Division of Intramural Research

Research Highlights

FY 2005 | FY 2004 | FY 2003 | FY 2002 | FY 2001 | FY 2000

FY 2006

• Monoclonal antibodies to vaccinia virus B5 protein neutralize vaccinia and smallpox viruses and protect mice against vaccinia virus.
  Investigators created chimpanzee/human monoclonal antibodies that could be developed for human use to protect against untoward reactions to vaccinia-based immunization or for passive protection and therapy for smallpox. They may also be useful for protection against other pox viruses, such as monkeypox virus. Proceedings of the National Academy of Science USA. 2006. 103:1882-1887.
• HIV-infected individuals receiving effective antiviral therapy resulting in suppression of viremia for extended periods of time continually replenish their viral reservoir. The authors demonstrated that HIV continually replicates in activated and resting CD4+ T cells in the absence of detectable plasma viremia resulting from effective antiretroviral therapy. This study suggests that intensification of existing drug regimens or the addition of a new class of drug, such as an HIV entry inhibitor, may be necessary to eliminate on-going, low-level viral replication in infected individuals receiving conventional therapy. Journal of Clinical Investigation. Nov. 2005.115:3250-3255.
• Discovery of a novel bacterium associated with lymphadenitis in a patient with chronic granulomatous disease.
  Investigators isolated a novel Gram-negative rod from a patient with chronic granulomatous disease (CGD) and fulfilled Koch's postulates for a new pathogen. Taxonomic analysis showed this organism to be a new genus and species. This is the first report of a new bacterium that is a cause of necrotizing lymphadenitis in CGD, and the team has discovered additional cases. PLoS Pathogens. Apr 2006. 2(4):e28.
• Yersinia pestis adapts to extracellular effectors of innate immunity during bubonic plague.
  The fulminant progression of plague has been largely attributed to the ability of Y. pestis to disrupt the normal innate immune response and avoid destruction. Investigators found that the bacterium also makes an adaptive response to antimicrobial reactive nitrogen molecules induced by plague infection. Proceedings of the National Academy of Science USA. 2006. 103:11766-71.
• Autoreactive B-cell responses to RNA-related antigens due to TLR7 gene duplication.
  Investigators found that, in mice, one extra copy of the TLR7 gene is enough to predispose them to severe autoimmunity—direct evidence that minor genetic mutations, small differences in gene expression, are important. This study provides new understanding of how this gene works and insight into the genetic basis of lupus. It also highlights TLR7 as another potential target for lupus therapies. Science. 2006. 312 (5780):1669-72.
• Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptor.
  The pre-ligand assembly domain (PLAD) is a portion of the extracellular region of TNFRs that mediates receptor-chain association essential for signaling. Investigators found that soluble versions of PLAD, especially those derived from P60, block the biochemical effects of TNF-alpha in vitro and potently inhibit arthritis in animal models. Thus, targeting the PLAD may have clinical value in the treatment of human arthritis and other disorders involving receptors of the TNFR superfamily. Nature Medicine. Oct. 2005.11(10):1066-72.
• Cystine transporter Xct identified as Kaposi's sarcoma-associated herpesvirus fusion-entry receptor.
  This discovery may lead to new avenues for treating KSHV infection and should enable scientists to determine whether levels of xCT determine disease severity. It also will allow researchers to study whether the expression of xCT on cells varies among different groups of people, whether these variations are genetic or environmental, and, ultimately, it may explain why certain groups are more at risk for Kaposi’s sarcoma. Science. 2006. 311:1921-1924.
• Insulin degrading enzyme is a cellular receptor for varicella-zoster virus infection and for cell-to-cell spread of virus.
  Investigators have identified a cellular receptor (insulin-degrading enzyme or IDE) for the varicella-zoster virus (VZV) and have found molecules that block the interaction of IDE with a virus glycoprotein and inhibit virus infection. Molecules that block the interaction of the receptor with the virus glycoprotein might be used to inhibit VZV infection in people. Cell. 2006. Oct. 20;127(2):305-16.
• Prions induce amyloid heart disease with high blood infectivity in transgenic mice.
  This work indicates that heart infection might be a new aspect of transmissible spongiform encephalopathies and provides cardiologists an animal model in which to study heart amyloidosis, a family of heart diseases that affect humans. This finding could help scientists develop a blood-based diagnostic test to identify brain-wasting diseases and possibly lead to a way to filter or chemically treat blood to remove any infectious prion disease agents. Science. 2006. Jul 7;313(5783):94-7.
• Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection.
  Investigators identified a mechanism by which mice send white blood cells to the brain to fight WNV infection. The mechanism involves a cell receptor for chemoattractants named CCR5, which is also used by HIV for entering target cells in man. Thus, the same receptor can act for or against the host depending on the virus. This finding suggested that humans deficient in CCR5 due to either a defective gene or drug blockade (in the case of HIV) might be more susceptible to symptomatic WNV infection. Journal of Experimental Medicine. Oct. 2005. 202:1087-1098.  A follow-up paper (Journal of Experimental Medicine. 2006. 203:35-40.) demonstrated directly that humans deficient in CCR5 due to an inactivating mutation named CCR5Δ32 are at increased risk of symptomatic West Nile virus infection.  

FY 2005

• RSV vaccine candidate developed and evaluated.

