The ancestors of modern organisms were colonized by viruses that were very rarely beneficial, and often deleterious to the host. Inevitably, hosts adapted to limit viral replication, and in so doing evolved various autonomous antiviral defense mechanisms. One of these is TRIM5, which is multimeric protein that recognizes incoming retroviral capsids, but its precise mechanisms of action are unclear.
In specific aim 1 we will develop new techniques to understand what happens to various incoming components of retroviral particles as they complete the early steps of their life cycle. These assays will very likely illuminate the mechanisms by which TRIM5 proteins and other antiretroviral factors exert their inhibitory effects. Moreover, these techniques are likely to have a wide range of applications in the study of these steps of the retroviral life cycle.
In specific aim 2 we will derive TRIM5-resistant HIV-1 capsids that will identify residues on the surface of the HIV-1 capsid that are targeted by TRIM5 and will serve a useful tools to probe the mechanism of action of TRIM5. Additionally these capsids will be used for generating simian-tropic HIV- strains that can replicate in rhesus macaques. In addition to known antiretroviral proteins like TRIM5, there are several reasons to think that there are more, perhaps many more, antiviral host defense genes in to be discovered.
In specific aim 3, we will attempt to identify such genes by constructing focused, arrayed cDNA libraries, each consisting of tens to hundreds of candidate genes, that either (i) have key properties exhibited by known antiretroviral genes or (ii) are selectively expressed in cells that exhibit constitutive or induced resistance to HIV-1 or SIV infection. These genes libraries will be arrayed each gene will be individually tested for its ability to inhibit retrovirus replication.

Public Health Relevance

Humans and laboratory animals have an array of antiviral defense mechanisms, of which we have only a rudimentary understanding. Identifying and understanding the mechanism of action of antiretroviral gene products could lead to completely new chemotherapeutic strategies for tackling infectious diseases, including AIDS. In addition, understanding species-specific variation and engineering resistance to antiretroviral genes could facilitate the development of animal models of human retroviral infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-AARR-K (02))
Program Officer
Embry, Alan C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Aaron Diamond AIDS Research Center
New York
United States
Zip Code
Kueck, Tonya; Cassella, Elena; Holler, Jessica et al. (2018) The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression. Elife 7:
Kane, Melissa; Rebensburg, Stephanie V; Takata, Matthew A et al. (2018) Nuclear pore heterogeneity influences HIV-1 infection and the antiviral activity of MX2. Elife 7:
Blanco-Melo, Daniel; Gifford, Robert J; Bieniasz, Paul D (2017) Co-option of an endogenous retrovirus envelope for host defense in hominid ancestors. Elife 6:
Del Prete, Gregory Q; Keele, Brandon F; Fode, Jeannine et al. (2017) A single gp120 residue can affect HIV-1 tropism in macaques. PLoS Pathog 13:e1006572
Del Prete, Gregory Q; Ailers, Braiden; Moldt, Brian et al. (2014) Selection of unadapted, pathogenic SHIVs encoding newly transmitted HIV-1 envelope proteins. Cell Host Microbe 16:412-8
Hatziioannou, Theodora; Del Prete, Gregory Q; Keele, Brandon F et al. (2014) HIV-1-induced AIDS in monkeys. Science 344:1401-5
Busnadiego, Idoia; Kane, Melissa; Rihn, Suzannah J et al. (2014) Host and viral determinants of Mx2 antiretroviral activity. J Virol 88:7738-52
Kane, Melissa; Yadav, Shalini S; Bitzegeio, Julia et al. (2013) MX2 is an interferon-induced inhibitor of HIV-1 infection. Nature 502:563-6
Rihn, Suzannah J; Wilson, Sam J; Loman, Nick J et al. (2013) Extreme genetic fragility of the HIV-1 capsid. PLoS Pathog 9:e1003461
Bitzegeio, Julia; Sampias, Marissa; Bieniasz, Paul D et al. (2013) Adaptation to the interferon-induced antiviral state by human and simian immunodeficiency viruses. J Virol 87:3549-60

Showing the most recent 10 out of 21 publications