Structural perspectives of antibody-dependent enhancement of infection of dengue virus.

Dengue virus (DENV) consists of four serotypes. Sequential serotype infections can cause increased disease severity, likely due to antibody-dependent enhancement (ADE) of infection. Here, we review two recent papers showing major advancements in the understanding of the ADE mechanism for both mature and immature DENV. The surface of both mature and immature DENV contains E and another protein - M in mature and prM in immature virus. On mature DENV, the orientation of anti-E antibody with respect to the virus surface determines the antibody enhancement properties. On the immature virus, binding of anti-prM antibody aids the dissociation of pr from the fusion loop of E protein allowing virus-endosomal membrane interaction, thus overcoming the hurdle in the early step of fusion.

Orthobunyavirus spike architecture and recognition by neutralizing antibodies.

Orthobunyaviruses (OBVs) form a distinct genus of arthropod-borne bunyaviruses that can cause severe disease upon zoonotic transmission to humans. Antigenic drift or genome segment re-assortment have in the past resulted in new pathogenic OBVs, making them potential candidates for causing emerging zoonoses in the future. Low-resolution electron cryo-tomography studies have shown that OBV particles feature prominent trimeric spikes, but their molecular organization remained unknown. Here we report X-ray crystallography studies of four different OBVs showing that the spikes are formed by an N-terminal extension of the fusion glycoprotein Gc. Using Schmallenberg virus, a recently emerged OBV, we also show that the projecting spike is the major target of the neutralizing antibody response, and provide X-ray structures in complex with two protecting antibodies. We further show that immunization of mice with the spike domains elicits virtually sterilizing immunity, providing fundamental knowledge essential in the preparation for potential newly emerging OBV zoonoses.

The low spike density of HIV may have evolved because of the effects of T helper cell depletion on affinity maturation.

The spikes on virus surfaces bind receptors on host cells to propagate infection. High spike densities (SDs) can promote infection, but spikes are also targets of antibody-mediated immune responses. Thus, diverse evolutionary pressures can influence virus SDs. HIV's SD is about two orders of magnitude lower than that of other viruses, a surprising feature of unknown origin. By modeling antibody evolution through affinity maturation, we find that an intermediate SD maximizes the affinity of generated antibodies. We argue that this leads most viruses to evolve high SDs. T helper cells, which are depleted during early HIV infection, play a key role in antibody evolution. We find that T helper cell depletion results in high affinity antibodies when SD is high, but not if SD is low. This special feature of HIV infection may have led to the evolution of a low SD to avoid potent immune responses early in infection.