A requisite step for the creation of an infectious HIV-1 particle is incorporation of the surface fusion glycoprotein (for retroviruses, referred to as Env) This incorporation only occurs if Env traffics to the precise patch of membrane in the cell that serves as the viral assembly site. The features of the viral assembly site that facilitate this translocation of viral glycoproteins remain a mystery. We have demonstrated that glycoproteins from diverse families of viruses are efficiently recruited to human immunodeficiency virus (HIV-1) assembly sites but that most host proteins are not. We hypothesize that enveloped viruses utilize a common mechanism to facilitate the redistribution of viral glycoproteins to viral assembly sites. Because many of the viral glycoproteins recruited to HIV-1 assembly sites contain no sequence similarity with the native HIV-1 glycoprotein (HIV-1 Env), it is unlikely that foreign glycoprotein recruitment is facilitated by a direct protein-protein interaction between HIV 1 structural protein (Gag) and the glycoprotein. The central objectives of this proposal, therefore, are (1) to identify the feature(s) in viral glycoproteins that dictate their attraction o viral assembly sites and (2) to identify the feature(s) of the viral assembly site that facilitate his attraction. This proposal contains four specific aims.
Aim 1 : Determine whether diverse viral glycoproteins co-package into the same viral particles.
Aim 2 : Utilize retroviral mutagenesis libraries to ascertain what features in viral glycoproteins dictate their attraction to viral assemly sites.
Aim 3 : Perform quantitative imaging of glycoprotein acquisition in real time.
Aim 4 : Apply positive selection to identify determinants of compatibility between Gag and glycoprotein CTDs.
These aims will help define the interactions that modulate this critical step in the HIV-1 lifecycl.
HIV-1 infections have caused a worldwide pandemic that has claimed the lives of over 20 million people and infected over 40 million more. It has long been recognized that viruses, including HIV, have distinct mechanisms for recruiting all of the viral components to the correct viral assembly site within the cell, but these mechanisms remain poorly understood. Understanding these mechanisms will shed light on how HIV-1 interacts with the host cell and could lead to new targets for antiviral therapies.
|Dick, Robert A; Zadrozny, Kaneil K; Xu, Chaoyi et al. (2018) Inositol phosphates are assembly co-factors for HIV-1. Nature 560:509-512|
|Vijayan, Madhuvanthi; Xia, Chuan; Song, Yul Eum et al. (2017) Sphingosine 1-Phosphate Lyase Enhances the Activation of IKK? To Promote Type I IFN-Mediated Innate Immune Responses to Influenza A Virus Infection. J Immunol 199:677-687|
|Salamango, Daniel J; Alam, Khalid K; Burke, Donald H et al. (2016) In Vivo Analysis of Infectivity, Fusogenicity, and Incorporation of a Mutagenic Viral Glycoprotein Library Reveals Determinants for Virus Incorporation. J Virol 90:6502-14|
|Salamango, Daniel J; Johnson, Marc C (2015) Characterizing the Murine Leukemia Virus Envelope Glycoprotein Membrane-Spanning Domain for Its Roles in Interface Alignment and Fusogenicity. J Virol 89:12492-500|
|Li, Minghua; Ablan, Sherimay D; Miao, Chunhui et al. (2014) TIM-family proteins inhibit HIV-1 release. Proc Natl Acad Sci U S A 111:E3699-707|
|Gregory, Devon A; Olinger, Grace Y; Lucas, Tiffany M et al. (2014) Diverse viral glycoproteins as well as CD4 co-package into the same human immunodeficiency virus (HIV-1) particles. Retrovirology 11:28|
|Janaka, Sanath Kumar; Gregory, Devon A; Johnson, Marc C (2013) Retrovirus glycoprotein functionality requires proper alignment of the ectodomain and the membrane-proximal cytoplasmic tail. J Virol 87:12805-13|
|Salamango, Daniel J; Evans, David A; Baluyot, Mariju F et al. (2013) Recombination can lead to spurious results in retroviral transduction with dually fluorescent reporter genes. J Virol 87:13900-3|