The mucosal secretions contain substances that can modify the infectivity and course of HIV-1 infection. The molecular constituents of these bathing fluids are generally similar, although the proportions might differ from tissue to tissue depending on the glandular and cellular sources. Among the mucosal fluids, whole and fractionated saliva, breast milk, colostrum, seminal plasma, and cervicovaginal secretions all show anti-HIV-1 activity associated with lactoferrin (Kazmi et al., 2006
). Seminal plasma and cervicovaginal fluids are less effective against HIV-1 than colostrum, whole milk, and whole saliva.
During primary clinical exposures, viable X4- and R5-tropic HIV-1 is introduced into the oral cavity and oropharynx in breast milk (Van de Perre et al., 1991
) or semen (Pasquier et al., 2009
). The bolus of HIV-1 is mixed and diluted, however imperfectly, in saliva. Salivary anti-HIV activity is likewise diluted and potentially neutralized given that breast milk and seminal plasma increase the titer of freshly harvested HIV-1 in vitro
(Acheampong et al., 2005
; Southern and Southern, 2002
). When primary HIV-1 infection is diagnosed, virions are no longer detectable in the oral cavity and oropharynx (Herzberg et al., 2006
), and shed virions in saliva are not infectious (Goto et al., 1991
). Virions are probably inactivated by salivary anti-HIV molecules (Kasmi et al., 2006
). In contrast to this conclusion, primary infection in the gastrointestinal mucosa is thought to result when the HIV-1 bolus passes unremarkably through the nonpermissive oral environment and is swallowed (Brenchley et al., 2006
The actual infectious titer (e.g.
) of HIV-1 in breast milk and semen, containing cell-free and cell-associated virus, is difficult to estimate (Chan, 2005
; Yamaguchi et al., 2007
). When incubated in fresh crude whole saliva, however, HIV-1 virions remain sufficiently infectious when harbored by oral keratinocytes to trans
-infect permissive cells (Dietrich et al
., unpublished data). Although saliva is swallowed at an average rate of 0.5 mL per minute (Rudney et al., 1995
), the HIV–breast milk or HIV-semen bolus mixes imperfectly with saliva and is able to interface for several minutes or longer with the oral epithelium. In some anatomic sites, the HIV-1 bolus may encounter stasis, remaining in prolonged apposition to mucosal keratinocytes. Indeed, spermatozoa, a surrogate marker for HIV-1 virions in seminal fluid, were retained within tonsillar crypts in ex vivo
organ culture experiments (Maher et al., 2004
). Hence, infectious inocula may show extended interactions with mucosal surfaces.
Coated with a salivary film, oral mucosal keratinocytes bind high-molecular-weight mucins (MG1; MUC5B) and other salivary molecules (Bradway et al., 1992
). Indeed, the salivary mucin glycoprotein MUC5B binds HIV-1 (Habte et al., 2006
), which likely docks with cell surface glycoproteins MUC1 and/or gp340 (DMBT1) on the keratinocyte (Stoddard et al., 2007
). The fate of HIV-1 in the oral cavity and oropharynx may depend on the rates of inactivation by saliva, clearance by swallowing, and capture by mucosal keratinocytes.
Most of the estimated 300 to 1300 salivary proteins (Guo et al., 2006
) are in solution (sol phase) (Glantz et al., 1996
), whereas the high-molecular-weight mucin fraction (MG1; MUC5B; > 1000 kDa) self-assembles into a gel phase (Wickstrom et al., 2000
). Crude separation of these phases can be accomplished by centrifugation at 10,000 × g
for 10 minutes (Herzberg et al., 1979
). The partitioned clarified supernatant contains smaller mucin glycoproteins and gp340, sIgA, amylase and other proteins, glycoproteins, and lipids. The sedimented mucous gel phase contains MUC5B and complexed proteins, desquamated oral epithelial cells, bacteria, and viruses. Indeed, mucoid proteins are known to bind influenza virus (Stone, 1949
), and saliva is hospitable and transmits many viruses, including members of the herpesvirus family (Miller et al., 2006
). As a bathing fluid for HIV-1, saliva maintains a pH of about 6.7 and is hypotonic relative to serum. Admixed breast milk or seminal fluid would increase osmolality to approach serum levels. As the flow rate increases to 1.5 mL per minute, the buffer capacity of saliva approaches that of plasma. HIV-1 should be stable in this fluid environment, except for the presence of antiviral molecules.
Putative salivary anti-HIV-1 molecules (Kazmi et al., 2006
) include secretory leukocyte protease inhibitor (McNeely et al., 1995
), β-defensin 2 (hBD-2) (Quinones-Mateu et al., 2003
), proline-rich proteins (Robinovitch et al., 2001
), thrombospondin (Crombie et al., 1998
), lysozyme (Lee-Huang et al., 1999
), salivary peroxidase and α-defensins (Kazmi et al., 2006
), lactoferrin (Saidi et al., 2006
), GP340 agglutinin (Wu et al., 2006
), and mucins, including MUC5B (Habte et al., 2006
). GP340 and MUC5B appear to agglutinate and sequester virus from CD4+ target cells in vitro
(Habte et al., 2006
; Malamud et al., 1997
). In infected individuals, salivary anti-HIV-1 molecules apparently attenuate HIV-1 virions sufficiently enough to virtually eliminate risk of salivary transmission to uninfected individuals. The converse may not be true. The effectiveness of saliva as an anti-HIV-1 agent depends on the mode of action, the kinetics of inactivation, and the ability of the virus to become harbored or shielded from inhibitors. When a bolus of HIV enters the oral cavity of an uninfected individual, saliva may be insufficiently effective (Yeh et al., 1992
) to inhibit uptake and infection of mucosal epithelial cells (Dietrich et al
., unpublished data).