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Faculty Profile

Felipe Diaz-Griffero, Ph.D.

Dr. Felipe Diaz-Griffero
 

Professional Interests

Our laboratory is interested on understanding the mechanism used by restriction factors (endogenously expressed proteins) to restrict HIV-1 replication. The restriction factors TRIM5alpha and TRIMCyp are monkey proteins that potently block HIV-1 during uncoating—the initial step of HIV-1 replication. Our investigations have demonstrated that TRIM5 proteins block HIV-1 replication by potently inhibiting reverse transcription--essential early step in HIV-1 replication that converts the viral RNA in viral DNA and allowing productive infection. We are using these restriction factors to carefully define the uncoating mechanism of HIV-1, which will give rise to new ways to inhibit HIV-1 replication and treat HIV-1/AIDS. We have established that these restrictions factors accelerate uncoating making HIV-1 replication abortive. Our investigations will attempt to mechanistically define the timing of uncoating and reverse transcription during replication. Interestingly but not surprisingly these restriction factors block HIV-1 replication extremely potently and better than any drug known to date. We like to say not surprisingly since these restriction factors were design by nature block HIV-1 replication, and nature knows best.

The main focus of the lab is to define HIV-1 uncoating by using biological and biochemical assays. One of the most important questions in the HIV-1 field is to understand the relationship between uncoating and reverse transcription. We currently have in vivo and vitro assays to follow the uncoating and reverse transcription of HIV-1. These assays had allowed us to better understand how reverse transcription is block during the accelerated uncoating triggered by TRIM5alpha and TRIMCyp. We are also studying the structural biology of these restriction factors attempting to identify the TRIM5alpha domains required to block HIV-1 replication. We have also created mice strains that do not contain TRIM5alpha to understand the in vivo role of TRIM5alpha.

To understand uncoating in a broader manner, we are also studying the molecule transportin-3 (TNPO3) known to be required for HIV-1 replication during the initial steps of HIV-1 replication. We are identifying which proteins of the HIV-1 virus is required to interact with TNPO3, which is a nuclear transporter. We think that this transporter promotes HIV-1 uncoating in the nuclear pore and assist the transport of HIV-1 to the nucleus of the cells allowing productive infection. We have also created mice strains that do not express transporting to better understand the role of TNPO3 in HIV-1 replication using and in vivo model.

Finally, we are studying HIV-1 infected patients known as elite controllers—HIV-1 infected patients that never develop AIDS. We strongly believe that these individuals have novel ways to restrict HIV-1 replication, which will help us to develop new therapies against HIV-1/AIDS. Among this novel ways to restrict HIV-1 replication, we hypothesize the existence of new restriction factors in T cells that block HIV-1 replication. For this purpose, we are currently investigating HIV-1 replication blocks in T cells. We have several T cell lines that block HIV-1 replication at early stages suggesting the existence of a block similar to the one imposed by TRIM5alpha to HIV-1 replication.

Overall, our laboratory is interested in defining the uncoating process of HIV-1 replication by using restriction factors such as TRIM5alpha, TRIMCyp and T cell restrictors, or proteins that assist uncoating such us transportin-3 (TNPO3).  We are certain that these investigations will lead to novel and unforeseeable ways to treat HIV-1/AIDS.

 

Selected Publications

1.         Chi, Y., et al., An NF-kappa B-dependent survival pathway protects against cell death induced by TVB receptors for avian leukosis viruses. J Virol, 2002. 76(11): p. 5581-7.

2.         Diaz-Griffero, F., et al., Expression of the crucifer-infecting TMV-Cg movement protein in tobacco plants complements in trans a TMV-U1 trafficking-deficient mutant. Biol Res, 2006. 39(2): p. 269-79.

3.         Diaz-Griffero, F., S.A. Hoschander, and J. Brojatsch, Endocytosis is a critical step in entry of subgroup B avian leukosis viruses. J Virol, 2002. 76(24): p. 12866-76.

4.         Diaz-Griffero, F., S.A. Hoschander, and J. Brojatsch, Bystander killing during avian leukosis virus subgroup B infection requires TVB(S3) signaling. J Virol, 2003. 77(23): p. 12552-61.

