Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions

Active host-pathogen interactions take place during infection of human immunodeficiency virus type 1 （HIV-1）. Outcomes of these interactions determine the efficiency of viral infection and subsequent disease progression. HIV-infected cells respond to viral invasion with various defensive strategies such as innate, cellular and humoral immune antiviral mechanisms. On the other hand, the virus has also developed various offensive tactics to suppress these host cellular responses. Among many of the viral offensive strategies, HIV-1 viral auxiliary proteins （Tat, Rev, Nef, Vif, Vpr and Vpu） play important roles in the host-pathogen interaction and thus have significant impacts on the outcome of HIV infection. One of the best examples is the interaction of Vif with a host cytidine deaminase APOBEC3G. Although specific roles of other auxiliary proteins are not as well described as Vif-APOBEC3G interaction, it is the goal of this brief review to summarize some of the preliminary findings with the hope to stimulate further discussion and investigation in this exhilarating area of research.     

Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions

INTRODUCTION In addition to the prototypical retroviral Gag, Pol, and Env proteins, HIV-1 produces six additional proteins, i.e., Tat, Rev, Nef, Vif, Vpr and Vpu (Fig. 1, adapted from [1]). While Tat and Rev are required for viral replication, Nef, Vif, V…     

Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions

Active host-pathogen interactions take place during infection of human immunodeficiency virus type 1 (HIV-1).Outcomes of these interactions determine the efficiency of viral infection and subsequent disease progression. HIV-infected cells respond to viral invasion with various defensive strategies such as innate, cellular and humoral immune antiviral mechanisms. On the other hand, the virus has also developed various offensive tactics to suppress these host cellular responses. Among many of the viral offensive strategies, HIV- 1 viral auxiliary proteins (Tat, Rev, Nef, Vif, Vpr and Vpu) play important roles in the host-pathogen interaction and thus have significant impacts on the outcome of HIV infection. One of the best examples is the interaction of Vif with a host cytidine deaminase APOBEC3G. Although specific roles of other auxiliary proteins are not as well described as Vif-APOBEC3G interaction, it is the goal of this brief review to summarize some of the preliminary findings with the hope to stimulate further discussion and investigation in this exhilarating area of research.     

Roles of the interactions between Env and Gag proteins in the HIV-1 replication cycle

The Env and Gag proteins of HIV-1 are the two major structural proteins of this retrovirus. The interactions between Env and Gag proteins and their regulation in HIV-1 are required for several steps of the replication cycle, involving not only virus assembly, specifically Env incorporation, but also entry steps after virus maturation. A large number of host factors and certain membrane microdomains appear to engage both in transport/trafficking of Env and/or Gag proteins, and in the interactions of these two proteins. The present review briefly summarizes our current knowledge regarding the roles of the interactions between Env and Gag proteins in the virus replication cycle.     

HIV-1 pathogenesis

Despite considerable advances in HIV science in the past 20 years, the reason why HIV-1 infection is pathogenic is still debated and the goal of eradicating HIV-1 infection remains elusive. A deeper understanding of the interplay between HIV-1 and its host and why simian immunodeficiency virus (SIV) is nonpathogenic in some natural hosts may provide a few answers.     

Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions

The NRAMP family of divalent-metal transporters plays a key role in the homeostasis of iron and other metals. NRAMP2 (DMT1) acts as an iron-uptake protein in both the duodenum and in peripheral tissues. NRAMP1 functions as a divalent-metal efflux pump at the phagosomal membrane of macrophages and neutrophils, and mutations in NRAMP1 cause susceptibility to several intracellular pathogens. NRAMP homologues have been identified in bacteria and are involved in acquiring divalent metals from the extracellular environment. Interestingly, bacterial and mammalian NRAMP proteins would compete for the same essential substrates within the microenvironment of the phagosome, at the interface of host-pathogen interactions.     

Lipidomics of host-pathogen interactions

The cell biology of intracellular pathogens (viruses, bacteria, eukaryotic parasites) has provided us with molecular information of host-pathogen interactions. As a result it is becoming increasingly evident that lipids play important roles at various stages of host-pathogen interactions. They act in first line recognition and host cell signaling during pathogen docking, invasion and intracellular trafficking. Lipid metabolism is a housekeeping function in energy homeostasis and biomembrane synthesis during pathogen replication and persistence. Lipids of enormous chemical diversity play roles as immunomodulatory factors. Thus, novel biochemical analytics in combination with cell and molecular biology are a promising recipe for dissecting the roles of lipids in host-pathogen interactions.     

Candida morphogenesis and host-pathogen interactions

The human fungal pathogen Candida albicans has many morphological forms. Recent advances in genomics and cell biology are providing an improved understanding of the molecular regulation of cell shape, and providing insights into the relationships between morphogenesis and virulence. This understanding may improve our ability to develop strategies to combat Candida infections.     

Deconstructing host-pathogen interactions in Drosophila

Many of the cellular mechanisms underlying host responses to pathogens have been well conserved during evolution. As a result, Drosophila can be used to deconstruct many of the key events in host-pathogen interactions by using a wealth of well-developed molecular and genetic tools. In this review, we aim to emphasize the great leverage provided by the suite of genomic and classical genetic approaches available in flies for decoding details of host-pathogen interactions; these findings can then be applied to studies in higher organisms. We first briefly summarize the general strategies by which Drosophila resists and responds to pathogens. We then focus on how recently developed genome-wide RNA interference (RNAi) screens conducted in cells and flies, combined with classical genetic methods, have provided molecular insight into host-pathogen interactions, covering examples of bacteria, fungi and viruses. Finally, we discuss novel strategies for how flies can be used as a tool to examine how specific isolated virulence factors act on an intact host.     

