Syncytium Formation and HIV-1 Replication Are Both Accentuated by Purified Influenza and Virus-associated Neuraminidase
2002; Elsevier BV; Volume: 277; Issue: 12 Linguagem: Inglês
10.1074/jbc.m110764200
ISSN1083-351X
AutoresJiangfeng Sun, Benoı̂t Barbeau, Sachiko Sato, Guy Boivin, Nathalie Goyette, Michel J. Tremblay,
Tópico(s)Bacteriophages and microbial interactions
ResumoThe degree of sialylation has been shown previously to modulate the process of human immunodeficiency virus type-1 (HIV-1) infection by affecting the interaction between the virus and CD4-expressing target cells. In the present study, we investigated whether HIV-1 replication cycle was affected by neuraminidase (NA) derived from the human influenza (flu) virus. We first demonstrate that the level of HIV-1-mediated syncytium formation was greatly enhanced in the presence of purified flu NA. Pretreatment of established monocytic and lymphocytic cell lines as well as primary mononuclear cells with purified flu NA augmented also the process of virus infection. A comparable up-regulating effect was observed when using several strains of UV-inactivated whole flu virus, thereby suggesting that virus-anchored NA enzymes positively modulate the HIV-1 life cycle. Furthermore, flu NA-mediated positive effect on HIV-1 biology was abrogated with zanamivir, a specific flu NA inhibitor. Our results provide a new model allowing the investigation of the potential benefit of using NA inhibitors in the treatment of HIV-1-infected patients suffering from coinfection with NA-bearing pathogens. The degree of sialylation has been shown previously to modulate the process of human immunodeficiency virus type-1 (HIV-1) infection by affecting the interaction between the virus and CD4-expressing target cells. In the present study, we investigated whether HIV-1 replication cycle was affected by neuraminidase (NA) derived from the human influenza (flu) virus. We first demonstrate that the level of HIV-1-mediated syncytium formation was greatly enhanced in the presence of purified flu NA. Pretreatment of established monocytic and lymphocytic cell lines as well as primary mononuclear cells with purified flu NA augmented also the process of virus infection. A comparable up-regulating effect was observed when using several strains of UV-inactivated whole flu virus, thereby suggesting that virus-anchored NA enzymes positively modulate the HIV-1 life cycle. Furthermore, flu NA-mediated positive effect on HIV-1 biology was abrogated with zanamivir, a specific flu NA inhibitor. Our results provide a new model allowing the investigation of the potential benefit of using NA inhibitors in the treatment of HIV-1-infected patients suffering from coinfection with NA-bearing pathogens. human immunodeficiency virus influenza neuraminidase peripheral blood mononuclear cell 2-(N-morpholino)ethanesulfonic acid 4-methylumbelliferyl-N-acetyl neuraminic acid fetal bovine serum interleukin minimal essential medium Dulbecco's modified Eagle's medium Madin-Darby canine kidney long terminal repeat multiplicity of infection plaque-forming unit(s) HIV-11 infection is dependent on a now well established interaction between the external viral envelope glycoprotein gp120 and CD4/chemokine receptors (1Horuk R. Immunol. Today. 1999; 20: 89-94Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Infected T cells expressing gp120 molecules on their surface, when fusing with uninfected T cells (a process known as syncytium formation), equally need the same intercellular interaction for such a virus-mediated cytopathic effect to resume (2Trkola A. Dragic T. Arthos J. Binley J.M. Olson W.C. Allaway G.P. Cheng-Mayer C. Robinson J. Maddon P.J. Moore J.P. Nature. 