The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) complex comprises three gp120 exterior glycoproteins each noncovalently linked to a gp41 transmembrane glycoprotein. Monomeric gp120 proteins can elicit antibodies capable of neutralizing atypically sensitive test viruses in vitro, but these antibodies are ineffective against representative primary isolates and the gp120 vaccines failed to provide protection against HIV-1 transmission in vivo. Alternative approaches to raising neutralizing antibodies are therefore being pursued. Here we report on the antibody responses generated in rabbits against a soluble, cleaved, trimeric form of HIV-1 JR-FL Env. In this construct, the gp120 and gp41 moieties are covalently linked by an intermolecular disulfide bond (SOS gp140), and an I559P substitution has been added to stabilize gp41-gp41 interactions (SOSIP gp140). We investigated the value of DNA priming and compared the use of membrane-bound and soluble priming antigens and of repeat boosting with soluble and particulate protein antigen. Compared to monomeric gp120, SOSIP gp140 trimers elicited approximately threefold lower titers of anti-gp120 antibodies. Priming with DNA encoding a membrane-bound form of the SOS gp140 protein, followed by several immunizations with soluble SOSIP gp140 trimers, resulted in antibodies capable of neutralizing sensitive strains at high titers. A subset of these sera also neutralized, at lower titers, HIV-1 JR-FL and some other primary isolates in pseudovirus and/or whole-virus assays. Neutralization of these viruses was immunoglobulin mediated and was predominantly caused by antibodies to gp120 epitopes, but not the V3 region.

We have studied IgG subclass responses to the HIV-1 proteins gp120, gp41, p24, and Tat in individuals who control their infection without using antiretroviral drugs (HIV-1 controllers; HC) or who progress to disease (chronic progressors; CP). We also measured IgG subclass titers to gp120 in vaccinated individuals. In all cases, the IgG1 subclass dominated the overall response to each antigen. The only IgG titer that differed significantly between the HC and CP groups was to the p24 Gag protein, which was higher in the HC group. IgG1 titers to both p24 and gp120 were significantly higher in the HC group, and IgG3 anti-gp120 antibodies, although rare, were detected more frequently in that group than in CP. Overall, significantly more patients had IgG2 antibodies to gp120 than to gp41. Antibodies to other IgG subclasses were infrequent and their frequency or titers did not differ between the two patient groups. Anti-gp41 and anti-Tat responses also did not correlate with immune control, and anti-Tat antibodies were infrequently detected. Although we found isotypic differences in IgG responses to HIV-1 antigens among vaccinees and the HC and CP individuals, there were no indications of differential T(H)1:T(H)2 polarization between the different groups.

According to recent theories, perception relies on summary representations that encode statistical information about the sensory environment. Here, we used perceptual priming to characterize the representations that mediate categorization of a complex visual array. Observers judged the average shape or color of a target visual array that was preceded by an irrelevant prime array. Manipulating the variability of task-relevant and task-irrelevant feature information in the prime and target orthogonally, we found that observers were faster to respond when the variability of feature information in the prime and target arrays matched. Critically, this effect occurred irrespective of whether the element-by-element features in the prime and target array overlapped or not, and was even present when prime and target features were drawn from opposing categories. This "priming by variance" phenomenon occurred with prime-target intervals as short as 100 ms. Further experiments showed that this effect did not depend on resource allocation, and occurred even when prime and target did not share the same spatial location. These results suggest that human observers adapt to the variability of visual information, and provide evidence for the existence of a low-level mechanism by which the range or dispersion of visual information is rapidly extracted. This information may in turn help to set the gain of neuronal processing during perceptual choice.decision making | cognitive control W hat information do sensory systems represent, and how do their computations allow us to make judgments about the external world? Canonical theories in perception and cognition suggest that visual neurons code exhaustively for the features or objects that populate natural scenes, from primitive colors and shapes to complex high-dimensional items, such as faces (1, 2). However, any theory of visual representation must account for two striking findings. First, visual judgments can be remarkably blind to local detail: for example, when observers fail to notice the removal of an object from a cluttered natural image, at least when it is outside of the focus of attention (3, 4). Second, both humans and monkeys are extremely good at extracting high-level information (e.g., the presence of an animal or a navigable path) from a scene in a single, rapid glance, despite the almost endless variability in natural images (5-10). One alternative theory that can account for both of these findings argues that the visual system rapidly computes "summary" statistical information about a scene (e.g., the average size of all of the round objects) as opposed to specific features (e.g., the presence of a large round object) (11-13). Encoding summary statistics might offer a crude but efficient representation of the visual world (14) that would facilitate rapid, accurate decisions that are critical for survival (e.g., whether to flee in the face of impending predation, and which route to take), but at the cost of discarding visual detail outside of the focus of attention. ...

Endoproteolytic processing of the human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoproteins is an obligate part of the biosynthetic pathway that generates functional, fusion-competent Env complexes, which are then incorporated into infectious virions. We have examined the influence of cleavage on Env-specific antibody reactivity, Env incorporation into pseudovirions, and the infectivity and neutralization sensitivity of Env-pseudotyped viruses. To do so, we have used both incompletely processed wild-type (Wt) Env and engineered, cleavage-defective Env mutants. We find that there is no simple association between antibody reactivity to cell surface-expressed Env, and the ability of the same antibody to neutralize virus pseudotyped with the same Env proteins. One explanation for the absence of such an association is the diverse array of Env species present on the surface of transiently transfected cells. We also confirm that cleavage-defective mutants are antigenically different from Wt Env. These findings have implications for the use of Env binding assays as predictors of neutralizing activity, and for the development of cleavage-defective Env trimers for use as subunit immunogens.

The Env glycoproteins gp120 and gp41 are used in humoral immunity-based vaccines against human immunodeficiency virus (HIV-1) infection. One among many obstacles to such a vaccine is the structural defenses of Env glycoproteins that limit their immunogenicity. For example, gp120 mannose residues can induce immunosuppressive responses in vitro, including IL-10 expression, via mannose C-type lectin receptors on antigen-presenting cells. Here, we have investigated whether mannose removal alters gp120 immunogenicity in mice. Administering demannosylated gp120 (D-gp120) in the TH2-skewing adjuvant Alum induced ~50-fold higher titers of anti-gp120 IgG, compared to unmodified gp120. While the IgG subclass profile was predominantly TH2-associated IgG1, Abs of the TH1-associated IgG2a and IgG3 subclasses were also detectable in D-gp120 recipients. Immunizing with D-gp120 also improved T-cell responses. Giving an IL-10 receptor blocking MAb together with unmodified gp120 in Alum increased the anti-gp120 IgG titer, implicating IL-10 as a possible mediator of auto-suppressive responses to gp120.