Attenuated lentivirus vectors expressing interferon

Details Attenuated lentivirus vectors expressing interferon Attenuated lentivirus vectors expressing interferon

1995-07-20

2001-12-04

Bui, Phuong T. (Department: 1638)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Virus or component thereof

C424S187100, C424S199100, C424S205100, C424S208100, C435S235100, C435S236000, C435S320100, C514S04400A, C530S350000, C536S023100, C536S023720

Reexamination Certificate

active

06326007

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the field of vaccines, particularly live attenuated recombinant pathogens that remain at very low microbial loads, and preferably do not persist in the vaccinated hosts. The preferred vaccines are recombinant viruses that are especially useful against retroviruses such as human immunodeficiency virus and against acquired immunodeficiency diseases.
BACKGROUND OF THE INVENTION
Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV)
Despite voluminous research from many different fronts, the development of safe, effective vaccines against the human immunodeficiency virus (HIV) has proven to be difficult. Like other lentiviruses, HIV has a remarkable ability to persist and to eventually induce a chronic, debilitating disease despite an apparently strong host immune response to the virus. HIV-infected humane may remain clinically well for years while maintaining detectable humoral and cellular immune responses, only to succumb eventually to the virus.
Simian immunodeficiency virus (SIV) is a nonhuman primate lentivirus that is the closest known relative of HITV-1 and HIV-2 strains. SIV closely parallels its human counterparts in genetic organization and biological properties. Similarities between SIV and HIV include: lentiviral morphology; tropism for CD4 lymphocytes and macrophages; extra genes called tat, rev, vif, vpr, and nef that other retroviruses are not known to have; use of the CD4 molecule for receptor; cytopathicity; and the ability to cause chronic disease after long-term persistent infection. All replication-competent retrovirus genomes contain gag (group-specific core antigen), pol (polymerase), and env (envelope) genes. HIV-1 has at least six additional genes: viral infectivity factor (vif), vpr, vpu, transactivator (tat), regulator of viral expression (rev) and negative effector (nef) genes; SIV from rhesus macaques (
Macaca mulatta
) and HIV-2 have a similar set of accessory genes as HIV-1 except that instead of vpu, the latter two have vpx. The vif, vpr, vpu, vpx, and nef genes have been termed “nonessential” since they can be deleted without completely abrogating the ability of the virus to replicate (Kestler, H. W., et al.,
Cell
, 65:651-662 (1991)). Unique strains of SIV have been recovered from several African primate species. In the natural host of origin, these viruses establish a latent or persistent infection and appear not to cause disease. Distinct strains of SIV have also been recovered from captive Asian macaques. An SIV from rhesus macaques (SIV
mac
) and one from a sooty-mangabey monkey (SIV
smm
) cause persistent infections in experimentally inoculated macaques, resulting in acquired immunodeficiency diseases (AIDS)-like disease that is similar to AIDS in individuals infected with HIV-1 or HIV-2, which involves immunodeficiency and opportunistic infections, and results in death {McCune, J. M.,
Cell
, 64:351-360 (1991) and Simon, M. A., et al.,
AIDS Res. Hum. Retroviruses
, 8:327-337 (1992)}. SIV uses the same CD4 receptor as does HIV on human T cells, and it can be blocked with the same monoclonal antibodies. Molecular clones of SIV isolates from several primate species show a genomic organization that is similar to that of HIV, and phylogenetic analysis of viral genome sequences has revealed the close evolutionary relationships of these simian and human lentiviruses {Myers, G., et al., Los Alamos National Laboratory, Los Alamos, N. Mex. (1992)}. Based on the antigenic genetic morphologic and functional similarities shared by HIV and SIV, SIV infection of macaques has come to be recognized as an animal model for HIV infection and AIDS {Hirsch, V. M., et al.,
Virology
