Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-03-02
2002-05-21
Crouch, Deborah (Department: 1632)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S320100, C435S325000, C435S029000
Reexamination Certificate
active
06391567
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to the binding, transport and infection of cells by retroviruses including HIV-1, and HIV-2. Methods of identifying agents that modulate such processes, the agents themselves and therapeutic uses of such agents are also provided. Related diagnostic methods are also included.
BACKGROUND OF THE INVENTION
The human immunodeficiency viruses infect CD4
30
macrophages and T helper cells. Although HIV-1 entry requires cell surface expression of CD4, to which the viral envelope glycoproteins bind, several studies have suggested that it is not sufficient for fusion of the viral envelope to the cellular plasma membrane. Early studies have shown that while human cells expressing a transfected CD4 gene were permissive for virus entry, murine cells expressing human CD4 were not. These findings led to the suggestion that there is a species-specific cell surface cofactor required in addition to CD4 for HIV-1 entry. Subsequent studies have shown that strains of HIV-1 that had been adapted for growth in transformed T-cell lines (T-tropic strains) could not infect primary monocytes or macrophages; in contrast, primary viral strains were found to infect monocytes and macrophages, but not transformed T cell lines. This difference in tropism was found to be a consequence of specific sequence differences in the gp120 subunit of the envelope glycoprotein, suggesting that multiple cell type-specific cofactors may be required for entry in addition to CD4.
The nature of the cofactors required for HIV entry proved elusive until it was recently discovered that the principal receptor for entry of macrophage-tropic (M-tropic) HIV-1 strains was CCR5, whereas the principal receptor for entry of T-cell line-tropic (T-tropic) strains was CXCR4. On the other hand, both M-tropic and T-tropic strains of simian immunodeficiency virus (SIV) can be mediated by CCR5, but not CXCR4 [Chew et al.,
J. Virol
, 71:2705-2714 (1997); Marcon et al.,
J. Virol
, 71:2522-2527 (1997); and Edinger et al.,
Proc. Natl. Acad. Sci. U.S.A
., 94:4005-4010 (1997)]. More importantly, SIV strains were also found to infect CD4
30
cells that lack CCR5 [Chen et al.,
J. ViroL
., 71:2705-2714 (1997); and Edinger et al,
Proc. Natl. Acad. Sci. U.S.A
., 94:4005-4010 (1997)].
In humans, CCR5-tropic viruses are primarily involved in transmission, while viruses with broader tropism, particularly for CXCR4, emerge during progression to immunodeficiency [Fauci,
Nature
, 384:529-534 (1996)]. It is not yet known whether appearance of CXCR4-tropic viruses is a consequence or the cause of immune system decline. Insight into this key problem of virus evolution is likely to require experimental manipulation in animal models. Infection of non-human primates with SIV is remains the only good animal model for studying pathogenesis of the immunodeficiency viruses [Desrosiers,
Annu Rev Immunol
, 8:557-578 (1990)]. Moreover, different species of non-human primates vary widely in their responses to SIV infection. For example, Rhesus macaques succumb to immunodeficiency that closely resembles AIDS in humans, but sooty mangabeys and African green monkeys can sustain infection with little evidence of immune system damage [Kestler,
Science
, 248:1109-1112 (1990)]. These interspecies differences provide important clues for understanding and combating disease progression in HIV-infected humans.
Transmission of Human Immunodeficiency Virus Type 1 (HIV-1) infection in humans requires the dissemination of virus from sites of infection at mucosal surfaces to T cell zones in secondary lymphoid organs, where extensive viral replication occurs in CD4
30
T-helper cells and macrophages [Fauci,
Nature
, 384(6609):529-534 (1996)]. These cells express both CD4 and the chemokine receptor CCR5, which together form the receptor complex required for entry by the R5 viral isolates that are prevalent early after infection [Littman,
Cell
, 93:677-680 (1998); Lu et al.,
Proc. Natl. Acad. Sci. U.S.A
., 94(12):6426-6431 (1997); Dragic et al,
Nature
, 381:667-673 (1996); U.S. Pat. No: 5,939,320, Issued Aug. 17, 1999; and U.S. patent application 09/116,498, Filed Jul. 7, 1998, the contents of which are hereby incorporated by reference in their entireties]. Viruses with tropism for other chemokine receptors, particularly CXCR4, are rarely transmitted, and generally appear only late in infection. Such CXCR4-tropic isolates replicate poorly in macrophages, and it has hence been proposed that infection of macrophages is a requisite component of viral transmission.