  Recombinant technology was used to create live-attenuated, intranasal RSV vaccine viruses containing combinations of known mutations. One candidate was evaluated in 1- to 2-month old infants and found to be well-tolerated, immunogenic, and protective against a second vaccine dose. Journal of Infectious Diseases. 2005. 191:1093-1104.

• Potent anthrax neutralizing monoclonal antibodies developed.

  These antibodies bind the PA toxin molecule with extraordinary affinity and protect against PA toxin in cell culture and in a rat model. The antibodies may serve as PA entry inhibitors for use in the emergency prophylaxis against and treatment of anthrax. Journal of Infectious Diseases. 2006. Mar 1;193(5):625-33.

• Interleukin-2 therapy prolongs survival of CD4 T cells in HIV-1-infected patients.

  Prolonged T-cell survival occurred after several courses of IL-2 therapy and affected both naïve and central memory CD4 T cells without significantly affecting CD8 T cells. This finding suggests that IL-2 can help maintain cells important for host defense against new antigens and those needed for long-term memory to opportunistic pathogens. Journal of Clinical Investigation. 2005.115:2139-2148.

• Mechanism of hemoglobin C’s malaria-protective effect discovered.

  Malaria parasites use a protein called PfEMP-1 to promote adherence of infected red blood cells (RBCs) to the lining of blood vessels. Hemoglobin C affects the display of PfEMP-1 by reducing both its expression level and distribution on RBCs. These effects mitigate obstruction and inflammation resulting from the adherence of parasitized erythrocytes in the microvasculature. Nature. 2005. 435:1117-21.

• New target to fight certain hospital-acquired infections identified.

  Poly-gamma-DL-glutamic acid, or PGA, found on the surface of Staphylococcus epidermidis was shown to protect the bacterium from innate immune defenses. A vaccine to negate the effect of PGA could be highly successful against all pathogens in which PGA is a basis for disease development, such as staph and the anthrax bacterium. Journal of Clinical Investigation. 2005.115(3):688-94.

• Human enzyme crucial to HIV replication determined.

  The process of how HIV genetic material—a long unedited strand of RNA—exits the cell nucleus has long puzzled scientists. NIAID researchers found that the virus uses a human enzyme known as DDX3 to straighten its RNA before threading it through a small pore in the nucleus. Cell. 2004 (Oct. 29).119:381-392.

• Blocking a newly identified attachment site in the sand fly gut prevents transmission of leishmaniasis.

  NIAID scientists identified and characterized the receptor on sand fly midguts that binds Leishmania parasites and controls their competence to transmit the most common form of cutaneous leishmaniasis. Cell. 2004 (Oct. 29). ). 119:329–41.

• Insight into prion pathogenesis reveals a potential new target for therapy of prion diseases.

  A variant form of abnormal prion protein—one lacking an anchor into the cell membrane—may be unable to signal cells to start the lethal disease process. This finding provides insight into how nerve cells in the brain are killed during the course of prion diseases and suggests a possible new approach for drug therapy for prion diseases. Science. 2005. 308:1435-9.

• An enzyme deficiency causing both autoimmunity and combined immunodeficiency explained.

  Caspase-8 deficiency in humans and in mice specifically abolishes activation of a lymphocyte nuclear factor, NF-kappaB, which is normally activated in response to recognition of antigens or inflammatory mediators. This work explains the paradoxical association of defective programmed cell death and combined immunodeficiency in human caspase-8 deficiency. Science. 2005. 307:1465-1468.

FY 2004

• Mouse model mimics real-world plague infection.

  A flea-to-mouse transmission model was developed for use in testing new candidate vaccines for the ability to protect against flea-borne plague. An experimental plague vaccine proved 100 percent effective when tested in the new model. Infection and Immunity. 2004. 72:2052-56.

• SARS mouse model advances development of vaccines and therapeutics.

  A mouse model of SARS replication revealed that antibodies alone can prevent replication of the SARS Co-V in the lung, a promising observation for the development of SARS vaccines and immunotherapies. Journal of Virology. 2004. 78:3572-3577.

• Treg cells suppress immune responses directed against HIV.

  NIAID scientists found evidence supporting the potential role of Treg cells in decreasing HIV-specific immune responses in HIV-infected individuals, which may have both beneficial and harmful effects. Journal of Experimental Medicine. 2004. 200:331-43.

• Modified vaccinia Ankara (MVA) may be a safer, effective alternative for persons who cannot receive the current U.S.-licensed smallpox vaccine.

  NIAID scientists and their colleagues compared immunization with MVA and Dryvax in a monkey model to evaluate MVA as a replacement vaccine or pre-vaccine for those with increased risk of severe side effects from Dryvax. Nature. 2004. 428:182-185.

• Neutralizing antibodies can protect against hepatitis C and are reliably detected by an in vitro assay.

  A new hepatitis C in vitro test generally correlated with the in vivo assay and could reproducibly detect and quantify neutralizing antibodies. NIAID scientists used the new assay to demonstrate that neutralizing antibodies protect humans from HCV infection. Proceedings of the National Academy of Science USA. 2003 (Nov.). 100:14199-14204; Proceedings of the National Academy of Science USA. 2004. 101:7705-7710.

• Discovery of a new pathway of nerve-cell killing opens new possibilities for treatment of prion diseases.

  Previous evidence suggested that for nerve cell damage to occur, abnormal prion protein had to bind directly to normal prion protein made in the targeted nerve cell. NIAID scientists and their collaborators at Lasswade Laboratory in Scotland indicate that this may not be the complete story. Annals of Neurology. 2004. 55: 781-792.