5.         Diaz-Griffero, F., A.P. Jackson, and J. Brojatsch, Cellular uptake of avian leukosis virus subgroup B is mediated by clathrin. Virology, 2005. 337(1): p. 45-54.

6.         Diaz-Griffero, F., et al., Comparative requirements for the restriction of retrovirus infection by TRIM5alpha and TRIMCyp. Virology, 2007. 369(2): p. 400-10.

7.         Diaz-Griffero, F., et al., Modulation of retroviral restriction and proteasome inhibitor-resistant turnover by changes in the TRIM5alpha B-box 2 domain. J Virol, 2007. 81(19): p. 10362-78.

8.         Diaz-Griffero, F., et al., Rapid turnover and polyubiquitylation of the retroviral restriction factor TRIM5. Virology, 2006. 349(2): p. 300-15.

9.         Diaz-Griffero, F., et al., A human TRIM5alpha B30.2/SPRY domain mutant gains the ability to restrict and prematurely uncoat B-tropic murine leukemia virus. Virology, 2008. 378(2): p. 233-42.

10.       Diaz-Griffero, F., et al., A B-box 2 surface patch important for TRIM5alpha self-association, capsid binding avidity, and retrovirus restriction. J Virol, 2009. 83(20): p. 10737-51.

11.       Diaz-Griffero, F., et al., Efficient production of HIV-1 viral-like particles in mouse cells. Biochem Biophys Res Commun, 2008. 368(3): p. 463-9.

12.       Diaz-Griffero, F., et al., Requirements for capsid-binding and an effector function in TRIMCyp-mediated restriction of HIV-1. Virology, 2006. 351(2): p. 404-19.

13.       Gosselin, A., et al., Peripheral blood CCR4+CCR6+ and CXCR3+CCR6+CD4+ T cells are highly permissive to HIV-1 infection. J Immunol. 184(3): p. 1604-16.

14.       Javanbakht, H., et al., The contribution of RING and B-box 2 domains to retroviral restriction mediated by monkey TRIM5alpha. J Biol Chem, 2005. 280(29): p. 26933-40.

15.       Javanbakht, H., et al., The ability of multimerized cyclophilin A to restrict retrovirus infection. Virology, 2007. 367(1): p. 19-29.

16.       Javanbakht, H., et al., Characterization of TRIM5alpha trimerization and its contribution to human immunodeficiency virus capsid binding. Virology, 2006. 353(1): p. 234-46.

17.       Kar, A.K., et al., Biochemical and biophysical characterization of a chimeric TRIM21-TRIM5alpha protein. J Virol, 2008. 82(23): p. 11669-81.

18.       Li, X., et al., Unique features of TRIM5alpha among closely related human TRIM family members. Virology, 2007. 360(2): p. 419-33.

19.       Mani, M., et al., BCL9 promotes tumor progression by conferring enhanced proliferative, metastatic, and angiogenic properties to cancer cells. Cancer Res, 2009. 69(19): p. 7577-86.

20.       Mische, C.C., et al., Retroviral restriction factor TRIM5alpha is a trimer. J Virol, 2005. 79(22): p. 14446-50.

21.       Pena-Cruz, V., et al., PD-1 on Immature and PD-1 Ligands on Migratory Human Langerhans Cells Regulate Antigen-Presenting Cell Activity. J Invest Dermatol.

22.       Song, B., et al., TRIM5alpha association with cytoplasmic bodies is not required for antiretroviral activity. Virology, 2005. 343(2): p. 201-11.

23.       Stremlau, M., et al., Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor. Proc Natl Acad Sci U S A, 2006. 103(14): p. 5514-9.

24.       Taube, R., et al., Lentivirus display: stable expression of human antibodies on the surface of human cells and virus particles. PLoS One, 2008. 3(9): p. e3181.

25.       Torimiro, J.N., et al., A rare null allele potentially encoding a dominant-negative TRIM5alpha protein in Baka pygmies. Virology, 2009. 391(1): p. 140-7.

 

 

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Contact

Albert Einstein College of Medicine
Michael F. Price Center
1301 Morris Park Avenue , Room 501
Bronx, NY 10461

Tel: 718.678.1191
felipe.diaz-griffero@einstein.yu.edu

 
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