, 3:175-183 (1992)}. This animal model is critical for elucidating mechanisms of pathogenesis and for the development of vaccines and anti-viral therapies. The above factors, together with the close immunological relationship of primate genera, argue that a vaccine proven to be effective in protecting rhesus macaques from infection and disease after experimental challenge with SIV will likely be effective in protecting humans at risk for HIV infection and AIDS {Murphey-Corb, M., et al.,
Science
, 246:1293-1297 (1989)}.
Two closely related molecular clones of SIV
mac
(SIV
mac
239
and SIV
mac
1
A
11
) have been extensively characterized iil vitro and in vivo. At the New England Regional Primate Research Center, a provirus was molecularly cloned from the SIV
mac
239
isolate to produce a cloned virus that was also designated SIV
mac
239
{Naidu, Y. M., et al.,
J. Virol
, 92: 491-4696 (1988)}. This clone replicates in peripheral blood mononuclear cells (PBMCS) but is restricted in macrophages {Bancroft, A. J., et al.,
J. Immunol
., 150:1395-402 (1993) and Ringler, D. J., et al.,
Lab. Inves
., 62:435-43 (1990)}. SIV
mac
1
A
11
, cloned at the Department of Medical Pathology, University of California, Davis, infects rhesus macaque PBMCs and both monocyto-derived and alveolar macrophages {Marthas, M. L., et al.,
J. Med. Primat
., 18:311-319 (1989); Bancroft, A. J., et al.,
J. Immunol
., 150:1395-402 (1993) and Unger, R. E., et al.,
J. Med. Primatol
., 24:74-81 (1992)}. The complete sequences of the proviral clones of SIV
mac
1
A
11
(GenBank accession number M76764) and SIV
mac
239
(GenBank accession number 33262) have been determined, the genes for these viruses show greater than 95% homology {Luciw, P. A., et al.,
AIDS Res. Hum. Retroviruses
, 8:395-402 (1992) and Regier, D. A., et al.,
AIDS Res. Hum. Retroviruses
, 6:1221-1231 (1990)}.
Previous attempts to develop vaccines for SIV have either failed to provide immunity or had limited success. Inactivated whole-virus, virion subunits, and live recombinant subunit vaccines have all provided limited or no protective immunity against infection with virulent STV in rhesus macaques. Inactivated whole-virus vaccines have provided protective immunity to macaques against challenge with SIV propagated in human, but not rhesus, PBMCs {Carlson, J. R., et al.,
Aids Research and Human Retroviruses
, 6:1239-1246 (1990); Desrosiers, R. C., et al.,
Proc. Natl. Acad. Sci. USA
, 86:6353-6357 (1989); Johnson, P. R., et al.,
Proc. Natl Acad. Sci. USA
, 99:2175-2179 (1992); Murphey-Corb, M., et al.,
Science
, 246:1293-1297 (1989) and Gardner, M. B.;
AIDS/HIV Treatment Directory
, compiled and published by AmFAR, Vol. 6: 5-10 (1992)}. Evidence has been presented that the protective antigens were not viral but human cellular antigens (HLA DR, &bgr;2m, and HLA class I) {Arthur, L. O., et al.,
Science
, 258:1935-1938 (1992); Langlois, A. J., et al.,
Science
, 255:292-293 (1992); Stott, E. J.,
Nature
, 253;393 (1991) and Sutjipto, S., et al.,
J. Virol
, 64:2290-7 (1990)}.
a) SIV
mac
1
A
11
: In rhesus macaques infected by the intravenous route (IV), SIV
mac
1
A
11
establishes a low virus load in which virus can be isolated from PBMCs during the first 2 to 6 weeks post-infection, but is not recoverable from PBMCs for observation periods of up to three years thereafter (Marthas, M. L., et al.,
J. Med. Primal
., 18:311-319 (1989) and Marthas, M. L., et al.,
J. Virol
., 64:3694-3700 (1990)). Macaques infected with SIV
mac
1
A
11
have remained healthy over three years {Marthas, M. L., et al.,
J. Virol
., 64:3694-3700 (1990); Marthas, M. L., et al.,
J. Virol
., 67:6047-6055 (1993)). Because SIV
mac
1
A
11
in macaques (I) caused no signs of disease, (ii) established a low virus load, and (iii) induced antiviral immune responses, its efficacy as a live attenuated vaccine was tested {Marthas, M. L., et al.,
J. Virol
., 64:3694-3700 (1990)}. Macaques immunized with SIV
mac
1
A
11
were resistant to infection with a low dose of uncloned pathogenic SIV
mac
251
, a strain distinct from but closely related to SIV
mac
239
, inoculated by the IV route {Marthas, M. L., et al.,
J. Virol
., 67:6047-6055 (1993)}. However, macaques immunized with the live attenuated virus

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