Tetherin (BST-2 or CD317) is an interferon-inducible transmembrane protein that inhibits virus release from infected cells. Whereas most simian immunodeficiency viruses (SIVs) use Nef to overcome restriction by tetherin in their non-human primate hosts, the Vpu protein of HIV-1 and the Env protein of HIV-2 have evolved to serve this function in humans due to the absence of sequences in the cytoplasmic domain of human tetherin that confer susceptibility to Nef. We recently identified compensatory changes in the gp41 tail that restore resistance to tetherin in a nef-deleted strain of SIV that regained a pathogenic phenotype in rhesus macaques. These observations are analogous to the adaptation of HIV-2 Env for antagonism of human tetherin and imply that resistance to tetherin is important for lentiviral pathogenesis. We have now identified HIV-1 Nef alleles that are able to counteract restriction by human tetherin, further underscoring the extraordinary plasticity of the primate lentiviruses in adapting to the tetherin proteins of their respective hosts and revealing a previously unappreciated role for Nef in HIV-1 infection. The studies outlined in this proposal seek to advance our understanding of the mechanisms of lentiviral resistance to tetherin and their role in immunodeficiency virus infection. The first objective of this proposal (Aim 1) is to define the molecular interactions and cellular trafficking pathways involved in SIV Nef antagonism of rhesus tetherin.
This aim will build on work by our group identifying Nef as the viral gene product of SIV that antagonizes restriction by tetherin to determinie the nature of the molecular interactions between Nef and tetherin and the fate of tetherin in SIV-infected cells. Our second objective (Aim 2) is define the genetic changes associated with the gain of anti-tetherin activity by HIV-1 Nef and the mechanism by which HIV-1 Nef counteracts human tetherin. These studies are important for determining how widespread this activity of Nef is among primary HIV-1 isolates, the circumstances that lead to tetherin antagonism by HIV-1 Nef, and the mechanistic differences in tetherin antagonism by HIV-1 Nef versus SIV Nef. Our third objective (Aim 3) is to assess the natural variation in anti-tetherin activity for primary HIV-2 En proteins and to define the sequences in Env required for this activity. These studies will reveal the prevalence/range of anti-tetherin activity for primary HIV-2 Env proteins and the molecular adaptations in Env that contribute to this activity. By comparing the activity of Env alleles derived from individuals with progressive courses of HIV-2 infection to Env alleles derived from asymptomatic individuals who contain virus replication, these studies may also reveal whether differences in tetherin antagonism are related to differences in HIV-2 pathogenesis.
Tetherin (BST-2 or CD317) is a component of innate immunity that inhibits virus release from infected cells. The studies in this proposal will advance our understanding of the mechanisms of HIV and SIV resistance to tetherin. A better understanding of the mechanisms used by AIDS viruses to counteract tetherin will be important for the development of novel antiretroviral drugs to enhance the susceptibility of HIV to tetherin.
|Schafer, Jamie L; Colantonio, Arnaud D; Neidermyer, William J et al. (2014) KIR3DL01 recognition of Bw4 ligands in the rhesus macaque: maintenance of Bw4 specificity since the divergence of apes and Old World monkeys. J Immunol 192:1907-17|
|Li, Qingsheng; Zeng, Ming; Duan, Lijie et al. (2014) Live simian immunodeficiency virus vaccine correlate of protection: local antibody production and concentration on the path of virus entry. J Immunol 193:3113-25|
|Arias, Juan F; Evans, David T (2014) Tethering viral restriction to signal transduction. Cell Host Microbe 16:267-9|
|Arias, Juan F; Heyer, Lisa N; von Bredow, Benjamin et al. (2014) Tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent cell-mediated cytotoxicity. Proc Natl Acad Sci U S A 111:6425-30|
|Serra-Moreno, Ruth; Zimmermann, Kerstin; Stern, Lawrence J et al. (2013) Tetherin/BST-2 antagonism by Nef depends on a direct physical interaction between Nef and tetherin, and on clathrin-mediated endocytosis. PLoS Pathog 9:e1003487|
|Evans, David T; Silvestri, Guido (2013) Nonhuman primate models in AIDS research. Curr Opin HIV AIDS 8:255-61|
|Rahmberg, Andrew R; Neidermyer Jr, William J; Breed, Matthew W et al. (2013) Tetherin upregulation in simian immunodeficiency virus-infected macaques. J Virol 87:13917-21|
|Serra-Moreno, Ruth; Evans, David T (2012) Adaptation of human and simian immunodeficiency viruses for resistance to tetherin/BST-2. Curr HIV Res 10:277-82|