Structural Characterizations of the Dimeric Anti-HIV Antibody 2G12 and the HIV-2 Envelope Glycoprotein

More than thirty years after the discovery that Human Immunodeficiency Virus (HIV) was the causative agent of Acquired Immunodeficiency Syndrome (AIDS), the disease remains pandemic as long as no effective universal vaccine is found. Over 34 million individuals in the world are infected with the virus, and the vast majority of them have no access to the antiretroviral therapies that have largely reduced HIV to a chronic disease in the developed world. The first chapter of this thesis introduces the history of the virus. The key to the infectious mechanism of the virus lies in its envelope glycoprotein (Env), a trimeric spike on the viral surface that utilizes host T cell receptors for entry. Though HIV-1 Env is immunogenic, most infected patients do not mount an effective neutralizing antibody response against it. Broadly-neutralizing anti-Env antibodies (bNAbs) present in the serum of a minority of infected individuals are usually sufficient to prevent the progression to full blown AIDS. Thus, the molecular details of these bNAbs as well as the antibody-antigen interface are of prime interest for structural studies, as insight gained would contribute to the design of a more effective immunogen and potential vaccine candidate. The second chapter of this thesis describes the low-resolution crystal structure of one such antibody, 2G12 dimer, which targets a high mannose epitope on the surface of Env. Patients infected with HIV-2, a related virus with ~35% sequence identity in the Env region, can generally mount a robust antibody response sufficient for viral control for reasons still unknown. The final two chapters of this thesis focus on the first reported structural studies of HIV-2 Env, the molecular details of which may inform HIV-1 therapy and immunogen design.

The conjugate representation of signal envelope

The problem of the representation of signal envelope is treated, motivated by the classical Hilbert representation in which the envelope is represented in terms of the received signal and its Hilbert transform. It is shown that the Hilbert representation is the proper one if the received signal is strictly bandlimited but that some other filter is more appropriate in the bandunlimited case. A specific alternative filter, the conjugate filter, is proposed and the overall envelope estimation error is evaluated to show that for a specific received signal power spectral density the proposed filter yields a lower envelope error than the Hilbert filter.

Observation and interpretation of tectonic strain release mechanisms

In four chapters various aspects of earthquake source are studied.

Chapter I

Surface displacements that followed the Parkfield, 1966, earthquakes were measured for two years with six small-scale geodetic networks straddling the fault trace. The logarithmic rate and the periodic nature of the creep displacement recorded on a strain meter made it possible to predict creep episodes on the San Andreas fault. Some individual earthquakes were related directly to surface displacement, while in general, slow creep and aftershock activity were found to occur independently. The Parkfield earthquake is interpreted as a buried dislocation.

Chapter II

The source parameters of earthquakes between magnitude 1 and 6 were studied using field observations, fault plane solutions, and surface wave and S-wave spectral analysis. The seismic moment, M_O, was found to be related to local magnitude, M_L, by log M_O = 1.7 M_L + 15.1. The source length vs magnitude relation for the San Andreas system found to be: M_L = 1.9 log L - 6.7. The surface wave envelope parameter AR gives the moment according to log M_O = log AR₃₀₀ + 30.1, and the stress drop, τ, was found to be related to the magnitude by τ = 0.54 M - 2.58. The relation between surface wave magnitude M_S and M_L is proposed to be M_S = 1.7 M_L - 4.1. It is proposed to estimate the relative stress level (and possibly the strength) of a source-region by the amplitude ratio of high-frequency to low-frequency waves. An apparent stress map for Southern California is presented.

Chapter III

Seismic triggering and seismic shaking are proposed as two closely related mechanisms of strain release which explain observations of the character of the P wave generated by the Alaskan earthquake of 1964, and distant fault slippage observed after the Borrego Mountain, California earthquake of 1968. The Alaska, 1964, earthquake is shown to be adequately described as a series of individual rupture events. The first of these events had a body wave magnitude of 6.6 and is considered to have initiated or triggered the whole sequence. The propagation velocity of the disturbance is estimated to be 3.5 km/sec. On the basis of circumstantial evidence it is proposed that the Borrego Mountain, 1968, earthquake caused release of tectonic strain along three active faults at distances of 45 to 75 km from the epicenter. It is suggested that this mechanism of strain release is best described as "seismic shaking."

Chapter IV

The changes of apparent stress with depth are studied in the South American deep seismic zone. For shallow earthquakes the apparent stress is 20 bars on the average, the same as for earthquakes in the Aleutians and on Oceanic Ridges. At depths between 50 and 150 km the apparent stresses are relatively high, approximately 380 bars, and around 600 km depth they are again near 20 bars. The seismic efficiency is estimated to be 0.1. This suggests that the true stress is obtained by multiplying the apparent stress by ten. The variation of apparent stress with depth is explained in terms of the hypothesis of ocean floor consumption.