• Clinical trial demonstrates anti-IL-12 may successfully treat Crohn’s disease.

  Crohn's disease is associated with excess cytokine activity mediated by type 1 helper T (Th1) cells. Interleukin-12 is a key cytokine that initiates Th1-mediated inflammatory responses. Encouraging results of this phase II trial of a human monoclonal antibody against IL-12 pave the way for a phase III trial in a large patient cohort. New England Journal of Medicine. 2004. 351:2069-79.

• A component of hypervirulent tuberculosis strains inhibits the innate immune response.

  The spectrum of TB disease in humans probably reflects the variable expression of both host and bacterial factors. DIR researchers identified and characterized a bacterial component that appears to make a subset of TB strains hyperlethal in mice. Nature. 2004. 431:84-7.

• A comprehensive international report on mutations in the interferon gamma receptor and the syndromes they cause.

  Over the last 10 years, NIAID scientists and their colleagues identified a series of patients with these mutations to draw a comprehensive picture of the clinical and biochemical aspects of this disease. Lancet. 2004. 364:2113-21.

• Autophagy is a key pathway in immune regulation-induced cell death.

  Cell death is key to the normal regulation of immune responses to avoid excessive inflammatory and immune responses that could result in autoimmunity. Apoptosis, the major mechanism of cell death, isn’t the only endgame in town. NIAID scientists, studying another major form of cell death called autophagy, found that it too plays a key role in immune cell death, and paradoxically, is induced by inhibiting one of the very enzymes that initiates apoptosis. Science. 2004. 304:1500-1502.

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FY 2003

• A novel function of immunoglobulins is to neutralize anaphylatoxins.

  Using a variety of scientific approaches, NIAID DIR scientists discovered that intravenous immunoglobulin (IVIG) binds the anaphylatoxins C3a and C3b that cause tissue damage in a variety of diseases from asthma to vasculitis. This binding by IVIG neutralizes their function and helps prevent tissue damage. This finding helps to explain the anti-inflammatory effect of intravenous immunoglobulins and will possibly expand their clinical applications. Nature Medicine. 2003. 9:431-438.

• Identification of novel immune cell defects associated with HIV disease.

  NIAID DIR scientists discovered that B cells of HIV-infected patients with high viral loads are defective in their responsiveness to stimulation by T-helper cells. Even though these patients' T-helper cells produced normal amounts of the cell surface molecule that mediates the direct interaction between T cells and B cells, their B cells did not respond properly to T-helper cell stimulation. Proceedings of the National Academy of Science USA. 2003. 100: 6057-6062.

• Clues into the survival and emergence of drug resistance in tuberculosis.

  M. tuberculosis uses an enzyme called DnaE2 to repair its DNA. NIAID DIR researchers determined that M. tb's DNA repairs occur in an error-prone manner and demonstrated that wild-type M. tb developed resistance to a common antibiotic, while strains lacking the Dna2 gene-and hence, the error-prone repair system-did not develop antibiotic resistance. These data provide evidence that DnaE2 is the primary mediator of M. tb survival through mutations that may cause drug resistance in vivo. Cell. 2003. 113:183-193.

• Mutations in a Plasmodium falciparum adhesin change its red cell specificity.

  Malaria parasites use specialized proteins called adhesins to gain entry into red blood cells (RBCs). NIAID DIR scientists found that P. falciparum uses an adhesin, BAEBL, which binds to glycophorin C, an RBC receptor with a high mutation rate. The scientists discovered that small changes in BAEBL allow the parasite to bind to RBC receptors other than glycophorin C. Thus, mutations in glycophorin C do not lead to resistance to RBC invasion by P. falciparum because of the flexibility of BAEBL. This flexibility suggests that BAEBL is a critical adhesin and may be an important malaria vaccine target. Journal of Experimental Medicine. 2002. 196:1523-1528.

• Changes in an immune system protein protect against cardiovascular disease.

  NIAID DIR scientists and their collaborators discovered that patients with a small change in the gene for the white blood cell receptor CX3CR1 have a lower risk of heart attack. They believe the genetic change may influence risk by reducing the level of immune activity responsible for atherosclerotic plaques. The genetic change causes a severe loss of function in CX3CR1 and mice lacking CX3CR1 are less susceptible to atherosclerosis. This finding may lead to new approaches to preventing or treating heart attacks and other diseases caused by atherosclerosis. Journal of Clinical Investigation. 2003. 111:1241-50; Circulation. 2003. 107: 1009-1016.

• Identification of a negative regulator of B-cell immune responses.

  When pathogens bind to receptors located on B cells, the B cells become activated to synthesize and secrete large quantities of antibodies, an important immune defense. NIAID DIR scientists demonstrated that a cellular protein known as Cbl-b dampens the signal initiated by the B-cell surface receptor by causing a protein known as Syk to become targeted for degradation. Understanding the protein interactions that mediate immune responses will enable better design of vaccines and treatments for autoimmune diseases. Journal of Experimental Medicine. 2003. 197:1-15.

• Subclinical infection with mad cow disease agents may lead to dangerous transmission in the future.

