RESULTS:
1 - 4 of 4 for "Greg J. Towers"
HIV capsids: orchestrators of innate immune evasion, pathogenesis and pandemicity
Human immunodeficiency virus (HIV) is an exemplar virus still the most studied and best understood and a model for mechanisms of viral replication immune evasion and pathogenesis. In this review we consider the earliest stages of HIV infection from transport of the virion contents through the cytoplasm to integration of the viral genome into host chromatin. We present a holistic model for the virus–host interaction during this pivotal stage of infection. Central to this process is the HIV capsid. The last 10 years have seen a transformation in the way we understand HIV capsid structure and function. We review key discoveries and present our latest thoughts on the capsid as a dynamic regulator of innate immune evasion and chromatin targeting. We also consider the accessory proteins Vpr and Vpx because they are incorporated into particles where they collaborate with capsids to manipulate defensive cellular responses to infection. We argue that effective regulation of capsid uncoating and evasion of innate immunity define pandemic potential and viral pathogenesis and we review how comparison of different HIV lineages can reveal what makes pandemic lentiviruses special.
Upregulation of TRIM5α gene expression after live-attenuated simian immunodeficiency virus vaccination in Mauritian cynomolgus macaques, but TRIM5α genotype has no impact on virus acquisition or vaccination outcome
Polymorphism in the TRIM5α/TRIMcyp gene which interacts with the lentiviral capsid has been shown to impact on simian immunodeficiency virus (SIV) replication in certain macaque species. Here in the context of a live-attenuated SIV vaccine study conducted in Mauritian-origin cynomolgus macaques (MCM) we demonstrate upregulation of TRIM5α expression in multiple lymphoid tissues immediately following vaccination. Despite this the restricted range of TRIM5α genotypes and lack of TRIMcyp variants had no or only limited impact on the replication kinetics in vivo of either the SIVmac viral vaccine or wild-type SIVsmE660 challenge. Additionally there appeared to be no impact of TRIM5α genotype on the outcome of homologous or heterologous vaccination/challenge studies. The limited spectrum of TRIM5α polymorphism in MCM appears to minimize host bias to provide consistency of replication for SIVmac/SIVsm viruses in vivo and therefore on vaccination and pathogenesis studies conducted in this species.
Analysis of the human immunodeficiency virus type 1 M group Vpu domains involved in antagonizing tetherin
Zoonosis of chimpanzee simian immunodeficiency virus cpz to humans has given rise to both pandemic (M) and non-pandemic (O N and P) groups of human immunodeficiency virus type-1 (HIV). These lentiviruses encode accessory proteins including Vpu which has been shown to reduce CD4 levels on the cell surface as well as increase virion release from the cell by antagonizing tetherin (CD317 BST2). Here we confirm that O group Vpus (Ca9 and BCF06) are unable to counteract tetherin or downregulate the protein from the cell surface although they are still able to reduce cell-surface CD4 levels. We hypothesize that this inability to antagonize tetherin may have contributed to O group viruses failing to achieve pandemic levels of human-to-human transmission. Characterization of chimeric O/M group Vpus and Vpu mutants demonstrate that the Vpu–tetherin interaction is complex involving several domains. We identify specific residues within the transmembrane proximal region that along with the transmembrane domain are crucial for tetherin counteraction and enhanced virion release. We have also shown that the critical domains are responsible for the localization of M group Vpu to the trans-Golgi network where it relocalizes tetherin to counteract its function. This work sheds light on the acquisition of anti-tetherin activity and the molecular details of pandemic HIV infection in humans.
Porcine endogenous retroviruses PERV A and A/C recombinant are insensitive to a range of divergent mammalian TRIM5α proteins including human TRIM5α
The potential risk of cross-species transmission of porcine endogenous retroviruses (PERV) to humans has slowed the development of xenotransplantation using pigs as organ donors. Here we show that PERVs are insensitive to restriction by divergent TRIM5α molecules despite the fact that they strongly restrict a variety of divergent lentiviruses. We also show that the human PERV A/C recombinant clone 14/220 reverse transcribes with increased efficiency in human cells leading to significantly higher infectivity. We conclude that xenotransplantation studies should consider the danger of highly infectious TRIM5α-insensitive human-tropic PERV recombinants.