David M. Rekosh

Education

  • PhD, Massachusetts Institute of Technology

Primary Appointment

  • Professor, Microbiology, Immunology, and Cancer Biology

Contact

Research Interest(s)

Human Immunodeficiency; Virus Gene Expression

Research Description

HIV is an important virus , not only because it is the cause of AIDS , but also because its study has led to the discovery of novel basic mechanisms that operate in eukaryotic cells. Over the past two decades , the study of HIV replication has provided insight into fundamental processes operating within the cell. Elucidating these processes provides information for the design of the next generation of anti-HIV drugs and also basic knowledge that will help us understand other disease processes unrelated to AIDS.

HIV Rev

The centerpiece of our HIV research is focused on the elucidation of the function of the HIV Rev protein. A primary function of this protein is to facilitate the nucleo-cytoplasmic export of mRNAs that retain complete introns. Cellular mRNAs with retained introns are usually restricted by the cell from exiting the nucleus and since many HIV mRNAs have this property , Rev is essential for HIV replication. To perform its export function , Rev binds to a specific element present in some HIV mRNAs called the Rev Response Element. This RNA-protein complex then interacts , through the leucine-rich nuclear export signal in Rev , with cellular factors such as CRM1 and Ran-GTP to facilitate mRNA export. In addition , we have recently shown that Rev promotes the translation of intron-containing RNA.

Many details about Rev function remain unexplored , and our recent experiments focus on some of these issues. In particular , we are studying how small variations in the sequence of Rev and the RRE can modulate HIV infection. We also are studying the basis for the efficient inhibition of HIV replication by an antisense RNA that is directed against the HIV env gene region. An RNA , very similar to the one we are studying , is in clinical trials , and our recent studies show that the trafficking of this molecule through the Rev pathway is essential for it to be a potent inhibitor of HIV replication.

We are also using cell-based screening assays to identify compounds that specifically target HIV Rev function. A recent screen of 40,000 compounds has led to the identification of two small molecules that inhibit HIV replication by interfering with Rev function. These compounds provide proof of principle that the targeting of Rev by small molecules could lead to the development of a novel class of HIV therapeutics.

The Emergence of Drug Resistance among non Clade B Human Immunodeficiency Viruses

HIV-1 drug resistance assays have become essential parts of monitoring in antiretroviral therapy , as they are useful in designing the selection of appropriate treatment regiments for AIDS patients. The genotypic DNA sequencing method has its limitation in that the algorithms defining drug resistance have only been developed for HIV clade B non-complex mutations and they are only an indrect measure of resistance. However, direct phenotypic methods overcome this problem. Based on a lentivirus Gag-Pol packaging system, we are developing systems using a luciferase reporter gene to easily allow drug resistance to be measured in non Clade B viruses. Using these assays , as well as genotypic sequencing methods , in collaboration with Dr. Pascal Bessong , of the University of Venda in South Africa we have been defining the prevalence of HIV resistance in the non-treated population in selected areas in Limpopo Province , a rural province in northern South Africa. We are also investigating the impact of polymorphisms on baseline resistance , resistance development and the resistance evolutionary patterns in HIV-1-C infected patients who are undergoing treatment.

