TSG101 exposure on the surface of HIV-1 infected cells: implications for monoclonal antibody therapy for HIV/AIDS.

HIV infection remains a major global public health problem, in part because of the ability of the virus to elude antiretroviral therapies. Most conventional drugs were designed to directly target virus-encoded mechanisms. However, there is increasing appreciation that certain host-encoded molecules are comparably important for the viral life cycle and could therefore represent potential antiviral targets. Prominent among these is TSG101, a cytoplasmic molecule that is "hijacked" by HIV and used to facilitate viral budding and release. In our present report, we demonstrate thatTSG101 is uniquely exposed on the surface of HIV-infected cells and is available to antibody-based therapies. We also characterize the development of a monoclonal antibody, CB8-2, which reduces virus production from infected cells. These studies demonstrate the potential of TSG101-directed antibodies to combat HIV/AIDS.

[1]  Frank Romanelli,et al.  Maraviroc, a CCR5 Coreceptor Antagonist That Blocks Entry of Human Immunodeficiency Virus Type 1 , 2009, Pharmacotherapy.

[2]  V. Lee,et al.  Chemokine receptors as targets for cancer therapy. , 2009, Current pharmaceutical design.

[3]  A. Hughes,et al.  HIV entry: new insights and implications for patient management , 2009, Current opinion in infectious diseases.

[4]  C. Salata,et al.  Role of multivesicular bodies and their components in the egress of enveloped RNA viruses , 2009, Reviews in medical virology.

[5]  R. König,et al.  Global Analysis of Host-Pathogen Interactions that Regulate Early-Stage HIV-1 Replication , 2008, Cell.

[6]  P. Thorpe,et al.  Targeting Inside-Out Phosphatidylserine as a Therapeutic Strategy For Viral Diseases , 2008, Nature Medicine.

[7]  S. Strathdee,et al.  Adherence to antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome among drug users: a systematic review. , 2008, Addiction.

[8]  S. Broyles,et al.  Use of tissue culture cell lines to evaluate HIV antiviral resistance. , 2008, AIDS research and human retroviruses.

[9]  Robert W Shafer,et al.  HIV-1 drug resistance mutations: an updated framework for the second decade of HAART. , 2008, AIDS reviews.

[10]  H. Volk,et al.  Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study , 2008, The Lancet.

[11]  Yuhua Liao,et al.  The renin-angiotensin system and therapeutic vaccines for hypertension. , 2008, Current opinion in investigational drugs.

[12]  M. Marcos,et al.  Adherence to highly active antiretroviral therapy in HIV-infected inmates. , 2008, Current HIV Research.

[13]  D. Bennett,et al.  The World Health Organization's global strategy for prevention and assessment of HIV drug resistance , 2008, Antiviral therapy.

[14]  J. Lieberman,et al.  Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen , 2007, Science.

[15]  Yu Zhou,et al.  Impact of single-chain Fv antibody fragment affinity on nanoparticle targeting of epidermal growth factor receptor-expressing tumor cells. , 2007, Journal of molecular biology.

[16]  A. Schroit,et al.  Regulated Externalization of Phosphatidylserine at the Cell Surface , 2007, Journal of Biological Chemistry.

[17]  H. Kräusslich,et al.  Ultrastructural Analysis of ESCRT Proteins Suggests a Role for Endosome‐Associated Tubular–Vesicular Membranes in ESCRT Function , 2006, Traffic.

[18]  J. Goedert,et al.  Consistent Effects of TSG101 Genetic Variability on Multiple Outcomes of Exposure to Human Immunodeficiency Virus Type 1 , 2006, Journal of Virology.

[19]  R. Siegel,et al.  Molecular evolution of antibody affinity for sensitive detection of botulinum neurotoxin type A. , 2005, Journal of molecular biology.

[20]  A. Saïb,et al.  Early stages of HIV replication: how to hijack cellular functions for a successful infection. , 2004, AIDS reviews.

[21]  K. Rosendal,et al.  The growth-regulatory protein HCRP1/hVps37A is a subunit of mammalian ESCRT-I and mediates receptor down-regulation. , 2004, Molecular biology of the cell.

[22]  D. Pillay,et al.  Transmission of HIV-1 drug resistance. , 2004, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[23]  S. Cohen,et al.  Tsg101 Control of Human Immunodeficiency Virus Type 1 Gag Trafficking and Release , 2003, Journal of Virology.

[24]  P. Bieniasz,et al.  Role of ESCRT-I in Retroviral Budding , 2003, Journal of Virology.

[25]  L. Enquist,et al.  Break ins and break outs: viral interactions with the cytoskeleton of Mammalian cells. , 2002, Annual review of cell and developmental biology.

[26]  Wesley I. Sundquist,et al.  Structure of the Tsg101 UEV domain in complex with the PTAP motif of the HIV-1 p6 protein , 2002, Nature Structural Biology.

[27]  J. Marks,et al.  Phage versus phagemid libraries for generation of human monoclonal antibodies. , 2002, Journal of molecular biology.

[28]  C. Carter.  Tsg101: HIV-1's ticket to ride. , 2002, Trends in microbiology.

[29]  E. Freed,et al.  Overexpression of the N-terminal domain of TSG101 inhibits HIV-1 budding by blocking late domain function , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[30]  P. Bieniasz,et al.  HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress , 2001, Nature Medicine.

[31]  Wesley I. Sundquist,et al.  Tsg101 and the Vacuolar Protein Sorting Pathway Are Essential for HIV-1 Budding , 2001, Cell.

[32]  L. Verplank,et al.  Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55Gag , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Y. Kan,et al.  Antibodies to human fetal erythroid cells from a nonimmune phage antibody library , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[34]  J. Gerhart,et al.  Efficient construction of a large nonimmune phage antibody library: the production of high-affinity human single-chain antibodies to protein antigens. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Chen,et al.  Isolation and characterization of two divergent infectious molecular clones of HIV type 1 longitudinally obtained from a seropositive patient by a progressive amplification procedure. , 1997, AIDS research and human retroviruses.

[36]  Stanley N Cohen,et al.  tsg101: A Novel Tumor Susceptibility Gene Isolated by Controlled Homozygous Functional Knockout of Allelic Loci in Mammalian Cells , 1996, Cell.

[37]  J. Condra,et al.  In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors , 1995, Nature.

[38]  V. Johnson,et al.  Standardized peripheral blood mononuclear cell culture assay for determination of drug susceptibilities of clinical human immunodeficiency virus type 1 isolates. The RV-43 Study Group, the AIDS Clinical Trials Group Virology Committee Resistance Working Group , 1993, Antimicrobial Agents and Chemotherapy.

[39]  H R Hoogenboom,et al.  By-passing immunization. Human antibodies from V-gene libraries displayed on phage. , 1991, Journal of molecular biology.

[40]  H. Gendelman,et al.  Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone , 1986, Journal of virology.

[41]  Shannon A. Miller,et al.  Angiotensin II vaccine: a novel approach in the treatment of hypertension. , 2008, Expert opinion on biological therapy.

[42]  B. Sodeik,et al.  The role of the cytoskeleton during viral infection. , 2005, Current topics in microbiology and immunology.