  NIAID DIR scientists studied subclinical infectivity of transmissible spongiform encephalopathy (TSE) agents by inoculating mice with the hamster scrapie agent and, over time, serially passaging brain tissue to additional mice while assessing the infectious potential of brain samples obtained after each passage. The results demonstrated that the hamster scrapie agent was eventually able to adapt and cause clinical disease in mice. Thus, even in the absence of clinical signs, TSE agents may be able to replicate and adapt over many years to become more dangerous to a resistant species. Journal of Infectious Diseases. 2002. 186: S166-70.

• Rare disorder of caspase-8 deficiency provides new insight into fighting infection.

  NIAID DIR scientists examined siblings who had a puzzling immune system disorder with symptoms similar to autoimmune lymphoproliferative syndrome (ALPS). Genetic tests showed no defects previously associated with ALPS, but revealed a mutation in the caspase-8 gene that rendered the caspase-8 enzyme inactive in these siblings. The siblings also had recurrent viral infections and poor response to vaccines. The scientists discovered that caspase-8 enzyme is also involved in activating immune cells to battle infections and might be a useful target for a new class of anti-inflammatory or immunosuppressive therapies. Nature. 2002. 419: 395-9.

• A protozoan pathogen triggers innate immunity by mimicking host chemokines.

  Toxoplasma gondii releases factors that potently stimulate the production of interleukin-12 (IL-12), a protein factor produced by dendritic cells. NIAID DIR scientists showed that cyclophilin-18 (C-18) is the principal factor, and antibodies that can bind to recombinant C-18 inhibited the synthesis of IL-12. rC-18 triggered cell activation signaling through CCR5, a receptor for immune system chemokines, which are important in parasite-induced IL-12 production by dendritic cells. Thus, the unusual potency of T. gondii in inducing the production of IL-12 by dendritic cells results from its synthesis of a unique chemokine mimic. Nature Immunology. 2003. 4: 485-90.

• Development of a recombinant vaccine against hepatitis E virus.

  Hepatitis E virus (HEV) is one of the most important causes of acute clinical hepatitis among adults in southeast and central Asia, the Middle East and North Africa and it poses a risk to travelers to these areas. NIAID DIR scientists and their colleagues developed a candidate vaccine that is highly effective in preventing both hepatitis E infection and disease in an animal model. The vaccine protected the animals against three strains of hepatitis E and is being tested for efficacy in a field trial in Nepal. Vaccine. 2003. 21: 2607-2615.

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FY 2002

• Development of a live attenuated vaccine candidate against West Nile virus.

  The West Nile virus usually causes only mild symptoms in humans, but can spread to the central nervous system and cause a potentially deadly brain inflammation called encephalitis. NIAID researchers constructed a candidate live attenuated vaccine for West Nile virus (WNV) by replacing genes for the structural pre-membrane and envelope proteins of DEN4 from an infectious cDNA clone with the corresponding genes of WNV strain NY99. The WNV/DEN4 chimera was highly attenuated in mice, yet elicited an immune response that completely protected against lethal WNV challenge. These observations provide the basis for pursuing the development of a live attenuated WN vaccine for humans.

  Pletnev AG, Putnak R, Speicher J, Wagar EJ, and Vaughn DW. West Nile virus/dengue type 4 virus chimeras that are reduced in neurovirulence and peripheral virulence without loss of immunogenicity or protective efficacy. Proceedings of the National Academy of Science USA. 2002. 99: 3036-3041.

• A novel approach to block HIV infection: implications for therapy and vaccine development.

  The next generation of anti-retroviral drugs may include entry inhibitors that prevent HIV from infecting CD4+ T cells. Past attempts to develop inhibitors of viral entry have failed, in part because entry inhibitors were unable to efficiently prevent HIV from binding to its primary receptor, CD4, and its coreceptor, CCR5. NIAID DIR investigators constructed a molecule derived from sCD4 that displays 12 HIV gp120 binding sites. Binding of this molecule to HIV gp120 appeared to be almost irreversible. Because of its enhanced avidity this molecule is able to neutralize a broad array of primary HIV isolates at relatively low concentrations.

  Arthos J, Cicala C, Steenbeke TD, Chun TW, Dela Cruz C, Hanback DB, Khazanie P, Nam D, Schuck P, Selig SM, Van Ryk D, Chaikin MA, Fauci AS. Biochemical and biological characterization of a dodecameric CD4-Ig fusion protein: implications for therapeutic and vaccine strategies. Journal of Biological Chemistry. 2002. 277(13):11456-64.

• Acquisition of a single gene allowed a benign bacillus to become the agent of "Black Death".

  Yersinia pestis, the cause of bubonic and pneumonic plague in humans, is transmitted by the bites of infected fleas. NIAID DIR scientists identified a gene of Y. pestis that is specifically required for it to survive in the flea. This research illustrates how a single genetic change can profoundly affect the evolution of disease, in this case, by setting the stage for a completely new route of disease transmission. This finding explains how the bacterium gradually changed from a germ that caused a mild human stomach illness acquired via contaminated food or water to the flea-borne agent of the "Black Death".

  Hinnebusch BJ, Rudolph AE, Cherepanov P, Dixon JE, Schwan TG, Forsberg A. Role of Yersinia murine toxin in survival of Yersinia pestis in the midgut of the flea vector. Science. 2002. 296: 733-735.

• Discovery of new influenza virus protein that causes cell death.