1996; 384: 184-187Crossref PubMed Scopus (956) Google Scholar, 3Lapham C.K. Ouyang J. Chandrasekhar B. Nguyen N.Y. Dimitrov D.S. Golding H. Science. 1996; 274: 602-605Crossref PubMed Scopus (336) Google Scholar, 4Wu L. Gerard N.P. Wyatt R. Choe H. Parolin C. Ruffing N. Borsetti A. Cardoso A.A. Desjardin E. Newman W. Gerard C. Sodroski J. Nature. 1996; 384: 179-183Crossref PubMed Scopus (1081) Google Scholar, 5Binley J. Moore J.P. Nature. 1997; 387: 346-348Crossref PubMed Scopus (63) Google Scholar). However, HIV-1 attachment to host cells often occurs under suboptimal conditions because of a low frequency of gp120/CD4 interaction events (6Moore J.P. Ho D.D. AIDS Res. Hum. Retroviruses. 1995; 9: S117-S136Google Scholar, 7Sattentau Q.J. Moore J.P. Vignaux F. Traincard F. Poignard P. J. Virol. 1993; 67: 7383-7393Crossref PubMed Google Scholar, 8Fouts T.R. Binley J.M. Trkola A. Robinson J.E. Moore J.P. J. Virol. 1997; 71: 2779-2785Crossref PubMed Google Scholar). Several factors have been proposed to explain this phenomenon. First, most cell types that are permissive for HIV-1 infection express little CD4 (9Sonza S. Maerz A. Uren S. Violo A. Hunter S. Boyle W. Crowe S. AIDS Res. Hum. Retroviruses. 1995; 11: 769-776Crossref PubMed Scopus (46) Google Scholar, 10Dick A.D. Pell M. Brew B.J. Foulcher E. Sedgwick J.D. AIDS Res. Hum. Retroviruses. 1997; 11: 1699-1708Google Scholar). Second, the weak association between gp120 and gp41 results in a rapid gp120 shedding and, consequently, a loss of virus infectivity (11Gelderblom H.R. Reupke H. Pauli G. Lancet. 1985; 2: 1016-1017Abstract PubMed Scopus (92) Google Scholar, 12Gelderblom H.R. Hausmann E.H. Ozel M. Pauli G. Koch M.A. Virology. 1987; 156: 171-176Crossref PubMed Scopus (406) Google Scholar). Third, the efficient attachment of circulating virions to target cells has to take place despite the presence of neutralizing antibodies that are directed predominantly against gp120 (13Sattentau Q.J. Curr. Opin. Immunol. 1996; 8: 540-545Crossref PubMed Scopus (43) Google Scholar). Finally, the electrostatic repulsive forces that result from net negative charges present on the surface of both virion and target cell represent an obstacle to the initial virus attachment process (14Fenouillet E. Gluckman J.C. Bahraoui E. J. Virol. 1990; 64: 2841-2848Crossref PubMed Google Scholar). Thus, it has been proposed that other interactions between the virus and the cell surface are necessary to overcome the various factors that might jeopardize the first step in the life cycle of an intracellular parasite such as HIV-1. Accumulating evidence suggest that the activity of bacterially derived neuraminidase (NA, also termed sialidase) can also modulate replication of this retrovirus, including the attachment process, by reducing the level of sialylation of glycoconjugates expressed on the surface of viruses and target cells (15Hu H. Shioda T. Moriya C. Xin X. Hasan M.K. Miyake K. Shimada T. Nagai Y. J. Virol. 1996; 70: 7462-7470Crossref PubMed Google Scholar, 16Stamatos N.M. Gomatos P.J. Cox J. Fowler A. Dow N. Wohlhieter J.A. Cross A.S. Virology. 1997; 228: 123-131Crossref PubMed Scopus (28) Google Scholar, 17Sun J. Barbeau B. Sato S. Tremblay M.J. Virology. 2001; 284: 26-36Crossref PubMed Scopus (28) Google Scholar).Sialic acids are monosaccharides transferred onto glycolipids and glycoproteins which travel through the secretory pathway (18Keppler O.T. Hinderlich S. Langner J. Schwartz-Albiez R. Reutter W. Pawlita M. Science. 1999; 284: 1372-1376Crossref PubMed Scopus (274) Google Scholar, 19Taylor G. Curr. Opin. Struct. Biol. 1996; 6: 830-837Crossref PubMed Scopus (209) Google Scholar). One of the distinct features of sialic acid is its outermost cellular location and its negative charge that increases the net negative charge present on the cell surface. In animals, NAs have been found in several tissues, where the enzymes play various roles in regulation of the surface sialic acid profile of cells. Thus, the balance between sialic acid content and sialidase activity is often found to affect many biological phenomena in animal cells, such as T and B cell activation, hematopoietic cell differentiation, apoptosis, and particularly the regulation of various cell-cell and cell-substrate interactions (20Powell L.D. Whiteheart S.W. Hart G.W. J. Immunol. 1987; 139: 262-270PubMed Google Scholar, 21Foxall C. Watson S.R. Dowbenko D. Fennie C. Lasky L.A. Kiso M. Hasegawa A. Asa D. Brandley B.K. J. Cell Biol. 1992; 117: 895-902Crossref PubMed Scopus (650) Google Scholar, 22Erbe D.V. Watson S.R. Presta L.G. Wolitzky B.A. Foxall C. Brandley B.K. Lasky L.A. J. Cell Biol. 1993; 120: 1227-1235Crossref PubMed Scopus (166) Google Scholar, 23Hennet T. Chui D. Paulson J.C. Marth J.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 4504-4509Crossref PubMed Scopus (306) Google Scholar, 24Acheson A. Sunshine J.L. Rutishauser U. J. Cell Biol. 1991; 114: 143-153Crossref PubMed Scopus (295) Google Scholar, 25Rutishauser U. Watanabe M. Silver J. Troy F.A. Vimr E.R. J. Cell Biol. 1985; 101: 1842-1849Crossref PubMed Scopus (216) Google Scholar). As the surface of both HIV-1 and its natural target cells contain highly sialylated glycoconjugates, previous works have scrutinized the potential implication of sialic acid and neuraminidase activity in the HIV-1 life cycle. For example, Hu et al.(15Hu H. Shioda T. Moriya C. Xin X. Hasan M.K. Miyake K. Shimada T. Nagai Y. J. Virol. 1996; 70: 7462-7470Crossref PubMed Google Scholar) reported that desialylation of HIV-1 increases virus infectivity, whereas others have reported that desialylation of freshly isolated human peripheral blood mononuclear cells (PBMCs) creates a cellular environment more suitable for virus growth (16Stamatos N.M. Gomatos P.J. Cox J. Fowler A. Dow N. Wohlhieter J.A. Cross A.S. Virology. 1997; 228: 123-131Crossref PubMed Scopus (28) Google Scholar, 26Xin X. Shioda T. Fukushima M. Hu H. Oka S. Iwamoto A. Nagai Y. Arch. Virol. 1998; 143: 85-95Crossref PubMed Scopus (5) Google Scholar). More recently, we reported that Arthrobacter-derived NA augmented HIV-1-mediated syncytium formation and the initial steps in the virus life cycle (i.e. binding and entry) (17Sun J. Barbeau B. Sato S. Tremblay M.J. Virology. 2001; 284: 26-36Crossref PubMed Scopus (28) Google Scholar).Human influenza (flu) virus represents a pathogen that bears NA activity. Indeed, the outer surface of flu virus consists of a lipid envelope from which project prominent glycoprotein spikes of two types,i.e. hemagglutinin and NA. Because flu hemagglutinin binds sialic acid on cellular and viral glycoproteins, the presence of enzymatically active NA is required for the release of virus particles from infected cells and to prevent aggregation of virus particles (27Air G.M. Laver W.G. Proteins. 1989; 6: 341-356Crossref PubMed Scopus (261) Google Scholar, 28Zambon M.C. J. Antimicrob. Chemother. 1999; 44: B3-B9Crossref PubMed Scopus (188) Google Scholar, 29Kiefel M.J. von Itzstein M. Prog. Med. Chem. 1999; 36: 1-28Crossref PubMed Scopus (28) Google Scholar). During the process of infection with flu, it is most likely that the membrane-bound NA removes sialic acid from both cellular and viral glycoconjugates to halt self-agglutination of viruses (30Els M.C. Laver W.G. Air G.M. Virology. 1989; 170: 346-351Crossref PubMed Scopus (22) Google Scholar). Human flu virus has the capacity to interact with and infect human macrophages and lymphocytes, two mononuclear cell types known to harbor HIV-1 (31Mock D.J. Domurat F. Roberts Jr., N.J. Walsh E.E. Licht M.R. Keng P. J. Clin. Invest. 1987; 79: 620-624Crossref PubMed Scopus (32) Google Scholar). In patients infected with flu virus, viral replication is occurring on the mucosal surface of respiratory tracts and virions are also found in mucosa-associated lymphoid tissue that is also one of the natural reservoir of HIV-1 (32Doherty P.C. J. Immunol. 1995; 155: 1023-1027PubMed Google Scholar, 33Mestecky J. Czerkinsky C. Russell M.W. Brown T.A. Prince S.J. Moldoveanu Z. Jackson S. Michalek S.M. McGhee J.R. Ann. Allergy. 1987; 59: 54-59PubMed Google Scholar, 34Frankel S.S. Tenner-Racz K. Racz P. Wenig B.M. Hansen C.H. Heffner D. Nelson A.M. Pope M. Steinman R.M. Am. J. Pathol. 1997; 151: 89-96PubMed Google Scholar), therefore suggesting the possible co-localization of both pathogens at the same site. Although previous studies have indicated that influenza vaccination could increase HIV-1 viral loads (35Ho D.D. Lancet. 1992; 3391549Abstract PubMed Scopus (115) Google Scholar, 36Rosok B. Voltersvik P. Bjerknes R. Axelsson M. Haaheim L.R. Asjo B. Clin. Exp. Immunol. 1996; 104: 203-207Crossref PubMed Scopus (48) Google Scholar), a recent study has indicated that influenza infection did not alter HIV-1 viral load or the rate of CD4+ T cell decline or clinical progression (37Golden M.P. Sajjad Z. Elgart L. Clin. Infect. Dis. 2001; 32: 1366-1370Crossref PubMed Scopus (14) Google Scholar). However, no study has directly addressed the role of flu-derived NA on the HIV-1 replicative cycle. In the present work, we provide evidence suggesting that flu NA either as purified enzymes or as virus-associated augments the processes of HIV-1-mediated syncytium formation and virus infection.DISCUSSIONThe effect of endogenous NA on the process of HIV-1 infection has been difficult to dissect because modification of NA activity is always accompanied by other simultaneous biological processes. Given that NAs from different species share the same substrates (e.g.glycoproteins, glycolipids, and oligosaccharides) (48Faillard H. Trends Biochem. Sci. 1989; 14: 237-241Abstract Full Text PDF PubMed Scopus (26) Google Scholar), exogenous NAs derived from few microorganisms (mostly of bacterial origin) have been used to deduce the role played by NAs with respect to the life cycle of HIV-1. Interestingly, several bacteria and viruses produce NA as virulence factors either on their surface or in a secreted form (19Taylor G. Curr. Opin. Struct. Biol. 1996; 6: 830-837Crossref PubMed Scopus (209) Google Scholar). Some of these microbial pathogens are recognized as opportunistic agents in the course of AIDS (49Ray P.K. Adv. Appl. Microbiol. 1977; 21: 227-267Crossref PubMed Scopus (27) Google Scholar, 50Roggentin P. Gutschker-Gdaniec G.H. Hobrecht R. Schauer R. Clin. Chim. Acta. 1988; 173: 251-262Crossref PubMed Scopus (16) Google Scholar, 51Corfield T. Glycobiology. 1992; 2: 509-521Crossref PubMed Scopus (293) Google Scholar, 52Vimr E.R. Trends Microbiol. 1994; 2: 271-277Abstract Full Text PDF PubMed Scopus (65) Google Scholar). Considering that secondary lymphoid organs are the preferential sites where microbial agents are concentrated during the normal immune response and where concomitantly high level of HIV-1 replication is thought to occur (53Pantaleo G. Graziosi C. Butini L. Pizzo P.A. Schnittman S.M. Kotler D.P. Fauci A.S. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 9838-9842Crossref PubMed Scopus (410) Google Scholar, 54Poli G. Pantaleo G. Fauci A.S. Clin. Infect. Dis. 1993; 17: S224-S229Crossref PubMed Scopus (116) Google Scholar, 55Graziosi C. Soudeyns H. Rizzardi G.P. Bart P.A. Chapuis A. Pantaleo G. AIDS Res. Hum. Retroviruses. 1998; 14: S135-S142PubMed Google Scholar), it is therefore of high importance to delineate the role of pathogen-derived NA in the biology of HIV-1.In this report, we have initially tested the modulatory role of purified flu NA on HIV-1-mediated syncytium formation and cell-free virus infection. We showed that treating cells with flu-derived NAs remarkably augmented the initial cell-cell interaction and thereby promoted HIV-1-mediated cytopathic effect (i.e. syncytium formation). We have also noticed that desialylation of target cells increased susceptibility of target cells to infection with cell-free HIV-1 particles. Here, we demonstrate for the first time that virion-associated flu NA exhibits a similar enhancing effect on HIV-1-mediated syncytium formation and cell-free virus infection.In our in vitro experimental systems, studied target cells, including freshly isolated PBMCs, were more prone to HIV-1-mediated syncytium formation in the presence of either purified flu NA enzyme or different strains of UV-inactivated flu virus that bear NA activity. The flu NA-dependent up-regulating effect on HIV-1-induced syncytium formation is likely to occur through a mechanism involving the removal of sialic acids from the cell surface as zanamivir, a specific flu NA inhibitor, suppressed the observed up-regulation. Sialic acid content is one of the key elements regulating cell-to-cell contact (56Kelm S. Schauer R. Int. Rev. Cytol. 1997; 175: 137-240Crossref PubMed Google Scholar) and desialylation caused by flu NA enzymatic activity results most likely in a higher rate of intercellular interaction, which eventually increases HIV-1-mediated syncytium formation. Given that our results demonstrate that flu NA treatment increases the intercellular interaction of a number of cells including PBMCs and T cells, the presence of NA-producing microorganisms in local lymph tissues could increase the stability of cell-cell interactions, thereby promoting transmission of HIV-1 between susceptible cells.Besides HIV-1-mediated syncytium formation, purified flu NA was also found to affect the process of cell-free HIV-1 infection in several different cell source, an increase in infection which was zanamivir-sensitive. Because transcriptional activity of HIV-1 LTR region in 1G5 cells was not modulated by purified NA, it can be postulated that NA is primarily affecting the early steps of the HIV-1 replication cycle. Experiments conducted with single-cycle luciferase reporter viruses supports the idea that flu NA is most likely affecting the initial events in HIV-1 life cycle. It should be noted that desialylation by bacterial-derived NA has also been observed to promote HIV-1 attachment and entry (15Hu H. Shioda T. Moriya C. Xin X. Hasan M.K. Miyake K. Shimada T. Nagai Y. J. Virol. 1996; 70: 7462-7470Crossref PubMed Google Scholar, 17Sun J. Barbeau B. Sato S. Tremblay M.J. Virology. 2001; 284: 26-36Crossref PubMed Scopus (28) Google Scholar). Such a modified interaction between target cells and HIV-1 particles in the presence of secreted NA by surrounding NA-producing pathogens might have a profound impact on HIV-1 spreading and infection. For example, a more rapid and stable binding of virions to susceptible cells under in vivoconditions will likely positively affect the HIV-1 attachment process.Most studies, which were aimed at defining the effect of NA on HIV-1 biology, were using purified soluble NA derived from various pathogens of bacterial origin. It can therefore be questioned whether the amount of NA released by or associated with such microorganisms are in the same order of magnitude as the concentrations of purified NA used in these experimental studies. Besides, NAs of several pathogens, including human flu virus A and B, are membrane-associated. Thus, the validity of the data obtained with purified soluble NA remains questionable and might not be representative enough to deduce the exact role played by membrane-bound NA on the biology of HIV-1 in patients dually infected with HIV-1 and NA-bearing pathogens. We therefore assessed whether flu-anchored NA would exhibit a similar positive effect on HIV-1 replication. This specific issue was addressed by using several flu virus isolates that were inactivated by UV treatment to eliminate possible expression of flu-encoded protein(s) within studied cells. This is founded on a previous report showing that expression of flu virus hemagglutinin in mammalian cells induces activation of NF-κB (57Pahl H.L. Baeuerle P.A. J. Virol. 1995; 69: 1480-1484Crossref PubMed Google Scholar), a transcription factor recognized as a powerful activator of HIV-1 transcription (58Nabel G. Baltimore D. Nature. 1987; 326: 711-713Crossref PubMed Scopus (1442) Google Scholar). Whole UV-inactivated flu viruses were first confirmed to harbor NA enzymatic activity on their surface but importantly were also capable of potentiating HIV-1-dependent giant cell formation and HIV-1 replication in both T cell lines and PBMCs. Both of these events were furthermore positively modulated by flu viruses in a zanamivir-sensitive fashion.On the basis of these latter results, it could be postulated that an effective treatment against flu infection in HIV-1-positive individuals might be beneficial for such patients. However, previous observations have reported that flu infection in HIV-1-positive individuals did not alter HIV-1 viral load or clinical progression (37Golden M.P. Sajjad Z. Elgart L. Clin. Infect. Dis. 2001; 32: 1366-1370Crossref PubMed Scopus (14) Google Scholar). In fact, because the flu virus is mainly localized in the upper respiratory tract, such interaction between this virus and HIV-1 target cells might not be sufficiently predominant. However, one important related issue concerns the safety and risk-benefit ratio of flu vaccination of HIV-1-infected adults, which is still a matter of debate because of the controversy surrounding putative changes in plasma levels of HIV-1 RNA following vaccination of HIV-1-infected patients against flu (35Ho D.D. Lancet. 1992; 3391549Abstract PubMed Scopus (115) Google Scholar, 36Rosok B. Voltersvik P. Bjerknes R. Axelsson M. Haaheim L.R. Asjo B. Clin. Exp. Immunol. 1996; 104: 203-207Crossref PubMed Scopus (48) Google Scholar, 59Staprans S.I. Hamilton B.L. Follansbee S.E. Elbeik T. Barbosa P. Grant R.M. Feinberg M.B. J. Exp. Med. 1995; 182: 1727-1737Crossref PubMed Scopus (275) Google Scholar, 60Glesby M.J. Hoover D.R. Farzadegan H. Margolick J.B. Saah A.J. J. Infect. Dis. 1996; 174: 1332-1336Crossref PubMed Scopus (116) Google Scholar, 61Fuller J.D. Craven D.E. Steger K.A. Cox N. Heeren T.C. Chernoff D. Clin. Infect. Dis. 1999; 28: 541-547Crossref PubMed Scopus (122) Google Scholar). It is plausible that this risk could be even higher with the use of live-attenuated flu vaccines in light of our results.Our results thus offer a model by which the interactions of NA-bearing pathogens with HIV-1 can be studied. Although in vivo, such interactions between flu viruses and HIV-1 are less likely to occur, other pathogens, which represent opportunistic infectious agents and which are NA-positive, could be tested in our cell lines model for their effect on HIV-1 replication and virus-mediated syncytium formation. In addition, the in vitro activity of zanamivir against flu NA-mediated positive modulation of the HIV-1 life cycle in our system calls for discovery and potential use of NA inhibitors of other NA-producing pathogens known to be frequently detected in HIV-1-infected individuals.In summary, our findings indicate that human flu virus through the enzymatic activity of NA, one of the two surface glycoproteins of this virus, accentuates syncytium formation and infection by HIV-1. A specific inhibitor of flu NA (i.e. zanamivir) was used to successfully block flu NA-mediated enhancing effect on HIV-1 life cycle. These findings should provide a new model, which has direct physiological relevance because microbial pathogens that produce NAs as virulence factors may affect HIV-1 pathogenesis via desialylating effect of these enzymes. In addition, we are presently studying the use of the ex vivo tonsil fragment model to study the impact of NA-bearing pathogens on HIV-1 replication. Through the results from the presented flu virus model, potent specific inhibitors of NA might be considered for the treatment of patients suffering from infection with HIV-1 and NA-encoding pathogens. HIV-11 infection is dependent on a now well established interaction between the external viral envelope glycoprotein gp120 and CD4/chemokine receptors (1Horuk R. Immunol. Today. 1999; 20: 89-94Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Infected T cells expressing gp120 molecules on their surface, when fusing with uninfected T cells (a process known as syncytium formation), equally need the same intercellular interaction for such a virus-mediated cytopathic effect to resume (2Trkola A. Dragic T. Arthos J. Binley J.M. Olson W.C. Allaway G.P. Cheng-Mayer C. Robinson J. Maddon P.J. Moore J.P. Nature. 1996; 384: 184-187Crossref PubMed Scopus (956) Google Scholar, 3Lapham C.K. Ouyang J. Chandrasekhar B. Nguyen N.Y. Dimitrov D.S. Golding H. Science. 1996; 274: 602-605Crossref PubMed Scopus (336) Google Scholar, 4Wu L. Gerard N.P. Wyatt R. Choe H. Parolin C. Ruffing N. Borsetti A. Cardoso A.A. Desjardin E. Newman W. Gerard C. Sodroski J. Nature. 1996; 384: 179-183Crossref PubMed Scopus (1081) Google Scholar, 5Binley J. Moore J.P. Nature. 1997; 387: 346-348Crossref PubMed Scopus (63) Google Scholar). However, HIV-1 attachment to host cells often occurs under suboptimal conditions because of a low frequency of gp120/CD4 interaction events (6Moore J.P. Ho D.D. AIDS Res. Hum. Retroviruses. 1995; 9: S117-S136Google Scholar, 7Sattentau Q.J. Moore J.P. Vignaux F. Traincard F. Poignard P. J. Virol. 1993; 67: 7383-7393Crossref PubMed Google Scholar, 8Fouts T.R. Binley J.M. Trkola A. Robinson J.E. Moore J.P. J. Virol. 1997; 71: 2779-2785Crossref PubMed Google Scholar). Several factors have been proposed to explain this phenomenon. First, most cell types that are permissive for HIV-1 infection express little CD4 (9Sonza S. Maerz A. Uren S. Violo A. Hunter S. Boyle W. Crowe S. AIDS Res. Hum. Retroviruses. 1995; 11: 769-776Crossref PubMed Scopus (46) Google Scholar, 10Dick A.D. Pell M. Brew B.J. Foulcher E. Sedgwick J.D. AIDS Res. Hum. Retroviruses. 1997; 11: 1699-1708Google Scholar). Second, the weak association between gp120 and gp41 results in a rapid gp120 shedding and, consequently, a loss of virus infectivity (11Gelderblom H.R. Reupke H. Pauli G. Lancet. 1985; 2: 1016-1017Abstract PubMed Scopus (92) Google Scholar, 12Gelderblom H.R. Hausmann E.H. Ozel M. Pauli G. Koch M.A. Virology. 1987; 156: 171-176Crossref PubMed Scopus (406) Google Scholar). Third, the efficient attachment of circulating virions to target cells has to take place despite the presence of neutralizing antibodies that are directed predominantly against gp120 (13Sattentau Q.J. Curr. Opin. Immunol. 1996; 8: 540-545Crossref PubMed Scopus (43) Google Scholar). Finally, the electrostatic repulsive forces that result from net negative charges present on the surface of both virion and target cell represent an obstacle to the initial virus attachment process (14Fenouillet E. Gluckman J.C. Bahraoui E. J. Virol. 1990; 64: 2841-2848Crossref PubMed Google Scholar). Thus, it has been proposed that other interactions between the virus and the cell surface are necessary to overcome the various factors that might jeopardize the first step in the life cycle of an intracellular parasite such as HIV-1. Accumulating evidence suggest that the activity of bacterially derived neuraminidase (NA, also termed sialidase) can also modulate replication of this retrovirus, including the attachment process, by reducing the level of sialylation of glycoconjugates expressed on the surface of viruses and target cells (15Hu H. Shioda T. Moriya C. Xin X. Hasan M.K. Miyake K. Shimada T. Nagai Y. J. Virol. 1996; 70: 7462-7470Crossref PubMed Google Scholar, 16Stamatos N.M. Gomatos P.J. Cox J. Fowler A. Dow N. Wohlhieter J.A. Cross A.S. Virology. 1997; 228: 123-131Crossref PubMed Scopus (28) Google Scholar, 17Sun J. Barbeau B. Sato S. Tremblay M.J. Virology. 2001; 284: 26-36Crossref PubMed Scopus (28) Google Scholar). Sialic acids are monosaccharides transferred onto glycolipids and glycoproteins which travel through the secretory pathway (18Keppler O.T. Hinderlich S. Langner J. Schwartz-Albiez R. Reutter W. Pawlita M. Science. 1999; 284: 1372-1376Crossref PubMed Scopus (274) Google Scholar, 19Taylor G. Curr. Opin. Struct. Biol. 1996; 6: 830-837Crossref PubMed Scopus (209) Google Scholar). One of the distinct features of sialic acid is its outermost cellular location and its negative charge that increases the net negative charge present on the cell surface. In animals, NAs have been found in several tissues, where the enzymes play various roles in regulation of the surface sialic acid profile of cells. Thus, the balance between sialic acid content and sialidase activity is often found to affect many biological phenomena in animal cells, such as T and B cell activation, hematopoietic cell differentiation, apoptosis, and particularly the regulation of various cell-cell and cell-substrate interactions (20Powell L.D. Whiteheart S.W. Hart G.W. J. Immunol. 1987; 139: 262-270PubMed Google Scholar, 21Foxall C. Watson S.R. Dowbenko D. Fennie C. Lasky L.A. Kiso M. Hasegawa A. Asa D. Brandley B.K. J. Cell Biol. 1992; 117: 895-902Crossref PubMed Scopus (650) Google Scholar, 22Erbe D.V. Watson S.R. Presta L.G. Wolitzky B.A. Foxall C. Brandley B.K. Lasky L.A. J. Cell Biol. 1993; 120: 1227-1235Crossref PubMed Scopus (166) Google Scholar, 23Hennet T. Chui D. Paulson J.C. Marth J.D. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 4504-4509Crossref PubMed Scopus (306) Google Scholar, 24Acheson A. Sunshine J.L. Rutishauser U. J. Cell Biol. 1991; 114: 143-153Crossref PubMed Scopus (295) Google Scholar, 25Rutishauser U. Watanabe M. Silver J. Troy F.A. Vimr E.R. J. Cell Biol. 1985; 101: 1842-1849Crossref PubMed Scopus (216) Google Scholar). As the surface of both HIV-1 and its natural target cells contain highly sialylated glycoconjugates, previous works have scrutinized the potential implication of sialic acid and neuraminidase activity in the HIV-1 life cycle. For example, Hu et al.(15Hu H. Shioda T. Moriya C. Xin X. Hasan M.K. Miyake K. Shimada T. Nagai Y. J. Virol. 1996; 70: 7462-7470Crossref PubMed Google Scholar) reported that desialylation of HIV-1 increases virus infectivity, whereas others have reported that desialylation of freshly isolated human peripheral blood mononuclear cells (PBMCs) creates a cellular environment more suitable for virus growth (16Stamatos N.M. Gomatos P.J. Cox J. Fowler A. Dow N. Wohlhieter J.A. Cross A.S. Virology. 1997; 228: 123-131Crossref PubMed Scopus (28) Google Scholar, 26Xin X. Shioda T. Fukushima M. Hu H. Oka S. Iwamoto A. Nagai Y. Arch. Virol. 1998; 143: 85-95Crossref PubMed Scopus (5) Google Scholar). More recently, we reported that Arthrobacter-derived NA augmented HIV-1-mediated syncytium formation and the initial steps in the virus life cycle (i.e. binding and entry) (17Sun J. Barbeau B. Sato S. Tremblay M.J. Vir
Referência(s)