Section: Research

Postdoctoral Position Available

Heinrich Gottlinger, Ph.D.,M.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Program in Gene Function and Expression
   Program in Molecular Medicine

Joint Faculty In:
   Biochemistry and Molecular Pharmacology

Other Affiliation(s):
   Center for AIDS Research
   Interdisciplinary Graduate Program
   Program in Immunology and Virology

Molecular Biology of HIV-1

The overall goal of the lab is to understand at the molecular level how an infectious HIV-1 virus particle is formed and what cellular proteins are involved.

HIV-1 particle assembly and budding are driven by the viral Gag protein, which contains specific domains that are absolutely required for the virus to detach from the host cell. Towards the goal of understanding the function of these “late assembly” domains, we recently identified AIP1 as a cellular binding partner involved in HIV-1 budding. AIP1 is a component of the cellular class E vacuolar protein sorting (Vps) machinery, which normally functions in an endosomal budding pathway that is conserved from yeast to man.

Our results indicate that AIP1 serves to link the late assembly domains of HIV-1 and other lentiviruses to a large endosomal sorting complex called ESCRT-III. Remarkably, the release of HIV-1 and various other enveloped viruses is completely blocked in the presence of defective ESCRT-III components. We are currently using a combination of siRNA knockdown and mutagenesis techniques to determine how the assembly of the ESCRT-III complex is regulated, and how AIP1 and ESCRT-III facilitate virus budding. Additionally, we use HIV as a model system to elucidate how the human class E Vps machinery functions in protein sorting and vesicular transport. 

We also study the role of Nef, a virulence factor of HIV-1 that is crucial for rapid progression to AIDS. Nef increases the intrinsic infectivity of HIV-1 progeny virions, but the mechanism is not understood. Our recent results show that Nef binds to a key regulator of endocytosis, which is required for the ability of Nef to increase viral infectivity. Since our results suggest that Nef down-modulates a cellular factor that restricts HIV-1 infectivity, we have used a high-resolution proteomics approach to compare the global protein content of wild type and mutant HIV-1 virions. This approach has yielded a number of cellular proteins that are selectively incorporated into HIV-1 particles in a manner that depends on a specific viral structural or regulatory protein.

The viral binding sites for these cellular proteins are currently being mapped, and the results will be used to construct and analyze HIV-1 mutants that lack these sites. To complement and validate these virological studies, we will use knockdown approaches to directly examine the relevance of specific host factors for the HIV-1 life cycle. We expect that these studies will provide insights not only into the function of Nef, but also into the mechanism of virus release, virus spreading via cell-to-cell transmission, and the unique ability of lentiviruses such as HIV-1 to infect non-dividing, terminally differentiated cells.
 

Office: LRB-526
Phone: 508-856-2843
E-mail: Heinrich.Gottlinger@umassmed.edu
Keywords: Intracellular Trafficking, Virology

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Postdoctoral Position Available A postdoctoral position is available to study in this laboratory.  Contact Dr. Gottlinger for additional details.