David Evans, PhD

Portrait of David Evans, PhD
Pathology and Laboratory Medicine
AIDS Vaccine Research Laboratory
585 Science Dr
Madison, WI 53711
(608) 265-1485
Focus Groups: 
PhD, Cellular and Molecular Biology, University of Wisconsin–Madison
Research Summary: 
Understanding host-pathogen interactions for human and simian immunodeficiency viruses
Research Detail: 

Current areas of investigation include (1) mechanisms of lentiviral resistance to tetherin/BST-2, (2) the role of KIR and MHC class I polymorphisms in regulating NK cell responses, (3) ADCC as a mechanism of protection, and (4) single-cycle SIV as an experimental AIDS vaccine approach.

Tetherin (BST-2 or CD317) is an interferon-inducible transmembrane protein that interferes with the detachment of enveloped viruses from infected cells. We identified Nef as the viral gene product of SIV that counteracts restriction by tetherin in Old World monkeys, and found that this activity is dependent on a five amino acid sequence that is missing from the cytoplasmic domain of human tetherin (Jia & Serra-Moreno et al. 2009. PLoS Pathog.). The absence of sequences in human tetherin that confer susceptibility to Nef explains why this activity was ultimately acquired by the Vpu and Env proteins of HIV-1 and HIV-2 respectively. We also identified compensatory changes in the cytoplasmic tail of Env that restore resistance to tetherin in a nef-deleted strain of SIV that regained a pathogenic phenotype in rhesus macaques (Serra-Moreno et al. 2011. Cell Host Microbe). This finding is entirely consistent with the adaptation of HIV-2 Env for antagonism of human tetherin, and provides the most direct evidence to date that the ability to counteract restriction by tetherin is important for lentiviral pathogenesis. More recently, we investigated the mechanism of tetherin antagonism by Nef, and found that this activity is dependent on a physical interaction between Nef and tetherin and on clathrin-mediated endocytosis (Serra-Moreno et al. 2013. PLoS Pathog.).

Natural killer (NK) cells recognize and kill infected or malignant cells without prior antigenic stimulation and thus provide an important innate immune defense against infectious agents and tumors. NK cell responses are regulated in part through interactions between highly polymorphic killer cell immunoglobulin-like receptors (KIRs) expressed on NK cells and their MHC class I ligands on target cells. Genetic evidence indicates that KIR and MHC class I polymorphisms play an important role in determining the rate of disease progression in HIV-1 infected individuals. However, the immunological mechanisms underlying these observations are poorly understood. We recently identified an interaction between an inhibitory KIR and a common MHC class I molecule in the rhesus macaque that is modulated by SIV peptides (Colantonio et al. 2011. PLoS Pathog.). One implication of these observations is that viruses may acquire changes in epitopes that increase the binding of MHC class I ligands to inhibitory KIRs as a mechanism of innate immune evasion to prevent the activation of certain NK cell subsets.

The role of ADCC in HIV-1 or SIV infection is poorly understood due in part to limitations of methods for measuring this immune response. We therefore developed a novel assay for measuring antibody titers capable of directing ADCC against virus-infected cells (Alpert et al. 2012. J. Virol.). Data obtained with this assay suggest that the time-dependent maturation of protection in macaques inoculated with nef-deleted, live-attenuated SIV is associated with an increase in ADCC titers to the challenge virus (Alpert et al. 2012. PLoS Pathog.). This assay was also selected by the US Military HIV Research Program as one of six primary assays for the immune correlates analysis of the phase III RV144 vaccine trial (or “Thai trial”) to determine if ADCC activity differed for HIV-infected versus uninfected vaccine recipients (Haynes et al. 2012. N. Engl. J. Med.). Current projects are now directed towards understanding the molecular mechanisms of HIV-1 and SIV resistance to ADCC.

Selected Publications: 
Evans DT, JH E, RC D. "Nonhuman lentiviruses.". In: Fields Virology. Sixth Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2013.
Evans DT, Silvestri G. "Nonhuman primate models in AIDS research." Curr Opin HIV AIDS. 2013;8(4):255-61.
Serra-Moreno R, Zimmermann K, Stern LJ, Evans DT. "Tetherin/BST-2 Antagonism by Nef Depends on a Direct Physical Interaction between Nef and Tetherin, and on Clathrin-mediated Endocytosis." PLoS Pathog.. 2013;9(7):e1003487.
Serra-Moreno R, Evans DT. "Adaptation of human and simian immunodeficiency viruses for resistance to tetherin/BST-2." Curr. HIV Res.. 2012;10(4):277-82.
Alpert MD, Harvey JD, W Lauer A, et al. "ADCC develops over time during persistent infection with live-attenuated SIV and is associated with complete protection against SIV(mac)251 challenge." PLoS Pathog.. 2012;8(8):e1002890.
Hatziioannou T, Evans DT. "Animal models for HIV/AIDS research." Nat. Rev. Microbiol.. 2012;10(12):852-67.
Bonsignori M, Pollara J, M Moody A, et al. "Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family." J. Virol.. 2012;86(21):11521-32.
Haynes BF, Gilbert PB, M McElrath J, et al. "Immune-correlates analysis of an HIV-1 vaccine efficacy trial." N. Engl. J. Med.. 2012;366(14):1275-86.
Moldt B, Shibata-Koyama M, Rakasz EG, et al. "A nonfucosylated variant of the anti-HIV-1 monoclonal antibody b12 has enhanced FcγRIIIa-mediated antiviral activity in vitro but does not improve protection against mucosal SHIV challenge in macaques." J. Virol.. 2012;86(11):6189-96.
Alpert MD, Heyer LN, Williams DEJ, et al. "A novel assay for antibody-dependent cell-mediated cytotoxicity against HIV-1- or SIV-infected cells reveals incomplete overlap with antibodies measured by neutralization and binding assays." J. Virol.. 2012;86(22):12039-52.