Single-Cell Microtools for Profiling Human Immune Responses to HIV

J. Christopher Love, Ph.D.

Massachusetts Institute of Technology

Department of Chemical Engineering
Funded in December, 2008: $400000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Understanding How Certain Cells Help Limit HIV Infection From Progressing to AIDS

Dr. Love will use “single-cell immunology” technology to understand how certain cells help limit HIV infection from progressing to AIDS, a situation that occurs in a small percent of infected individuals who never develop the disease.

A small percentage of people infected with the HIV virus have not developed AIDS, even 15 years after infection.  Immune responses in these “non-progressors,” as they are called, are thought to confer protections against the deleterious effects of the virus.  Non-progressors are not limited to HIV infection; for instance, there are non-progressors among people infected with tuberculosis, Hepatitis C, and malaria.  Studying how immune responses confer protection in non-progressors is hampered by difficulties in obtaining sufficient numbers of immune cells from patient samples, and especially in obtaining ample numbers of the highly specialized immune cells that attack the specific virus involved.  New technologies have been recently developed, however, that can enable investigators simultaneously to analyze the functional, clinical, and genetic characteristics of individual immune cells. 

Called “microengraving,” Dr. Love will apply these new technologies to studying individual immune cells in blood samples taken from people infected with the HIV virus.  He will explore how immune responses limit the progression of viral replication in non-progressors but not in those whose infection has progressed to AIDS.  He hypothesizes that there are distinct differences in populations of immune cells circulating in the bloodstream of HIV-infected progressors and non-progressors; and that differences occur both in responses by innate immune cells (dendritic cells and natural killer cells, which mount a generalized first line of defense) and by adaptive immune cells (specific T cells that mount a highly targeted attack of the HIV virus). 

He will determine: (1) the breadth of the various immune substances, called cytokines, produced by T cells; (2) the genetic diversity among HIV-specific T cells that exhibit varied cytokine responses during different phases of HIV infection; and (3) the functions of innate immune cells that respond to the HIV virus to block the infection’s progression.

ABSTRACT

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Single-Cell Microtools for Profiling Human Immune Responses to HIV

Two challenges inherent to studies in human immunology are (1) the number of cells available in most clinical samples is often very limited, and (2) unique cells, such as antigen-reactive T cells, can be rare.  These limitations make it difficult to build a comprehensive snapshot of the state of the immune system and to identify mechanisms of protection against pathogens.

One area in human immunology where transformative technologies are urgently needed is HIV/AIDS.  We hypothesize that new technologies for generating comprehensive cellular profiles that map multiparametric data about lineages, functions, and genotypes to single cells will reveal distinct differences in the circulating mononuclear cells from HIV+ progressors and non-progressors.  This proposal aims to address how the clonal diversity among HIV-specific CD8+ T cells impacts the functional responses generated during different phases of infection, and what are the functional signatures of the cells involved in the innate immune response to HIV.

The approach will use newly developed, highly multiplexed assays enabled by microfabricated devices to assess the cytokine profiles of many individual cells in parallel.  Single cells of interest will be retrieved for additional study and genetic analysis to determine clonality.

INVESTIGATOR BIOGRAPHIES

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J. Christopher Love, Ph.D.

J. Christopher Love is an assistant professor in chemical engineering at MIT and an associate member at the Eli and Edythe L. Broad Institute.  Chris received his Ph.D. in 2004 in physical chemistry at Harvard University, where he developed a number of unconventional methods to fabricate micro- and nanoscale structures using both soft lithography and self-assembly.  He then extended his research into immunology and pathology, first as a research fellow at Harvard Medical School from 2004-2005, and then as an Instructor at the Immune Disease Institute (formerly CBRI) from 2005-2007.  Drawing on his expertise in surface chemistry and microtechnologies, he studied both the dynamics of phagosomal maturation in dendritic cells and the activation of naïve B cells by live cell imaging and microfluidics; he also developed a process for generating monoclonal antibodies by high-throughput, single-cell screening.

His current research centers on using simple microsystems to measure and correlate multiple phenotypic and functional characteristics of individual lymphocytes, and from these single-cell data, generate quantitative, system-wide profiles of immune responses.  By employing state-of-the-art methods, he aims to resolve patterns in a host’s cellular responses that correlate with protective immunity to infectious diseases, and to discover rare subsets of cells that are critical in the pathogenesis of autoimmune diseases.

Current areas of research in the lab include (1) multiplexed, functional profiling of lymphocytes from long-term, HIV+ non-progressors, (2) clonal analysis of autoantibody-producing B cells from type 1 diabetic subjects, and (3) development of quantitative, cell-based diagnostics for allergy testing.  The strategic goals of his research are to improve the development of vaccines and immunotherapies in these disease areas using quantitative immunological profiling for discovery, assessment, and monitoring, and to enable broadly new technological platforms for cell-based studies in human immunology.