutralizing/immunology , B-Lymphocytes/immunology , Humans , HIV Infections/immunology , HIV Infections/prevention & control , Broadly Neutralizing Antibodies/immunology , Mutation , Vaccine Development , Immunization, Secondary , env Gene Products, Human Immunodeficiency Virus/immunology , env Gene Products, Human Immunodeficiency Virus/geneticsABSTRACT
OBJECTIVE: To compare frontal plane knee mechanics among the operated and nonoperated limbs after total knee arthroplasty (TKA) and a healthy control limb. DESIGN: A cross-sectional analysis with age-matched control group. SETTING: A biomechanics and sports medicine laboratory. PARTICIPANTS: Subjects (n=16; 8 men, 8 women; mean age, 61+/-7 y; height, 1.71+/-0.10 m; weight, 87.5+/-15.1 kg) and age-matched healthy controls (n=16; 8 men, 8 women; mean age, 63+/-7 y; height, 1.7+/-.09 m; weight 72.5+/-13.9 kg). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Peak knee adduction angle, first peak knee adduction moment, and the frontal plane knee angle and moment at loading peak during the stance phase of walking. RESULTS: Peak knee adduction angle (P=.176), and the frontal plane knee angle (P=.116) and moment (P=.260) at loading peak were similar across the operated, nonoperated, and healthy control limbs. The first peak knee adduction moment was higher in the nonoperated limb when compared with the operated limb and with the healthy control (P=.003). First peak knee adduction moment was similar in the operated knee and the healthy control. CONCLUSIONS: The greater first peak knee adduction moment in the nonoperated knee indicates a possible mechanism for the predictable deterioration of this knee after unilateral TKA of the contralateral knee.