RNA profiling in host-pathogen interactions

The development of novel anti-bacterial treatment strategies will be aided by an increased understanding of the interactions that take place between bacteria and host cells during infection. Global expression profiling using microarray technologies can help to describe and define the mechanisms required by bacterial pathogens to cause disease and the host responses required to defeat bacterial infection.     

Syndecans and HIV-1 pathogenesis

The exploitation of receptors represents a common microbial strategy to survive in the hostile environment of the host. A growing body of evidence suggests that HIV-1 exploits a specific class of receptors-the syndecans-to facilitate colonization of the host.     

The pursuit of cryptococcal pathogenesis: heterologous hosts and the study of cryptococcal host-pathogen interactions

Analysis of the molecular mechanisms by which a pathogen interacts with the human host is most commonly performed using a mammalian model of infection. However, several virulence-related genes previously shown to be involved in mammalian infection with Cryptococcus neoformans have also been shown to play a role in the interaction of these pathogens with invertebrates, such as Acanthamoeba castellanii, Caenorhabditis elegans, Dictyostelium discoideum, Drosophila melanogaster and Galleria mellonella. The study of host-pathogen interactions using these model hosts has allowed rapid screening of mutant libraries and can be used for the study of evolutionarily preserved aspects of microbial virulence and host response.     

Multiphoton imaging of host-pathogen interactions

Studying the events that occur when a pathogen comes into contact with its host is the basis of the field of infection biology. Over the years, work in this area has revealed many facets of the infection process, including attachment, invasion and colonization by the pathogen, and of the host responses, such as the triggering of the immune system. Recent advancements in imaging technologies, such as multiphoton microscopy (MPM), mean that the field is in the process of taking another big leap forward. MPM allows for cellular-level visualization of the real-time dynamics of infection within the living host. The use of live animal models means that all the interplaying factors of an infection, such as the influences of the immune, lymphatic and vascular systems, can be accounted for. This review outlines the developing field of MPM in pathogen-host interactions, highlighting a number of new insights that have been ‘brought to light’ using this technique.     

The allometry of host-pathogen interactions

Background

Understanding the mechanisms that control rates of disease progression in humans and other species is an important area of research relevant to epidemiology and to translating studies in small laboratory animals to humans. Body size and metabolic rate influence a great number of biological rates and times. We hypothesize that body size and metabolic rate affect rates of pathogenesis, specifically the times between infection and first symptoms or death.

Methods and Principal Findings

We conducted a literature search to find estimates of the time from infection to first symptoms (t_S) and to death (t_D) for five pathogens infecting a variety of bird and mammal hosts. A broad sampling of diseases (1 bacterial, 1 prion, 3 viruses) indicates that pathogenesis is controlled by the scaling of host metabolism. We find that the time for symptoms to appear is a constant fraction of time to death in all but one disease. Our findings also predict that many population-level attributes of disease dynamics are likely to be expressed as dimensionless quantities that are independent of host body size.

Conclusions and Significance

Our results show that much variability in host pathogenesis can be described by simple power functions consistent with the scaling of host metabolic rate. Assessing how disease progression is controlled by geometric relationships will be important for future research. To our knowledge this is the first study to report the allometric scaling of host/pathogen interactions.     

Early events in host-pathogen interactions.

Research focused on early events in host-pathogen interactions has provided new insights into fundamental aspects of microbial pathogenicity and plant responses. Considerable progress has been made in understanding regulation of the delivery of pathogenicity determinants from bacteria into plant cells, signal cascades involved in fungal pathogenicity, the co-ordinating role of the plant cytoskeleton in plant defence and calcium flux as a primary signalling function during the hypersensitive reaction.     

HLA-binding regions of HIV-1 proteins. II. A systematic study of viral proteins.

To detect HLA-binding peptides in 10 HIV-1 proteins (Rev, Tat, Vif, Vpr, Vpu, Gag p18, Gag p24, Gag p15, Env gp120 and Env gp41), the peptide binding assay (PBA) has been performed using three HLA class I molecules. Correlations have been searched between the PBA results and the peptide competitor activity in a functional test using HLA-A2-restricted CTL and target cells. A correlation between the data found in the PBA and well-defined CTL epitopes could be attempted only for the three Gag proteins. For these proteins, our results are in agreement with the known existence of epitopes reacting with human CD8+ CTL, with some exceptions. Together with the results reported with a panel of Nef peptides, these experiments showed that at least 18/20 of the already reported CTL epitopes from HIV-1 Gag, Nef, and Env proteins could be detected by the PBA, most (17/18) corresponding to strong reactivities. Perhaps more important, the regions of HIV-1 Gag p24 or Nef proteins that contain multiple associated CTL epitopes, with different HLA restrictions, were clearly identified by the reactivities in the PBA of several overlapping peptides and the major practical interest of the PBA might be the detection of such polyepitopic regions. Prediction are proposed in this report for 10 proteins, including several proteins for which CTL epitopes remain presently unknown.     

ZIKV viral proteins and their roles in virus-host interactions

The re-emergence of Zika virus(ZIKV) and its associated neonatal microcephaly and Guillain-Barré syndrome have led the World Health Organization to declare a global health emergency. Until today, many related studies have successively reported the role of various viral proteins of ZIKVin the process of ZIKVinfection and pathogenicity. These studies have provided significant insights for the treatment and prevention of ZIKV infection. Here we review the current research advances in the functional characterization of the interactions between each ZIKV viral protein and its host factors.