Retrovirus from the HIV type O and its use (MVP-2901/94)

Details Retrovirus from the HIV type O and its use (MVP-2901/94) Retrovirus from the HIV type O and its use (MVP-2901/94)

2000-07-06

2003-04-15

Stucker, Jeffrey (Department: 1648)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

15 to 23 amino acid residues in defined sequence

C530S812000, C435S005000, C435S007100, C435S974000, C435S975000, C436S531000

Reexamination Certificate

active

06548635

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel retrovirus from the HIV group which is presently designated more precisely as HIV subtype O, and to variants or parts thereof which contain the essential properties of the virus. A process is described for culturing the retrovirus. The invention furthermore relates to the isolation of this retrovirus and to the use of the virus, its parts or extracts for medicinal purposes, for diagnosis and in the preparation of vaccines.
BACKGROUND OF THE INVENTION
In humans who are infected with them, retroviruses which belong to the so-called HIV group lead to disease symptons which are summarized under the collective term immunodeficiency or AIDS (acquired immune deficiency syndrome).
Epidemiological studies verify that the human immunodeficiency virus (HIV) is the etiological agent for the overwhelming majority of AIDS (acquired immune deficiency syndrome) cases. A retrovirus which was isolated from a patient and characterized in 1983 was given the designation HIV-1 (Barre-Sinoussi, F. et al., Science 220, 868-871 [1983]). A variant of HIV-1 is described in WO 86/02383.
A second group of human immunodeficiency viruses was identified in West Africa in 1985 (Clavel, F. et al., Science 233, 343-346 [19863]) and designated human immunodeficiency virus type 2 (HIV-2) (EP-A-O 239 425). HIV-2 retroviruses clearly differ from HIV-1 but are also related to monkey immunodeficiency viruses (SIV-2). Like HIV-1, HIV-2 also gives rise to an AIDS symptomatology.
New HI viruses, as represented by ANT70 (J. Vir., 1994, Vol. 68, No. 3, pp. 1586-1596) and MVP-5180/91 (J. Vir., 1994, Vol. 68, No. 3, pp. 1581-1585) have recently been described which can not be classified in HIV-1 subtypes A-F. Owing to their clear structural differences from the known HIV-1 strains, both isolates have provisionally been classified together under subtype O (G. Myers, Los Alamos Data Base), although they clearly differ from each other in their genomic nucleotide sequences.
It is a characteristic of human immunodeficiency viruses that they exhibit a high degree of variability which markedly complicates the comparability of the different isolates. When different HIV-1 isolates are compared, high degrees of variability are found, for example, in some regions of the genome whereas other genome regions are comparatively well conserved (Benn, S. et al., Science 230, 949-951 [1985]). HIV-2 ha3 also been reported to exhibit a very high degree of polymorphism (Clavel, F. et al., Nature 324, 691-695 [1986]). Regions in the gag and pol genes which encode proteins which are structurally and enzymatically essential possess the greatest genetic stability. By contrast, some regions in the env gene, and also the genes (vif, vpr, tat, rev, nef) which encode regulatory proteins, exhibit a high degree of variability.
It was furthermore demonstrated that antisera against HIV-1 also cross-react with HIV-2 gag and pol gene products even though only low sequence homologies were present. The hybridization between these two viruses was likewise of no great significance unless conditions of very low stringency were used (Clavel, F. et al., Nature 324, 691-695 [1986]).
Due to the wide distribution of the retroviruses from the HIV group, and to the fact that a period of from a few to many years (2-20) elapses between the time of infection and the time at which definite symptoms of pathological changes are recognizable, it is epidemiologically of great importance to ascertain infection with retroviruses of the HIV group at as early a stage as possible and, in particular, in a reliable manner. This is of importance not only in the diagnosis of patients who are exhibiting signs of immunodeficiency, but, even more so, in the screening of blood donors. It has emerged that when retroviruses, or components thereof, of the HIV-1 or HIV-2 type are used in detection systems, antibodies either cannot be detected or can be detected only weakly in some sera, even though signs of immunodeficiency occur in the patients from whom the sera are derived. In certain cases, such detection is possible using the HIV group retrovirus according to the invention.
The genotypic diversity of the HIV viruses presents a substantial problem for diagnosis in particular. In the case of the HIV-1 viruses, it is assumed that one nucleotide is changed per genome in each replication cycle. As a result of this genetic variability, the HIV viruses are able to respond in an extraordinarily flexible manner to the in-vivo selection pressure and to generate, extremely rapidly, mutants which either are resistant to pharmacological agents or are able to attack individuals who have built up a certain degree of immunological protection (Sharp et al., “Origins and diversity of human immunodeficiency viruses”, AIDS 1994, vol. 8, Suppl. 1; S 27-S 42).
In order to prevent the spread of infections, in particular in association with blood transfusions but also in association with organ donations, it should be possible to ascertain an infection with an HIV virus with, if possible, 100% certainity. For this reason, it is also necessary diagnostically to detect those infections which are caused by a virus which, while currently only being distributed in certain geographical regions, is able without difficulty—unless suitable preventive measures are taken—to spread into Europe or the United States of America.
SUMMARY OF THE INVENTION
A description is given of the isolation and characterization of a novel human immunodeficiency virus, designated MVP-2901/94 hereinafter, which was isolated in 1994 from the peripheral lymphocytes of a 24 year old female patient from the Cameroons who was exhibiting signs of immunodeficiency. From the point of view of geography, this retrovirus originates from a region in Africa which is located between West Africa, where infection with HIV-2 and HIV-1 viruses is endemic, and East Africa, where it is almost exclusively HIV-1 which is disseminated. Consequently, the present invention relates to a novel retrovirus of the HIV subtype O group, which retrovirus is designated MVP-2901/94, and to its variants, to DNA sequences, amino acid sequences and constituent sequences derived therefrom, and to test kits containing the latter.
MVP-2901/94 can be propagated in the MT2 and Jurkat cell lines. The isolation and propagation of viruses are described in detail in the book “Viral Quantitation in HIV Infection, Editor Jean-Marie Andrieu, John Libbey Eurotext, 1991”. The procedural methods described therein are incorporated in the disclosure of the present application by reference.
In order to provide a better understanding of the differences between the MVP-2901/94 virus according to the invention and the HIV-1 and HIV-2 retroviruses, the structure of the retroviruses which cause immunodeficiency will first of all be explained briefly. In the centre of the virus, the RNA is located in a conical core which is assembled from protein subunits which carry the designation p 24 (p for protein). This inner core is surrounded by a protein coat which is constructed from protein p 17 (outer core), and by a glycoprotein coat which, in addition to lipids, which originate from the host cell, contains the transmembrane protein gp 41 and the coat protein 120 (gp 120). This gp 120 then binds to the CD-4 receptors of the host cells.
As far as is known, the RNA of the HIV viruses—portrayed in a simplified manner—possesses the following gene regions: so-called long terminal repeats (LTR) at each end, together with the following gene regions: gag, pol, env and nef. The gag gene encodes, inter alia, the core proteins, p 24 and p 17, the pol gene encodes the reverse transcriptase, the protease, the RNAse H and the intearase, and the env gene encodes the glycoproteins, gp 41 and gp 120, of the virus coat. The nef gene encodes a protein having a regulatory function. The arrangement of the genome of retroviruses of the HIV type is shown diagrammatically in FIG.
1
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The so-called PCR (polymerase chain r

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