  Influenza A virus remains a major cause of disease and death in the USA and maintains the potential to cause devastating global epidemics. NIAID DIR scientists discovered a new influenza A virus protein that seems to trigger the death of certain cells involved in the early immune response to the virus. The scientists are studying whether this new protein enables influenza A virus to replicate faster by disarming this important part of the immune system. The team also will study whether this protein may help explain especially virulent flu epidemics, such as the pandemic of 1918, which killed 20 million people worldwide.

  Chen W, Calvo PA, Malide D, Gibbs J, Schubert U, Bacik I, Basta S, O'Neill R, Schickli J, Palese P, Henklein P, Bennink JR, Yewdell JW. A novel influenza A virus mitochondrial protein that induces cell death. Nature Medicine. 2001. 7, 1306-12.

• Mechanism of emergence of virulence in group A streptococcus.

  Serotype M3 strains of group A streptococcus (GAS) are a common cause of severe invasive infections with high rates of morbidity and mortality. NIAID DIR scientists and their colleagues sequenced the genome of an M3 GAS isolated from a patient with toxic shock syndrome and found that bacterial viruses, or phages, accounted for the great majority of variation in gene content relative to the sequenced M1 and M18 GAS strains. This work shows that phage-mediated recombination has played a critical role in the emergence of a new, unusually virulent clone of serotype M3 GAS.

  Beres SB, Sylva GL, Barbian KD, Lei B, Hoff J.S, Mammarella ND, Liu M-Y, Smoot JC, Porcella SF, Parkins LD, McCormick JK, Leung DYM, Schlievert PM, Musser JM. Genome sequence of a serotype M3 strain of group A streptococcus: Phage-encoded toxins, the high-virulence phenotype, and clone emergence. Proceedings of the National Academy of Science USA. 2002. 99(15):10078-83.

• The role of adenosine in controlling inflammation and implications for therapy.

  Inflammation is the body's response to injury and a critical defense against attack by infectious organisms. But too much inflammation can cause harm, such as the tissue damage seen in sepsis, hepatitis, rheumatoid arthritis, multiple sclerosis and other diseases. NIAID DIR scientists demonstrated that excess extracellular adenosine acts as a signal for excessive tissue damage. When tissue damage mounts due to prolonged inflammation, oxygen levels in the damaged area fall. This in turn leads to increased adenosine outside cells, which binds to adenosine receptors, initiating a chain reaction that slows and eventually stops inflammation. This finding suggests opportunities for the design of novel modulators of inflammation that target extracellular adenosine and the A2a adenosine receptor.

  Ohta A, Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature. 2001. 414: 917-920.

• Determination of the structural basis of natural killer cell recognition of virus- infected cells.

  Immune system cells called natural killer (NK) cells have the ability to recognize and kill tumor cells and virus-infected cells while leaving normal healthy cells alone. To understand how NK cells recognize their targets, NIAID DIR scientists determined the three dimensional structure of an NK cell activating receptor, NKG2D, bound to its ligand, a glycoprotein produced by human cytomegalovirus ULBP3. Significantly, comparisons to NKG2D bound to another ligand revealed a plasticity in the binding that helps explain the discriminatory capability of NK cells.

  Radeav S, Rostro B, Brooks AG, Colonna M, Sun PD. Conformational plasticity revealed by the cocrystal structure of NKG2D and its class I MHC-like ligand ULBP3. Immunity. 2001. 15:1039-1049.

• Genetic studies of the human malaria parasite reveal ancient origin.

  Genetic variation of the parasite is the major hindrance to developing effective and lasting vaccines and drugs to fight P. falciparum malaria, and the amount of genetic diversity in and origin of the parasite is the subject of considerable debate. NIAID DIR scientists studied single nucleotide polymorphisms from more than 200 genes and concluded that the parasite has a diverse genome and a history of population expansion coinciding with human population growth ~100,000-180,000 years ago. This ancient origin and diversity suggest a long battle ahead to control the deadly disease.

  Mu J, Duan J, Makova K, Joy DA, Huynh CQ, Branch OH, Li WH, Su XZ. Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum. Nature. 2002. 418:323-6.

• Genetic variants of two chemokine receptors are associated with reduced risk of transplant rejection.

  Chemokines control the movement of white blood cells to sites of inflammation. CCR5 and CCR2 are chemokine receptors found on the surface of white blood cells. NIAID scientists and their collaborators have discovered that patients with certain changes in the genes for these receptors have lower risk of kidney transplant rejection. These genetic changes may be influencing the risk of rejection by affecting the level of immune activity against the foreign kidney mediated by these receptors. Better understanding of the roles of such genetic factors may lead to new approaches to improving the outcome of organ transplantation.

  Abdi R, Huong, TT, Sahagun-Ruiz A, Murphy PM, Brenner BM, Milford EL, McDermott DH. Chemokine receptor polymorphism and risk of acute rejection in human renal transplantation. Journal of the American Society of Nephrology. 2002. 13:754-758.

• An improved animal model for varicella-zoster virus.

  Varicella-zoster virus (VZV) causes chickenpox and can reactivate later in life to cause zoster or shingles. At present, no small animal model reproduces the clinical and pathogenic features of chickenpox and shingles. NIAID DIR scientists infected cotton rats with VZV and showed that about two-thirds of the animals develop a latent infection that mimics several aspects of latency in humans. This animal model should be useful for evaluating the role of viral genes and antiviral compounds in establishing latent infection by the virus.

  Sato H, Pesnicak L, Cohen JI. Varicella-zoster virus ORF2 encodes a membrane phosphoprotein that is dispensable for viral replication and for establishment of latency. Journal of Virology. 2002. 76:3575-3578.

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FY 2001

• Determination of the structure of a human gammadelta T-cell antigen receptor.

  The gammadelta T-cell receptors (TCRs) recognize small antigens in the blood and in this regard resemble antibodies. In contrast, the alphabeta TCRs see small pieces of antigens bound to cell surface structures. The present study is the first description of the structure of a human gammadelta TCR that is reactive with phosphate-containing small molecules released by the pathogens that cause tuberculosis, malaria, and several other diseases. The gammadelta TCR differs in overall shape from alphabeta TCRs, has similarity to antibodies, and displays a site for its interaction with antigen that appears suited to the binding of phosphate-containing antigens.

  Allison TJ, Winter CC, Fournié JJ, Bonneville M, and Garboczi D. Structure of a human gammadelta T cell antigen receptor. Nature. 2001. 411: 820-824.

• Amyloid ß is a potent activator of a white blood cell receptor that mediates both cell movement and production of toxic forms of oxygen: implications for Alzheimer's disease pathogenesis.

  In Alzheimer's disease, a protein named amyloid ß for unknown reasons forms large aggregates in the brain that lead to progressive loss of mental function. The research described in this citation proves that amyloid ß is a potent and specific activator of a particular type of white blood cell receptor named FPRL1R that is connected to both cell movement and to production of toxic forms of oxygen. The receptor was found to be concentrated on cells in the diseased brain areas in Alzheimer's patients. This receptor may explain how aggregation of this protein causes inflammation and disease. This is a new direction in basic research on Alzheimer's disease that has the potential to lead to new treatments.

  Tiffany HL, Lavigne MC, Cui Y-H, Wang J-M, Leto TL, Gao J-L, Murphy PM. Amyloid-beta induces chemotaxis and oxidant stress by acting at formylpeptide receptor 2 (FPR2), a G protein-coupled receptor expressed in phagocytes and brain. Journal of Biological Chemistry. 2001. 276:23645-52.

• B cells bind HIV and transmit infectious virus to activated T cells.

  HIV primarily infects and leads to a depletion of CD4+ T cells, resulting in the immunocompromised status of infected individuals. B cells are also affected by HIV infection. We demonstrated that HIV bound to B cells is passed to T cells, especially in lymphoid tissues where B cells and CD4+ T cells are in close proximity, and thus may contribute to the spread of HIV in an infected individual. Also, binding of HIV to B cells results in a profound down-regulation of expression of the important B cell receptor, CD21, which may contribute in a significant way to the immunological dysfunction of B cells that is observed in HIV infection.

  Moir S, Malaspina A, Li Y, Chun TW, Lowe T, Adelsberger J, Baseler M, Ehler LA, Liu S, Davey RT, Jr., Mican JA, Fauci AS. B cells of HIV-1-infected patients bind virions through CD21-complement interactions and transmit infectious virus to activated T cells. Journal of Experimental Medicine. 2000. 192: 637-46.

• A live attenuated dengue type 4 vaccine candidate derived using cDNA technology was safe and immunogenic in human volunteers.

  A recombinant dengue virus type 4 vaccine candidate, 2Adelta30, was well tolerated and did not cause systemic illness in any of the 20 phase I volunteers. This is the first live attenuated recombinant flavivirus vaccine candidate to be evaluated in humans, indicating the feasibility of using modern molecular techniques to derive dengue virus vaccines to prevent the 50-100 million cases of dengue that occur annually worldwide.

  Durbin AP, Karron RA, Wellington S, Vaughn DW, Reynolds MJ, Perreault JR, Bhavin T, Men R, Lai C-J, Elkins WR, Chanock RM, Murphy BR, Whitehead SS. Attenuation and immunogenicity in humans of a live dengue virus type-4 vaccine candidate with a 30 nucleotide deletion in its 3'-untranslated region. American Journal of Tropical Medicine and Hygiene. 2001. 65:405-13.

  Troyer JM, Hanley KA, Whitehead SS, Strickman D, Karron RA, Durbin AP, Murphy BR. A live attenuated recombinant dengue-4 virus vaccine candidate with restricted capacity for dissemination in mosquitoes and lack of transmission from vaccinees to mosquitoes. American Journal of Tropical Medicine and Hygiene. 2001. 65:414-9.

• Identification of gene mutations that increase the lifetime risk of developing lymphoma.

  In 1995, scientists in NIAID identified a new genetic disease known as autoimmune lymphoproliferative syndrome (ALPS). The most common mutation in ALPS is in a gene that codes for a protein called Fas. When Fas fails to work properly lymphocytes fail to die and accumulate in the tissues and provoke autoimmune injury. Assessment of families with Fas mutations demonstrated that inherited mutations in Fas increase the risk of various types of lymphomas by 14- to 50-fold. This work identifies a new class of genes associated with an inborn increased risk of cancer, and links immunological and autoimmune diseases together with that risk.

  Straus SE, Jaffe ES, Puck JM, Dale JK, Elkon KB, Rosen-Wolff A, Peters AMJ, Sneller MC, Hallahan CW, Wang J, Fischer R, Jackson CM, Lin AY, Baumler C, Siegert E, Marx A, Vaishnaw AK, Grodzicky T, Fleisher TA, Lenardo MJ. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood. 2001. 98:1-7.

