Harvard Medical School

David Evans


Contact Information:

Harvard Medical School

New England Primate Research Center,
RSB6

One Pine Hill Drive

Southborough, MA   01772-9102

Tel: (508) 624-8025

Fax: (508) 786-3317

 

email: devans@hms.harvard.edu

 

Research Summary

Simian immunodeficiency virus (SIV) causes AIDS in rhesus macaques with a course of disease progression that closely resembles HIV infection of humans, and is currently the best animal model for AIDS vaccine development and for studies of lentiviral pathogenesis. Our research focuses on mechanisms of protective immunity and immune evasion using SIV infection of the rhesus macaque as an animal model. 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 host-cell factor that interferes with the detachment of enveloped viruses from infected cells. Whereas HIV-1 Vpu and HIV-2 Env antagonize human tetherin, most SIVs use Nef to counteract restriction by the tetherin proteins of their non-human primate hosts. We identified Nef as the viral gene product of SIV that counteracts 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 HIV-1 Vpu and HIV-2 Env. More recently, we identified compensatory changes in the cytoplasmic tail of SIV 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 implies that the ability to counteract restriction by tetherin is important for lentiviral pathogenesis.

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 antibody-dependent cell-mediated cytotoxicity (ADCC) in protection against immunodeficiency viruses is poorly understood due in part to limitations in the methods used for measuring this functional activity of antibodies against virus-infected cells. We have developed a novel assay for measuring antibody titers capable of directing ADCC against SIV- and HIV-infected cells. We are currently using this assay to investigate the role of ADCC in the protection afforded by infection of rhesus macaques with live-attenuated SIV and by vaccination of human subjects with recombinant canarypox and soluble gp120 in a recent phase III vaccine trial (RV144).

As a novel vaccine approach designed to uncouple immune activation from ongoing virus replication and destruction of CD4+ T lymphocytes, we devised a genetic system for producing strains of SIV that are limited to a single cycle of infection. This system is based on a unique combination of mutations specifically designed to prevent the recovery of replication-competent viruses by recombination or nucleotide reversion. Immunization of macaques with single-cycle SIV (scSIV) elicited a broad spectrum of virus-specific immune responses, including T cell responses to each of the viral gene products and antibodies to the native, oligomeric conformation of the envelope glycoprotein as it exists on virions. After challenging with a strain of SIV that is notoriously difficult to control by vaccination, scSIV-immunized animals exhibited significant containment of the challenge virus relative to unvaccinated control animals (Jia et al. 2009. PLoS Pathog.). We are now using scSIV as a tool to define mechanisms of protective immunity important for the design of more effective vaccines against HIV-1.

Selected Publications

Serra-Moreno, R, Jia, B, Breed, M, Alvarez, X, Evans DT. 2011. Compensatory changes in the cytoplasmic tail of gp41 confer resistance to tetherin/BST-2 in a pathogenic nef-deleted SIV. Cell Host & Microbe. 9: 46-57.

Colantonio, AD, Bimber, BN, Neidermyer, WJ Jr, Reeves, RK, Alter, G, Altfeld, M, Johnson, RP, Carrington, M, O’Connor, DH, Evans, DT. 2011. KIR polymorphisms modulate peptide-dependent binding to an MHC class I ligand with a Bw6 motif. PLoS Pathog. 7: e1001316.

Alpert, MD, Rahmberg, AR, Neidermyer, W, Ng, S., Carville, A, Camp, JV, Wilson, RL, Piatak, M, Mansfield, KG, Li, W, Miller, CJ, Lifson, JD, Kozlowski, PA, Evans, DT. Envelope-modified single-cycle SIV selectively enhances antibody responses and partially protects against repeated, low-dose vaginal challenge. J. Virol. 2010. 84: 10748-10764.

Jia B, Serra-Moreno R, Neidermyer W Jr., Rahmberg A, Mackey J, Fofana IB, Johnson WE, Westmoreland S, Evans DT. 2009. Species-specific activity of SIV Nef and HIV-1 Vpu in overcoming restriction by tetherin/BST2. PLoS Pathog. 5: e1000429.

Jia B, Ng SK, DeGottardi MQ, Piatak M Jr., Yuste E, Carville A, Mansfield MG, Li W, Richardson BA, Lifson JD, Evans DT. 2009. Immunization with single-cycle SIV significantly reduces viral loads after an intravenous challenge with SIVmac239. PLoS Pathog. 5: e1000272.