Lymphotropic agents and vectors

Details Lymphotropic agents and vectors Lymphotropic agents and vectors

1996-07-23

2003-01-07

McGarry, Sean (Department: 1635)

Chemistry: molecular biology and microbiology

Vector, per se

C435S006120, C536S023100, C536S024500

Reexamination Certificate

active

06503752

ABSTRACT:

FIELD OF THE INVENTION
The present invention is generally in the field of targeted therapeutic agents. By one of its embodiments, the present invention concerns an agent which specifically binds to receptors on certain cells. By a second embodiment the present invention concerns vectors specifically targeted to certain cells.
A specific aspect of the present invention concerns the prophylaxis and treatment of AIDS.
PRIOR ART
The following are references considered to be relevant for the subsequent description.
1. Salahuddin, S. Z., Ablashi, D. V., Markham, P. D., Josephs, S. F., Sturzenegger, S., Kaplan, M., Halligan, G., Biberfeld, P., Wong-Staal, F., Kramarsky, B., and Gallo, R. C. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders.
Science
, 234:596, 601, 1986.
2. Schirmer, E. C., Wyatt, L. S., Yamanishi, K., Rodriguez, W. J., and Frenkel, N. Differentiation between two distinct classes of viruses now classified as human herpesvirus 6
. Proc. Natl. Acad. Sci
., USA, 88:199-208, 1991.
3. Frenkel, N., Roffman, E., Schirmer, E. C., Katsafanas, G., Wyatt, L. S. and June, C. Cellular and growth factor requirements for the replication of human herpesvirus 6 in primary lymphocyte cultures, in: Immunology and Prophylaxis of Human Herpesvirus Infections, eds. Lopez, C., Mori, R., Roizman, B. and Whitley R. J., Plenum Publishing Corp. pp 1-8, 1990.
4. Kondo, K., Kondon, T., Okuno, T., Takahashi, M. and Yamanishi K. Human herpesvirus 6 infection of human monocytes/macrophages.
J. Gen. Virol
. 72:1401-1408, 1991.
5. Lusso, P., Ensoli, B., Markham, P. D., Ablashi, D. V., Salahuddin, S. Z., Tschachler, E., Wong-Staal, F., and Gallo, R. C. Production dual infection of human CD4
+
lymphocytes by HIV-1 and HHV-6,
Nature
, 337:370-373, 1989.
6. Frenkel, N., Schirmer, E. C., Wyatt, L. S., Katsafanas, G., Roffman, E., Danovich, R. M., and June, C. H. Isolation of a new herpesvirus from human CD4
+
T cells.
Proc. Natl. Acad. Sci
., USA, 87:748-752, 1990.
7. Wyatt, L. S., Rodriguez, W. J., Balachandran, N., and Frenkel, N. Human herpesvirus 7: antigenic properties and prevalence in children and adults.
J. Virol
., 65:6260-6265, 1991.
8. Wyatt, L., and Frenkel, N. Human herpesvirus 7 is a constitutive inhabitant of adult human saliva.
J. Virol
. 66:3206-3209, 1992.
9. Pellett, P. E., Lindquester, G. J., Feorino, P., and Lopez, C. Genomic heterogeneity of human herpesvirus 6 isolates.
Adv. Exp. Med. Biol
. 278:9-18, 1990.
10. Lawurence, P. J., Chee, M., Craxton, M. A., Gompels, U. A.,Honess, R. W., and Barrell, G. B. Human herpesvirus 6 is closely related to human cytomegalovirus.
J. Virol
. 64:287-299, 1990.
11. Lindquester, G. J., and Pellett, P. E. Properties of the human herpes-virus 6 strain Z29 genome: G+C content, length, and presence of variable-length directly repeated terminal sequence elements.
Virology
. 82:102-110, 1991.
12. Martin, M. E., Thomson, B. J., Honess, R. W., Craxton, M. A., Gompels, U. A., Liu, M. Y., Littler, E., Arrand, J. R., Teo, I., and Jones, M. D. The genome of human herpesvirus 6: maps of unit-length and concatemeric genomes for nine restriction endonucleases.
J. Gen. Virol
. 72:157-168, 1991b.
13. Frenkel, N., and Wyatt, L. S. Human herpesviruses 6 and 7 as exogenous agents in human lymphocytes.
Develop. Biol. Standard
. 76:259-265, 1992.
14. Lopez, C., Pellett, P. Stewart, J., Coldsmith, C., Sanderlin, K., Black, J., Warfield, D. and Feorino, P. J.
Infect. Dis
., 157:1271-1273, 1988.
15. DiLuca, D., Katsafanas, G., Schirmer, E., Balachanran, N. and Frenkel,
N. Virology
, 175:199-210, 1990.
16. Frenkel, N., Schirmer, E. C., Wyatt, L. S., Katsafanas, G., Roffman, E., Danowich, R. M. and June, C. H.
Proc. Natl. Acad. Sci
., USA, 87:748-752, 1990.
Human herpes virus-6 (HHV-6) was first isolated from peripheral blood mononucleur cells (PBMC) of patients with lympho proliforative disorders as well as from patients suffering from acquired immune deficiency syndrome (AIDS) (Salahuddin et al. 1986).