The mechanism of early viral dissemination remains vague, but based on anatomical distribution of different hematopoietic lineage cells and on in vitro infectivity studies it has been inferred that immature dendritic cells (DC) residing in the skin and at mucosal surfaces are the first cells targeted by HIV-1. DC are the most potent antigen-presenting cells in vivo [Banchereau and Steinman,
Nature
, 392:245-252 (1998); Valitutti et al.,
Nature
, 375:148-151 (1995)]. Immature DC in peripheral tissues capture antigens efficiently and have a unique capacity to subsequently migrate to the T cell areas of secondary lymphoid organs. As the cells travel, they mature and alter their profile of expression of cell surface molecules, including chemokine receptors, lose their ability to take up antigen, and acquire competence to attract and activate resting T cells in the lymph nodes [Banchereau and Steinman,
Nature
, 392:245-252 (1998); Adema et al.,
Nature
, 387(6634):713-717 (1997)]. HIV-1 is thought to subvert the trafficking capacity of DC to gain access to the CD4
+
to T cell compartment in the lymphoid tissues [Steinman and Inaba,
J. Leukoc. Biol
., 66(2):205-208 (1999); Rowland-Jones, S. L.,
Curr. Biol
., 9(7):R248-R250 (1999); and Grouard and Clark,
Curr. Opin. Immunol
., 9(4):563-567 (1997)].
Immature DC express CD4 and CCR5, albeit at levels that are considerably lower than on T cells [Granelli-Pipemo et al.,
J. Exp. Med
., 184:2433-2438 (1996); Rubbert et al,
J. Immunol
., 160(8):3933-3941 (1998)], and they have been reported to be injectable with R5 strains of HIV-1. In contrast, immature DC do not express CXCR4 and are resistant to infection with CXCR4-tropic isolates of HIV-1 [Granelli-Pipemo et al.,
J. Virol
., 72:2733-2737 (1998); Blauvelt et al.,
J. Clin. Invest
., 100:2043-2053 (1997); and Weissman et al.,
Proc. Natl. Acad. Sci. U.S.A
., 92:826-830 (1995)]. Entry of HIV-1 into immature DC has also been reported to proceed through a CD4-independent mechanism [Blauvelt et al.,
J. Clin. Invest
., 100:2043-2053 (1997)], suggesting that receptors other than CD4 could be involved. There have been conflicting reports regarding the significance of HIV-1 replication within DC [Canque et al.,
Blood
, 93(11):3866-3875 (1999); Ayehunie et al.,
Blood
, 90(4):1379-1386 (1997); Cameron et al.,
J. Leukoc. Biol
., 56(3):257-265 (1994)]. Although replication can be observed in some circumstances, it has also been reported that, in immature DC, replication is incomplete and that only early HIV-1 genes are transcribed.
It has been proposed that virus-infected immature DC migrate to the draining lymph nodes where they initiate both a primary anti-viral immune response and a vigorous productive infection of T cells, allowing systemic distribution of HIV-1 [Cameron et al.,
Science
, 257(5068):383-387 (1992); Weisman et al.,
Proc. Natl. Acad. Sci. U.S.A
., 92:826-830 (1995)]. However, in a non-human primate model of mucosal infection with the simian immunodeficiency virus, it has been difficult to demonstrate productive infection of DC despite rapid dissemination of virus [Stahl-Henning et al.,
Science
, 285(5431):1261-1265 (1999)]. Other efforts to model primary HIV-1 infection in vitro by exposing DC derived from skin or blood to HIV-1 have indicated that these cells are poorly infe
Geijtenbeek Teunis
Kooyk Yvette Van
Kwon Douglas
Littman Dan R.
Crouch Deborah
Gregg Valeta
Klauber & Jackson
New York University
Ton Thai-an N.
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