Dataset Information

Structural insights into key sites of vulnerability on HIV-1 Env and influenza HA.

ABSTRACT: Human immunodeficiency virus-1 (HIV-1) envelope protein (Env) and influenza hemagglutinin (HA) are the surface glycoproteins responsible for viral entry into host cells, the first step in the virus life cycle necessary to initiate infection. These glycoproteins exhibit a high degree of sequence variability and glycosylation, which are used as strategies to escape host immune responses. Nonetheless, antibodies with broadly neutralizing activity against these viruses have been isolated that have managed to overcome these barriers. Here, we review recent advances in the structural characterization of these antibodies with their viral antigens that defines a few sites of vulnerability on these viral spikes. These broadly neutralizing antibodies tend to focus their recognition on the sites of similar function between the two viruses: the receptor-binding site and membrane fusion machinery. However, some sites of recognition are unique to the virus neutralized, such as the dense shield of oligomannose carbohydrates on HIV-1 Env. These observations are discussed in the context of structure-based design strategies to aid in vaccine design or development of antivirals.

SUBMITTER: Julien JP

PROVIDER: S-EPMC3479221 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structural insights into key sites of vulnerability on HIV-1 Env and influenza HA.

Julien Jean-Philippe JP Lee Peter S PS Wilson Ian A IA

Immunological reviews 20121101 1

Human immunodeficiency virus-1 (HIV-1) envelope protein (Env) and influenza hemagglutinin (HA) are the surface glycoproteins responsible for viral entry into host cells, the first step in the virus life cycle necessary to initiate infection. These glycoproteins exhibit a high degree of sequence variability and glycosylation, which are used as strategies to escape host immune responses. Nonetheless, antibodies with broadly neutralizing activity against these viruses have been isolated that have m ...[more]

PMID: 23046130

Similar Datasets

Project description:INTRODUCTION:HIV prevention strategies often include outreach to female sex workers at social venues identified as places where people meet new sexual partners. Patrons and staff at these venues may include female sex workers, their clients, as well as others who have high rates of new sexual partnerships. Few studies have compared HIV/STI among venue-based and general populations, across types of venues, or by sub-group of the venue population. Program planners often assume that the prevalence of infection is highest among female sex workers and considerably lower among other people at these venues, but there are few empiric studies assessing the prevalence of infection by sex worker status and type of venue. METHODS:In 2011, we used the PLACE method to identify public venues where people meet new sexual partners across Jamaica. The study team visited all venues with reported sex work as well as a 10% random sample of other venues and subsequently interviewed and tested a probability sample of 991 venue patrons and workers for HIV and other STI. RESULTS:Community informants identified 1207 venues. All venues where sex work was reported (735 venues) and a random sample of the remainder (134 of 472) were selected for onsite visits. Of these, 585 were found and operational. At a stratified random sample of venues, survey teams interviewed and tested 717 women and 274 men. 394 women reported recent sex work and 211 of these women reported soliciting clients on the street. Women exchanging sex for money were more likely to be infected with HIV (5.4% vs 1.0%; OR = 5.6, 95% CI = 1.8,17.3) or syphilis (11.7% vs. 5.8%, OR = 2.2, 95% CI = 1.7,4,0) than other women, but not significantly more likely to be infected with gonorrhea (8.4% vs 7.8%; OR = 1.1,95% CI = 0.6,1.9), chlamydia (16.2% vs 21.6%;OR = 0.7,95% CI = 0.5,1.0) or trichomoniasis (23.0% vs 17.0%, OR = 1.5,95% CI = 0.9,2.2). Women at venues were more likely to report sex work and multiple partners than women interviewed in a 2008 national population-based household survey commissioned by the Ministry of Health. CONCLUSIONS:In Jamaica, although the highest HIV prevalence was among street-based sex workers, the risk of HIV and STI extends to men and women at high risk venues, even those who do not self-identify as sex workers. Findings confirm the appropriateness of outreach to all men and women at these venues.

Project description:UNLABELLED:The HIV-1 Vif protein inactivates the cellular antiviral cytidine deaminase APOBEC3F (A3F) in virus-infected cells by specifically targeting it for proteasomal degradation. Several studies identified Vif sequence motifs involved in A3F interaction, whereas a Vif-binding A3F interface was proposed based on our analysis of highly similar APOBEC3C (A3C). However, the structural mechanism of specific Vif-A3F recognition is still poorly understood. Here we report structural features of interaction interfaces for both HIV-1 Vif and A3F molecules. Alanine-scanning analysis of Vif revealed that six residues located within the conserved Vif F1-, F2-, and F3-box motifs are essential for both A3C and A3F degradation, and an additional four residues are uniquely required for A3F degradation. Modeling of the Vif structure on an HIV-1 Vif crystal structure revealed that three discontinuous flexible loops of Vif F1-, F2-, and F3-box motifs sterically cluster to form a flexible A3F interaction interface, which represents hydrophobic and positively charged surfaces. We found that the basic Vif interface patch (R17, E171, and R173) involved in the interactions with A3C and A3F differs. Furthermore, our crystal structure determination and extensive mutational analysis of the A3F C-terminal domain demonstrated that the A3F interface includes a unique acidic stretch (L291, A292, R293, and E324) crucial for Vif interaction, suggesting additional electrostatic complementarity to the Vif interface compared with the A3C interface. Taken together, these findings provide structural insights into the A3F-Vif interaction mechanism, which will provide an important basis for development of novel anti-HIV-1 drugs using cellular cytidine deaminases. IMPORTANCE:HIV-1 Vif targets cellular antiviral APOBEC3F (A3F) enzyme for degradation. However, the details on the structural mechanism for specific A3F recognition remain unclear. This study reports structural features of interaction interfaces for both HIV-1 Vif and A3F molecules. Three discontinuous sequence motifs of Vif, F1, F2, and F3 boxes, assemble to form an A3F interaction interface. In addition, we determined a crystal structure of the wild-type A3F C-terminal domain responsible for the Vif interaction. These results demonstrated that both electrostatic and hydrophobic interactions are the key force driving Vif-A3F binding and that the Vif-A3F interfaces are larger than the Vif-A3C interfaces. These findings will allow us to determine the configurations of the Vif-A3F complex and to construct a structural model of the complex, which will provide an important basis for inhibitor development.

Dataset Information

Structural insights into key sites of vulnerability on HIV-1 Env and influenza HA.

Publications

Structural insights into key sites of vulnerability on HIV-1 Env and influenza HA.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure