Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Digestive system
Reexamination Certificate
1999-04-16
2001-09-11
Stucker, Jeffrey (Department: 1648)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Digestive system
C424S537000, C436S518000, C435S975000
Reexamination Certificate
active
06287605
ABSTRACT:
BACKGROUND OF THE INVENTION
The role of human saliva in modulating the acquisition of HIV infection via the oral route or the transmission of HIV via infected oral secretions is important to our understanding of the transmission of AIDS and the development of effective prevention and treatment methods. Although there have been numerous reports detailing the identification and isolation of HIV nucleotide sequences from oral samples such as saliva (Levy et al., 1988, Lancet 2:1248; Barr et al., 1992, J. Am. Dent. Assoc. 123:39-48; Goto et al., 1991, AIDS Res. Human Retro. 7:343-347), buccal scrapings (Qureshi et al., 1995, J. Infect. Dis. 171:190-193) and gingival crevicular fluid (Chebbi et al., 1997, AIDS 11:927-928; O'Shea et al., 1990, J. Med. Virol. 4:291-296), the isolation of infectious HIV virus from the oral cavity of a patient is rare, and when present, viral titers are low (Barr et al., 1992, J. Am. Dent. Assoc. 123:39-48; Malamud and Friedman, 1993, Crit. Rev. Oral Biol. Med. 4:461-466; Melvin et al., 1997, Arch. Pediatr. Adolesc. Med. 151:228-232). Several reports have demonstrated the presence of HIV nucleotide sequences using PCR in up to 80% of oral samples obtained from seropositive individuals (Liuzzi et al., 1996, AIDS 10: F51-56; Chebbi et al., 1997, AIDS 11:927-928; Goto et al., 1991, AIDS res. Human Retro. 7:343-347; Qureshi et al., 1995, J. Infect. Dis. 171:190-193). However, infectious virus could only be isolated from less than 5% of these individuals (Barr et al., 1992, J. Am. Dent. Assoc. 123:39-48).
Thus, the infectivity of HIV in saliva is clearly different from other biologic fluids such as blood and semen. This striking discrepancy between the physical evidence for virus in saliva and the lack of infectious virus suggests that saliva contains HIV inhibitors which are effective at blocking infectivity.
It is now generally accepted that incubation of HIV-1 with human saliva results in a marked decrease (about an 80-95% reduction) in viral infectivity assayed in vitro (Fultz, 1986, Lancet ii:1215) and (Fox et al., 1988, J. Am. Dent. Assoc. 116:735-637). This observation has been reproduced in many laboratories (Malamud and Friedman, 1993, Crit. Rev. Oral Biol. Med. 4:461-466; Robinovitch and Iverson, 1993, Crit. Rev. Oral Biol. Med. 4:455-459; Bergey et al., 1993, Crit. Rev. Oral Biol. Med. 4:467-474; McNeely et al., 1995, J. Clin. Invest. 96:456-464; Yeh et al., 1992, J.Acq. Defic. Synd. 5:898-903; Moore et al., 1993, J. Am. Dent. Assoc. 124:67-74). The experiment involves incubating whole, parotid or submandibular saliva from HIV seronegative individuals with HIV-1, and then adding the HIV/saliva mixture to CD4+ cells, and monitoring virus production after 3-10 days. In many cases, the saliva/HIV mixture is filtered prior to addition to the host cells. These studies have demonstrated anti-HIV activity in whole and ductal saliva from both seronegative and seropositive patients. There is evidence that the anti-viral effect is exerted both at the level of the virus (Malamud et al., 1997, Oral Diseases, 3: S58-S63) and at the level of the host cell (Wahl, et al., 1997, Am. J. Pathol. 150:1275-1284; Wahl et al., 1997, Oral Diseases, 3: S64-S69). It has also been reported that submandibular saliva agglutinates HIV, and that this agglutination might be involved in the inhibitory mechanism (Bergey et al., 76 1994, J. Acq. Imm. Defic. Syn. 7:995-1002), and (Malamud et al., 1993, AIDS Res. Human Retro. 9:633-637).
Proteins present in human saliva which have anti-viral activity have been characterized in previous reports. Much of the work has focused on understanding the role of salivary proteins in host defenses. Salivary agglutinin (SAG) is a high molecular weight (MW=350 kDa) mucin-like glycoprotein produced by both parotid and submandibular salivary glands (Demuth et al., 1988, Inf. Immun. 56:2484-2490). It has been reported that this glycoprotein contains about 40% carbohydrate divided equally between N- and O-linked sugars (Demuth et al., 1990, J. Biol. Chem. 265:7120-7126; Takano et al., 1992, Anat. Rec. 230:307-318; Ericson and Rundergren, 1983, Eur. J. Biochem. 133:255-261). While SAG has been referred to as “mucin-like,” it is synthesized in serious acinar cells and serious demilunes of mucin producing acini, but not in mucinous acini where high molecular weight salivary mucin (MG1) and low molecular weight salivary mucin (MG2) are synthesized (Takano et al., 1992, Anat. Rec. 230:307-318).
Human submandibular saliva also contains two proteins termed mucins, MG1 (MW>1000 kDa) and MG2 (MW 130 kDa), which have also been reported to have anti-HIV activity (Bergey et al., 1994, J. Acquired Imm. Defic. Syn. 7:995-1002). Both mucins comprise about 70% carbohydrate, which is predominantly O-linked (Tabak, 1995, Annu. Rev. Physiol. 57:547-564) and has extensive microheterogeneity (Reddy and Levine, 1993, Crit. Rev. Oral Biol. Med. 4:315-323). MG2 is a unique gene product expressed only in the submandibular and sublingual glands, and contains at least one N-linked carbohydrate chain. Both MG1 and MG2 are found in coatings of oral surfaces, and serve as a general protective barrier in humans (Tabak, 1990, Crit. Rev. Oral Biol. CRC Press, pp 229-234). Levels of MG2 in whole saliva vary over a 100-fold range in young adults (18-35 years old), and lower values have been reported in older adults (Denny et al., 1991, J. Dent. Res. 70:1320-1327). MG2 has been reported to bind non-covalently with IgA (Biesbrock et al., 1991, Infect. Immun. 59:3492-3497) and fibronectin (Slomiany et al., 1992, Intl. J. Biochem. 24:1003-1015). Recently, the gene for apomucin MG2, designated MUC7, was cloned and mapped to chromosome 4q 13-q21 (Bobek et al., 1996, Genomics 31:277-282). The glycosylated form of the molecule has not yet been expressed in vitro. Considerable information is available on the structure of the gene, the apoprotein, and the glycosylated mucin.
Human saliva appears to inhibit HIV infection by several different mechanisms. Fultz (1986, Lancet 2:1215) demonstrated that incubation of HIV-1 with human or chimpanzee saliva blocks infection of peripheral blood mononuclear cells (PBMCs). Other reports have demonstrated that incubation of virus with saliva causes virus aggregation, as demonstrated by electron microscopy, and subsequent loss of virus titer upon filtration (Fox et al., 1988, J. Am. Dent. Assoc., 116:635-637; Malamud et al., 1993, AIDS Res. Hum. Retroviruses 9:633-637; Archibald and Cole, 1990, AIDS Res. Hum. Retroviruses 6:1425-1432; Bergey et al., 1993, Critic Rev. Oral Biol. 4:467-474; Bergey et al., 1994, J. Acquired Immune Defic. Syndr. 7:995-1002; Yeh et al., 1992, J. Acquired Immune Defic. Syndr. 5:898-903). It has been suggested that salivary mucin mediates this activity, (Bergey et al., 1994, J. Acquired Immune Defic. Syndr. 7:995-1002) present in both whole saliva and submandibular saliva, with the highest activity being observed in submandibular saliva (Malamud et al., 1993, AIDS Res. Hum. Retroviruses 9:633-637). Saliva obtained from many seronegative patients has been shown to exhibit anti-HIV activity in the absence of a filtration step (Nagashunmugam et al., 1997, AIDS Res Human Retroviruses 13:371-376), and the inhibitory activity was demonstrated to be specific for HIV-1, with little or no inhibitory activity being observed to be directed against adenovirus, herpes simplex virus type I (HSV-1), HIV-2 and SIV (Malamud et al., 1993, AIDS Res. Hum. Retroviruses 9:633-637; Nagashunmugam et al., 1997, AIDS Res Human Retroviruses 13:371-376). Another report has identified a salivary protein termed secretory leukocyte protease inhibitor (SLPI) which reduces the susceptibility of monocytes, macrophages and CD4
+
T cells to infection by HIV (McNeely et al., 1995, J. Clin. Invest. 96:456-464). In yet another report, the inhibition of HIV infectivity by saliva was attributed to another protein, thrombospondin I (TSP1) (Crombie et al., 1998, J. Exp. Med. 187:25-35).
While epidemiological studies suggest that the oral transmiss
Abrams William
Bergey Earl J.
Friedman Harvey M.
Malamud Daniel
Nagashunmugam Thandavarayan
Morgan, Lewis & Bockius, L.L.P.
Stucker Jeffrey
The Trustees of the University of Pennsylvania
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