• Identification and characterization of new group A streptococcus vaccine candidates.

  Group A streptococcus is a pathogenic bacterium that causes many types of human infections, including sore throats, rheumatic heart disease, and necrotizing fasciitis (the "flesh-eating" syndrome). There is no licensed vaccine available for preventing infections caused by this germ, in part because there are many different strains of the organism found in nature. We identified 11 new group A streptococcus molecules, produced when the germ infects humans, by all strains examined from worldwide sources. These may be useful as components of a human vaccine for control of streptococcus infections.

  Reid SD, Green NM, Buss JK, Lei B, Musser JM. Multilocus analysis of extracellular putative virulence proteins made by group A streptococcus: population genetics, human serologic response, and gene transcription. Proceedings of the National Academy of Science USA. 2001. 98: 7552-7.

• An anti-leishmania vaccine composed of salivary proteins of the sand fly vector produces powerful protective immunity in mice.

  Leishmania parasites are transmitted to their host by infected phlebotomine sand fly bites. A DNA vaccine containing the predominant salivary protein (named SP15) of Phlebotomus papatasi, the vector of Leishmania major, provided protection that lasted at least 3 months after immunization. This vaccine, coding only for the salivary component of the vector, produced the most powerful protection against leishmania infection ever described, demonstrating that salivary proteins or their cDNA are viable vaccine targets against leishmaniasis and possibly other vector borne diseases such as malaria.

  Valenzuela JG, Belkaid Y, Garfield MK, Mendez S, Kamhawi S, Rowton ED, Sacks DL, Ribeiro JMC. Toward a defined anti-leishmania vaccine targeting vector antigens: characterization of a protective salivary protein. Journal of Experimental Medicine. 2001. 194:331-42.

• Nonmyeloablative conditioning with T-cell-depleted hematopoietic stem cell allograft transplantation can correct the immune defect of chronic granulomatous disease.

  We applied a non-myeloablative conditioning (chemotherapy and no radiation) approach to a study of allogeneic stem cell transplantation for 5 pediatric and 5 adult CGD patients, where the donors of normal hematopoietic stem cells were the tissue matched normal siblings of the patients. After a median follow up of more than 2 years, 6 of the 10 patients remain partially or fully engrafted and none of this successfully transplanted group has suffered from any CGD-related infections since the first month after transplant.

  Horwitz ME, Barrett AJ, Brown MR, Carter CS, Childs R, Gallin JI, Holland SM, Linton GF, Miller JA, Leitman SF, Read EJ, Malech HL. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. New England Journal of Medicine. 2001. 344:881-888.

• A genetic variant of the chemokine receptor CX3CR1 is associated with markedly reduced risk for coronary artery disease.

  Heart attacks are due in part to narrowing of coronary arteries by inflammatory processes in the blood vessel wall. These narrowings are due to a complex process known as atherosclerosis. The familial nature of atherosclerosis suggests a genetic risk factor. Gene variants are known that affect inflammation. One variant called CX3CR1-I249, which causes a particular protein on the surface of white blood cells to be made in lower amounts, was found to be a protective factor in this disease. This opens a new direction in basic research of atherosclerotic heart disease with the potential for clinical translation in the form of drugs that block CX3CR1 and thus could retard the atherosclerotic process.

  Moatti D, Faure S, Fumeron F, Amara MEW, Seknadji P, McDermott DH, Debré P, Aumont MC, Murphy PM, de Prost D, Combadière C. Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease. Blood. 2001. 97:1925-1928.

  McDermott DH, Halcox JP, Schenke WH, Waclawiw MA, Merrell MN, Epstein N, Quyyumi AA, Murphy PM. Association between polymorphisms in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Journal of the American College of Cardiology. 2001. 37:302A-302A Suppl. A.

• Malaria parasites induce a novel feeding channel on the human red blood cell membrane, providing a potential new target for future vaccine or chemotherapy development against malaria.

  Growth of the malaria parasite (Plasmodium falciparum) within red blood cells (RBCs) is accompanied by an increased uptake of many solutes including anions, sugars, amino acids, and purines. We identified a small ion channel on the infected RBC surface called the plasmodial surface anion channel (PSAC) that is responsible for the increased uptake of all small solutes by infected RBCs. PSAC's surface location and permeability to organic solutes needed for parasite growth indicate that it may have a primary role in parasite nutrient acquisition.

  Desai SA, Bezrukov SM, Zimmerberg J. A voltage-dependent channel involved in nutrient uptake by red blood cells infected with the malaria parasite. Nature. 2000. 406:1001-1005.

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FY 2000

• Heterosexual transmission of HIV correlates with viral load in a dose-response manner, suggesting a public health benefit to individual anti-HIV drug therapy.

  This study of 415 HIV serodiscordant couples in rural Uganda also indicated that male circumcision may afford a significant degree of protection from HIV infection.

  Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F, Meehan MO, Lutalo T. Viral load and heterosexual transmission of human immunodeficiency virus type 1. New England Journal of Medicine. 2000. 342:921-29.

• Malaria parasites can be grown in the fruit fly, creating an easily manipulated insect model for studying parasite development.

  The ability to cultivate malaria parasites in an animal model whose sequence is fully known allows investigators to identify the specific genes involved in the fruit fly's response to the parasites and then look for the corresponding genes in the mosquito.

