Abstract

The goal of this project is to analyze quantitatively infections by primary patient (PR) and laboratory-adapted (LA) isolate viruses and to learn how differences in CD4 affinities affect cellular tropisms. The first of the investigator's three specific aims is to study quantitatively adsorption and penetration of PR and LA T cell-tropic HIV isolates into CD4- positive cells using cell clones with diverse amounts of CD4. The author proposes to study the kinetics of the steps of HIV attachment and to determine the order of CD4 involvement in each step. He will identify cellular factor(s) other than CD4 that limit attachment of LA viruses and their placement in the infection pathway.
The second aim i s to use molecularly cloned env genes of PR and LA viruses and of mutant viruses that have reduced CD4 affinities, and to identify features of env glycoproteins that control discrete steps of viral entry pathways.
The third aim i s to learn how absorptive properties of PR viruses change throughout disease progression. The fourth and last aim is to develop a novel system to study gp120- gp41- and CD4-dependent cell-cell fusion and to use it to study and possibly to clone cDNAs for cellular accessory factors.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA067358-09
Application #
6626657
Study Section
Special Emphasis Panel (ZRG5-AARR-1 (01))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1995-03-15
Project End
2004-04-14
Budget Start
2003-01-01
Budget End
2004-04-14
Support Year
9
Fiscal Year
2003
Total Cost
$284,402
Indirect Cost

  Institution

Name
Oregon Health and Science University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239

  Publications

Marin, Mariana; Golem, Sheetal; Kozak, Susan L et al. (2016) Movements of HIV-1 genomic RNA-APOBEC3F complexes and PKR reveal cytoplasmic and nuclear PKR defenses and HIV-1 evasion strategies. Virus Res 213:124-139
Platt, Emily J; Durnin, James P; Kabat, David (2015) Short Communication: HIV-1 Variants That Use Mouse CCR5 Reveal Critical Interactions of gp120's V3 Crown with CCR5 Extracellular Loop 1. AIDS Res Hum Retroviruses 31:992-8
Platt, Emily J; Gomes, Michelle M; Kabat, David (2014) Reversible and efficient activation of HIV-1 cell entry by a tyrosine-sulfated peptide dissects endocytic entry and inhibitor mechanisms. J Virol 88:4304-18
López, Claudia S; Sloan, Rachel; Cylinder, Isabel et al. (2014) RRE-dependent HIV-1 Env RNA effects on Gag protein expression, assembly and release. Virology 462-463:126-34
Platt, Emily J; Gomes, Michelle M; Kabat, David (2012) Kinetic mechanism for HIV-1 neutralization by antibody 2G12 entails reversible glycan binding that slows cell entry. Proc Natl Acad Sci U S A 109:7829-34
Platt, Emily J; Kozak, Susan L; Durnin, James P et al. (2010) Rapid dissociation of HIV-1 from cultured cells severely limits infectivity assays, causes the inactivation ascribed to entry inhibitors, and masks the inherently high level of infectivity of virions. J Virol 84:3106-10
Platt, Emily J; Bilska, Miroslawa; Kozak, Susan L et al. (2009) Evidence that ecotropic murine leukemia virus contamination in TZM-bl cells does not affect the outcome of neutralizing antibody assays with human immunodeficiency virus type 1. J Virol 83:8289-92
Platt, Emily J; Durnin, James P; Shinde, Ujwal et al. (2007) An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations. J Mol Biol 374:64-79
Melikyan, Gregory B; Platt, Emily J; Kabat, David (2007) The role of the N-terminal segment of CCR5 in HIV-1 Env-mediated membrane fusion and the mechanism of virus adaptation to CCR5 lacking this segment. Retrovirology 4:55
Platt, Emily J; Durnin, James P; Kabat, David (2005) Kinetic factors control efficiencies of cell entry, efficacies of entry inhibitors, and mechanisms of adaptation of human immunodeficiency virus. J Virol 79:4347-56

Showing the most recent 10 out of 28 publications