Two types of HHV-6 strains are recognized today and designated as variant A and variant B which differ as regards to their growth properties, restriction enzyme patterns and antigenicity and they are also distinct epidemiologically (Schirmer et al., 1991). Only the HHV-6 B variant appears to be associated with human disease and has been found to be the causative agent of exanthem subitum (ES, roseola infantum).
HHV-6 is shown to replicate only in interluken-2 (IL-2) activated T cells (Frenkel et al., 1990) and is inhibited by very high concentrations of IL-2. After the initial infection process, the HHV-6 virus undergoes a latency period in the infected cells (Kondo et al. 1991).
Recently, it has been shown that HHV-6 may effect the efficiency of expression of the human immunodeficiency virus-1 (HIV-1) when the two viruses have infected a single cell (Lusso et al., 1989).
Human herpes virus-7 (HHV-7) is a DNA virus first isolated in the laboratory of the inventor of the present invention from activated T cells expressing the CD4 antigen (see U.S. Ser. No. 07/553,798 and Frenkel et al., 1990). Cells expressing this antigen on their membrane will hereinafter be referred to as “CD4
+
cells”.
HHV-7 was found to be distinct, both molecularly and antigenically, from all previously identified herpes viruses. HHV-7 replicates well in lymphocytes and particularly in T cells including CD4
+
T cells and possibly other cells carrying the CD4 marker. The HHV-7 virions specifically target the T cells wherein the viral DNA is synthesized in the nucleus as concatemers which are then cleaved and packaged into structural infectious particles. It has been shown recently that HHV-7 binds specifically to the CD4 receptor by which it infects CD4
+
cells.
HHV-7 is found in sera of more than 95% of humans (Wyatt et al., 1991). In addition, the virus is very often found in human saliva (Wyatt et al., 1992). No known disease is associated with HHV-7 and no symptoms have been discovered in individuals infected by the virus at early childhood.
HHV-6 and HHV-7 DNA comprise a long unique sequence which is flanked by terminal direct repeats (TR) on each side (Pellet et al., 1990, Lawrence et al., 1990, Lindquester et al., 1991 and Martin et al., 1991). Each TR contains on one side a sequence which is heterogenous in size, designated het. The het sequence was thought to be a variable and unstable sequence but later was found to be a unique sequence for each virus strain and to remain stable in a single strain over many passages of the virus (Schirmer et al., 1991). On the other side of the TR there is a repeated telomeric-like sequence having repeated units of the sequence GGGTTA.
CD4
+
cells are also the target cells of the human immunodeficiency virus (HIV) which is the cause of acquired immuno deficiency syndrome (AIDS).
HIV binds to the CD4 receptor on the target cell with a high affinity, integrates itself into the host cells' genome and is believed to undergo a long latency period during which it is virtually undetectable. Activation of the virus to induce the disease may occur at different time periods after the first infection.
Many attempts have been aimed at delaying or inhibiting the activation of the latent HIV in an infected individual. Such attempts include various treatments targeted at inhibiting the HIV's regulatory replication and structural proteins, e.g. Tat and Rev or by down regulation of these or other regulatory proteins of HIV. Examples of such treatments include the use of the drug AZT, both alone or in combination with other drugs such as ddI and nevipapine and methods of gene therapy by the use of an RNA virus vector.
In addition to treatments such as the above, research has centered mainly in trying to immunize individuals against infection or against a spread of HIV in the body of already infected individuals. For this purpose, both classic vaccination approaches as well as the use of various genetically engineered immunogens have been tested, but to date, none of these vaccination appr

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