  Schneider D, Shahabuddin M. Malaria parasite development in a Drosophila model. Science. 2000. 288:2376-79.

• Latently infected resting CD4+ T cells are not the only source of resurgent viremia when HAART is discontinued.

  The study used a heteroduplex tracking assay to compare viral nucleic acid from plasma after cessation of HAART and from latently infected resting CD4+ T cells. In most cases, molecular analysis indicated that these pools of virus were distinct; therefore, although latently infected resting CD4+ T cells remain a theoretical obstacle to viral eradication, they do not appear to be the only source of resurgent viremia when HAART is discontinued.

  Chun TW, Davey RT, Jr. Ostrowski M, Justement J, Engel D, Mullins JI, Fauci AS. Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti- retroviral therapy. Nature Medicine. 2000. 6:757-61.

• Identification of a new class of compounds that slows the development of a prion disease in mice.

  DIR scientists had previously reported that cyclic tetrapyrroles block the conversion of normal prion protein to an altered, disease causing form in the test tube. New studies have now demonstrated that these same agents significantly slow TSE disease progression in mice that were experimentally infected with a large dose of scrapie, which causes normal prion proteins to convert to the disease-causing form.

  Priola SA, Raines A, Caughey WS. Porphyrin and phthalocyanine anti-scrapie compounds. Science. 2000. 287:1503-06.

• Mutations in the preligation association domain (PLAD) of Fas cause defects in apoptosis explaining certain cases of ALPS.

  Fas mutants from ALPS patients with truncated or mutated death domains are potent dominant-negative inhibitors of normal Fas function. However, if the PLAD was removed from Fas molecules lacking the death domain or harboring an ALPS death domain point mutation, dominant interference was lost and Fas-mediated cell death capability was restored. Thus, receptor self-association through PLAD is independent of ligand binding, yet critical for both normal function and dominant interference.

  Siegel RM, Frederiksen JK, Zacharias DA, Chan FKM, Johnson M, Lynch D, Tsien RY, Lenardo MJ. Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science. 2000. 288:2354-57.

• Identification of a gene conferring resistance to chloroquine.

  DIR scientists and colleagues have used genetic studies to identify an entirely new type of transporter that determines chloroquine resistance in P. falciparum. Mutations in this transporter associate completely with chloroquine resistance in Southeast Asia, Africa and South America.

  Wellems TE, et al. Mutations in the Plasmodium falciparum digestive vacuole transmembrane protein "PfCRT" and evidence for their role in chloroquine resistance. Molecular Cell. 2000. 6(4):861-71.

• A clinical study led by Christopher V. Plowe, Abdoulaye Djimde, and their colleagues at the University of Maryland School of Medicine in Baltimore, the University of Mali in Bamako, and NIAID, is the first of several ongoing field studies to confirm these laboratory findings.

  Djimde A, et al. A molecular marker for chloroquine-resistant falciparum malaria. New England Journal of Medicine. 2001. 344:257-63.

• Determination of the crystal structure of a natural killer cell inhibitory receptor in complex with its class I MHC ligand.

  The structure is significant in revealing the molecular basis of the recognition of MHC class I molecules by a killer-cell immunoglobulin-like inhibitory receptor and the characteristics of this interaction that distinguish it from that of the T cell receptor-MHC class I interaction. In addition, the structure raises several important unanswered questions concerning the evolution and function of this important family of receptors.

  Boyington JC, Motyka SA, Brooks A, Sun PD. Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature. 2000. 405:537-43.

• Changes in a viral surface protein during the acute stage predict the outcome of hepatitis C infection.

  This is the first study to correlate such viral behavior with disease progression in hepatitis C. The researchers also determined a region on virus surface proteins where most of the changes occur. Future studies will focus on the types of genetic mutations that help HCV evade the immune system and on the types of antibodies produced during the early immune response.

  Farci P, Shimoda A, Coiana A, Diaz G, Peddis G, MelpolderJC, Strazzera A, ChienD, Munoz SJ, Balestrieri A, Purcell RH, Alter HJ. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science. 2000. 288:339-44.

• Rapid degradation of newly synthesized cellular and viral proteins produces antigenic peptides to stimulate immune responses.

  This work demonstrates that a pool of antigens (including viral and tumor) can be presented to the immune system irrespective of protein half-life, allowing the immune system to react very early to virus infections while the viral proteins are still being produced and potentially before the virus spreads.

  Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature. 2000. 404:770-74.

• Intranasal administration of naked TGF-B DNA may be used to treat inflammatory diseases.

  Investigators explored the therapeutic potential of intranasal delivery of plasmid DNA encoding active TGF-ß1 (pCMV-TGF-ß1) in a murine model of experimental colitis (TNBS colitis), and showed that the administered plasmid was highly effective both in preventing induction of colitis and in ameliorating established colitis. Their work further demonstrated that the mechanism of this effect is via the induction of IL-10 and the downregulation of the IL-2 receptor, both of which abrogate Th1 T cell differentiation.

  Kitani A, Fuss IJ, Nakamura K, Schwartz OM, Usui T, Strober W. Treatment of experimental (trinitrobenzene sulfonic acid) colitis by intranasal administration of transforming growth factor (TGF)-ß1 plasmid: TGF-ß-mediated suppression of T helper cell type 1 response occurs by interleukin (IL)-10 induction and IL-12 receptor ß2 chain downregulation. Journal of Experimental Medicine. 2000. 192:41-52.

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