Selected Publications

  • Murgai M, Thomas J, Cherepanova O, Delviks-Frankenberry K, Deeble P, Pathak V, Rekosh D, Owens G. Xenotropic MLV envelope proteins induce tumor cells to secrete factors that promote the formation of immature blood vessels. Retrovirology. 2013;10 34. PMID: 23537062 | PMCID: PMC3681559
  • Sloan E, Kearney M, Gray L, Anastos K, Daar E, Margolick J, Maldarelli F, Hammarskjold M, Rekosh D. Limited nucleotide changes in the Rev response element (RRE) during HIV-1 infection alter overall Rev-RRE activity and Rev multimerization. Journal of virology. 2013;87(20): 11173-86. PMID: 23926352 | PMCID: PMC3807272
  • Coyle J, Bor Y, Rekosh D, Hammarskjold M. The Tpr protein regulates export of mRNAs with retained introns that traffic through the Nxf1 pathway. RNA (New York, N.Y.). 2011;17(7): 1344-56. PMID: 21613532 | PMCID: PMC3138570
  • Hammarskjold M, Rekosh D. A long-awaited structure is rev-ealed. Viruses. 2011;3(5): 484-92. PMID: 21941623 | PMCID: PMC3176729
  • Iweriebor B, Mavhandu L, Masebe T, Rekosh D, Hammarskjold M, Mphahlele J, Bessong P. Molecular epidemiology of HIV in two highly endemic areas of northeastern South Africa. Archives of virology. 2011;157(3): 455-65. PMID: 22189822
  • Shuck-Lee D, Chang H, Sloan E, Hammarskjold M, Rekosh D. Single-nucleotide changes in the HIV Rev-response element mediate resistance to compounds that inhibit Rev function. Journal of virology. 2011;85(8): 3940-9. PMID: 21289114 | PMCID: PMC3126119
  • Moore M, Nikolaitchik O, Chen J, Hammarskjöld M, Rekosh D, Hu W. Probing the HIV-1 genomic RNA trafficking pathway and dimerization by genetic recombination and single virion analyses. PLoS pathogens. 2009;5(10): e1000627. PMID: 19834549 | PMCID: PMC2757677
  • Legiewicz M, Badorrek C, Turner K, Fabris D, Hamm T, Rekosh D, Hammarskjöld M, Le Grice S. Resistance to RevM10 inhibition reflects a conformational switch in the HIV-1 Rev response element. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(38): 14365-70. PMID: 18776047 | PMCID: PMC2567145
  • Olivieri K, Scoggins R, Broderick B, Powell M, Alexander M, Hammarskjöld M, Rekosh D, Camerini D. Nef does not contribute to replication differences between R5 pre-AIDS and AIDS HIV-1 clones from patient ACH142. Retrovirology. 2008;5 42. PMID: 18510766 | PMCID: PMC2440386
  • Shuck-Lee D, Chen F, Willard R, Raman S, Ptak R, Hammarskjold M, Rekosh D. Heterocyclic compounds that inhibit Rev-RRE function and human immunodeficiency virus type 1 replication. Antimicrobial agents and chemotherapy. 2008;52(9): 3169-79. PMID: 18625767 | PMCID: PMC2533482
  • Ward A, Rekosh D, Hammarskjold M. Trafficking through the Rev/RRE pathway is essential for efficient inhibition of human immunodeficiency virus type 1 by an antisense RNA derived from the envelope gene. Journal of virology. 2008;83(2): 940-52. PMID: 18971264 | PMCID: PMC2612364
  • Bessong P, Mphahlele J, Choge I, Obi L, Morris L, Hammarskjold M, Rekosh D. Resistance mutational analysis of HIV type 1 subtype C among rural South African drug-naive patients prior to large-scale availability of antiretrovirals. AIDS research and human retroviruses. 2007;22(12): 1306-12. PMID: 17209775
  • Medeiros M, Arruda E, Guerrant R, Brown C, Hammarskjold M, Rekosh D, Lima A. Genotype testing and antiretroviral resistance profiles from HIV-1 patients experiencing therapeutic failure in northeast Brazil. The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases. 2007;11(4): 390-4. PMID: 17873990
  • Swartz J, Bor Y, Misawa Y, Rekosh D, Hammarskjold M. The shuttling SR protein 9G8 plays a role in translation of unspliced mRNA containing a constitutive transport element. The Journal of biological chemistry. 2007;282(27): 19844-53. PMID: 17513303
  • Bor Y, Swartz J, Morrison A, Rekosh D, Ladomery M, Hammarskjöld M. The Wilms' tumor 1 (WT1) gene (+KTS isoform) functions with a CTE to enhance translation from an unspliced RNA with a retained intron. Genes & development. 2006;20(12): 1597-608. PMID: 16738405 | PMCID: PMC1482480
  • Li Y, Bor Y, Misawa Y, Xue Y, Rekosh D, Hammarskjöld M. An intron with a constitutive transport element is retained in a Tap messenger RNA. Nature. 2006;443(7108): 234-7. PMID: 16971948
  • Olivieri K, Scoggins R, Bor Y, Matthews A, Mark D, Taylor J, Chernauskas D, Hammarskjöld M, Rekosh D, Camerini D. The envelope gene is a cytopathic determinant of CCR5 tropic HIV-1. Virology. 2006;358(1): 23-38. PMID: 16999983
  • Lévesque L, Bor Y, Matzat L, Jin L, Berberoglu S, Rekosh D, Hammarskjöld M, Paschal B. Mutations in tap uncouple RNA export activity from translocation through the nuclear pore complex. Molecular biology of the cell. 2005;17(2): 931-43. PMID: 16314397 | PMCID: PMC1356601
  • Alexander M, Bor Y, Ravichandran K, Hammarskjöld M, Rekosh D. Human immunodeficiency virus type 1 Nef associates with lipid rafts to downmodulate cell surface CD4 and class I major histocompatibility complex expression and to increase viral infectivity. Journal of virology. 2004;78(4): 1685-96. PMID: 14747534 | PMCID: PMC369412
  • Jin L, Guzik B, Bor Y, Rekosh D, Hammarskjöld M. Tap and NXT promote translation of unspliced mRNA. Genes & development. 2004;17(24): 3075-86. PMID: 14701875 | PMCID: PMC305259