HIV-1 group O antigens and uses thereof

Details HIV-1 group O antigens and uses thereof HIV-1 group O antigens and uses thereof

2000-04-03

2003-01-28

Stucker, Jeffrey (Department: 1648)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving virus or bacteriophage

C435S007100, C435S007920, C435S974000, C435S975000, C436S536000, C530S326000, C530S826000, C424S208100

Reexamination Certificate

active

06511801

ABSTRACT:

The current invention relates to new HIV-1 group O antigens, nucleic acids encoding them, and the use of said antigens and/or nucleic acids as reagents in the diagnosis and prophylaxes of AIDS. It also relates to new HIV-1 group O strains comprising these antigens.
The human immunodeficiency virus (HIV) is the responsible agent for the acquired immunodeficiency syndrome (AIDS) in humans. AIDS is usually associated with two distinct types of HIV: HIV-1 and HIV-2, initially described by Gallo et al. (1984) and Barré-Sinoussi et al. (1983) on the one hand, and Clavel et al. (1986) on the other hand. Although both types, HIV-1 and HIV-2, cause a dysfunction of the immune system and induce similar clinical symptoms in infected persons, they are genetically distinct (Clavel et al. 1986) Epidemiological studies have shown that the prevalence of HIV-2 infection is confined mainly to West Africa, whereas HIV-1 infection is a world wide problem. Numerous HIV-1 isolates have been obtained and sequenced from diverse geographical locations. At present, at least ten distinct subgroups or clades (A to J) of HIV-1 have been described, equidistantly related in phylogenetic analysis of the env-and/or gag-gene (Kostrikis et al. 1995; Louwagie et al. 1993; Myers et al 1995).
More recently, HIV-1 group O (for “Outlier”) strains have been described as divergent viruses, belonging to an independent cluster (Charneau et al. 1994; Gürtler et al. 1994; Myers et al 1995; Sharp et al. 1994; Vanden Haesevelde et al. 1996), when compared to the vast majority of worldwide HIV-1 strains classified as group M (for “Major”). Although these two groups of viruses share the same genomic structure, the elevated level of divergence between them supports the hypothesis of independent origins.
Most of the currently described group O strains have been characterized from Cameroonian patients or from patients who have travelled in Cameroon (De Leys et al. 1990; Gürtler et al. 1994; Loussert-Ajaka et al. 1995; Vanden Haesevelde et al. 1996). Group O infection is not restricted to Cameroon and its neighbouring countries, but it has also been documented in West, East, and Southern Africa (Peeters et al. 1996; Peeters et al. submitted). In addition, cases of group O infection have been described in several European countries (France, Spain, Germany, Norway) and in the USA (Centres for Disease control and Prevention 1996; Charneau et al. 1994; Hampl et al 1995; Soriano et al. 1996).
Several hypotheses have been developed to explain the paradoxical observation that HIV-1 has been present in African countries for many decades (probably about a century) and that it has only become apparent over the past 15 years. The answer should probably take in account numerous parameters such as demographic, sociologic, ethologic, ethnologic, and virologic parameters. In a mathematical model, May and Anderson (1990) suggest that initial chains of infection were found in isolated populations at low rates with some ‘sparks’ thrown in the neighbouring villages, and the exponential epidemic has started when there was a sufficient number of fire-boxes. To date, no differences were observed between HIV-1 group M and O pathogenic potential even though a limited number of patients infected by these latter strains have been reported. However some of them have already died or reached stage IV in the CDC classification (Charneau et al. 1994; Gürtler et al. 1994; Loussert-Ajaka et al. 1995). It is possible that group O epidemics, compared to group M, could be rampant at this time. In the next years, it will therefore be extremely important to monitor the prevalence of these viruses, in Africa but also in the developed countries, to detect them as early as possible and to prevent a new HIV epidemic.
HIV-1 group O strains present a public health challenge since they are documented to give incomplete and atypical HIV-1 Western blot profiles (Charneau et al. 1994; Gürtler et al. 1994). Some commercially available ELISA or rapid tests were unable to detect HIV-antibodies in HIV-1 group O infected patients (Loussert-Ajaka et al 1994; Simon et al. 1994). The distribution of group O infections may be much more wide spread than currently thought, because of a lack of adequate detection techniques. Moreover, whereas HIV-1 group M strains have been extensively studied and characterized as to their genetic variability, there is at present no clear view on the genetic diversity of strains belonging to HIV-1 group O.
At present, sequence information on the complete genome is only available for the prototype isolates of HIV-1 group O, namely ANT70 (Vanden Haesevelde et al. 1994), MVP-5180 (Gürtler et al. 1994), and VAU (Charneau et al. 1994). Some additional HIV-1 group O strains have been sequenced in the gag and env regions (for example WO 96/27013, WO 96/12809, EP 0727483).
HIV-viruses show a high degree of genetic variability. In the case of HIV-1 viruses it is more or less accepted that at least one nucleotide change occurs during one replication cycle. Certain regions of the genome, for example those encoding structurally or enzymatically important proteins, may be rather conserved, but other regions, especially the env-region, may be subject of very high genetic variability.
The envelope proteins of HIV are the viral proteins most accessible to immune attack, and much attention has been directed towards elucidating their structure and function. The env gene encoding the envelope proteins consists of hypervariable sequences (V-regions) alternated by more constant regions (C-regions) (Starcich et al, 1986; Willey et al, 1986). The envelope protein is first synthesized as a heavily glycosylated precursor protein (gp160), which is later cleaved by a non-viral protease to generate a transmembrane protein, also referred to as gp41, and an outer surface protein often referred to as gp120. One particular region of the gp120 glycoprotein derived from the HIV-1 virus type has been studied extensively, namely the third hypervariable domain (V3) also known as the principal neutralizing determinant (PND) (Javaherian et al., 1989). The V3 domain of HIV-1 contains a loop structure of 35 amino acids (V3-loop) which is formed by a cysteine-cysteine disulfide bridge (Leonard et al. 1990). The gp41 protein contains an immunodominant domain (ID) as found in all retroviruses. For HIV-viruses, this domain has been divided in two distinct regions, corresponding to an immunosuppressive peptide (ISU) of about 17 aa, and a cysteine loop being the principal immunodominant domain (PU)). The delineation of these respective regions in the gp41 protein is demonstrated in FIG.
1
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The genetic variability of HIV-viruses considerably complicates both diagnosis and prevention of HIV-infection. Sera from patients infected with unknown types of HIV-virus, may contain antibodies which are not detected by the current assay methods, which are based on (poly)peptide sequences of known viral strains. The detection of virus or viral antigen in certain samples, like organs for transplantation, or blood transfusion samples, may be missed due to the presence of hitherto unknown variant types. Variation may occur in those genomic regions which are considered to be important in future vaccines. Finally, it is not known at present if different genoric types may influence the course of the AIDS disease, i.e. its virulence and/or susceptibility for therapeutics.
Therefore, there is a constant need for characterization and sequencing of new HIV-strains, and especially of new HIV-1 group O strains, which until now have only scarcely been characterized. Information on the genetic variability of this “Outlier” group may enable a more rational approach for optimization of diagnostic tests and for development of vaccines. Especially the variability of certain regions in the genome, known to be important target regions for the immune response, or for certain therapeutic drugs, is of utmost importance. New sequencing data may require the revision of existing diagnostic assays, and/or the development of new assays. D

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