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, HIV-1 Vpu and HIV-2 Env 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 cytoplasmic tail of gp41 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, underscoring the extraordinary plasticity of the primate lentiviruses in adapting to the tetherin proteins of their hosts and revealing a previously unappreciated role for Nef in HIV-1 infection. The studies outlined in this proposal build on this work to reveal the fundamental mechanisms of lentiviral resistance to tetherin and their role in immunodeficiency virus infection. Our first objective (Aim 1) is to define the molecular interactions and cellular trafficking pathways involved in tetherin antagonism by Nef, and the fate of tetherin (degradation versus sequestration) in SIV-infected cells. These studies will build on work by our group identifying Nef as the viral gene product of SIV that counteracts restriction by tetherin and will lead to a better understanding of the mechanisms of lentiviral resistance to tetherin. 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 anti-tetherin activity is for Nef alleles of primary HIV-1 isolates, the circumstances that lead to the gain of this function 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 Ev 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 will reveal whether differences in tetherin antagonism are related to differences in HIV-2 pathogenesis.

Public Health Relevance

Tetherin (BST-2 or CD317) is a component of innate immunity that inhibits virus release from infected cells. The goal of this proposal is to understan the mechanisms of HIV and SIV resistance to tetherin. A better understanding of the mechanisms used by AIDS viruses to overcome tetherin may lead to the development of novel antiretroviral drugs to enhance the ability of this factor to suppress HIV replication.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Veterinary Sciences
Schools of Medicine
United States
Zip Code
Banerjee, Priyankana; Ries, Moritz; Janaka, Sanath Kumar et al. (2018) Diversification of Bw4 Specificity and Recognition of a Nonclassical MHC Class I Molecule Implicated in Maternal-Fetal Tolerance by Killer Cell Ig-like Receptors of the Rhesus Macaque. J Immunol 201:2776-2786
Richard, Jonathan; Prévost, Jérémie; von Bredow, Benjamin et al. (2017) BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity. J Virol 91:
Arias, Juan F; Colomer-Lluch, Marta; von Bredow, Benjamin et al. (2016) Tetherin Antagonism by HIV-1 Group M Nef Proteins. J Virol :
Bimber, Benjamin N; Evans, David T (2015) The killer-cell immunoglobulin-like receptors of macaques. Immunol Rev 267:246-58
Schafer, Jamie L; Ries, Moritz; Guha, Natasha et al. (2015) Suppression of a Natural Killer Cell Response by Simian Immunodeficiency Virus Peptides. PLoS Pathog 11:e1005145
Gardner, Matthew R; Kattenhorn, Lisa M; Kondur, Hema R et al. (2015) AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature 519:87-91
Hölzemer, Angelique; Thobakgale, Christina F; Jimenez Cruz, Camilo A et al. (2015) Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. PLoS Med 12:e1001900; discussion e1001900
Pomplun, Nicholas; Weisgrau, Kim L; Evans, David T et al. (2015) OMIP-028: activation panel for Rhesus macaque NK cell subsets. Cytometry A 87:890-3
Scull, Margaret A; Shi, Chao; de Jong, Ype P et al. (2015) Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice. Hepatology 62:57-67
von Bredow, Benjamin; Arias, Juan F; Heyer, Lisa N et al. (2015) Envelope Glycoprotein Internalization Protects Human and Simian Immunodeficiency Virus-Infected Cells from Antibody-Dependent Cell-Mediated Cytotoxicity. J Virol 89:10648-55

Showing the most recent 10 out of 25 publications