8a. HIV-1 mucosal transmission: more than one road leads to Rome
Severe flu-like symptoms related to the acute phase of HIV-1 infection are more often than not the reason why newly infected patients come to medical attention. In terms of the battle between the host immune system and the virus, it’s already too late: the war is over (Haase, 2005). Within the first two to three weeks since the initial infection, HIV-1 has already spread systemically and has established itself in lymphoid tissues throughout the host (Haase, 1999). Because of this very reason, understanding the very early events of HIV-1 infection is key to develop ways to prevent infection. For this purpose, a relevant non-human primate model, namely Rhesus monkeys intravaginally exposed to SIV (Miller et al., 1989), has been studied in conjunction with clinical data from HIV-1-infected patients (Haase, 2005; Turville et al., 2006). The resulting model of HIV-1 mucosal transmission proposes that, upon or after crossing the mucosal barrier, HIV-1 establishes infection at the port of entry by infecting DC, macrophages as well as ‛resting’ CD4+ T cells of the lamina propria (Fig. 15). Although ‛resting’ CD4+ T cells have been described to contain five times less viral RNA than activated T cells (Zhang et al., 1999), their elevated numbers at the site of viral entry make up for their lower producing capacity, thus playing a key role in spreading infection (Pope and Haase, 2003). As discussed many times in this manuscript, DC certainly play also an important role in HIV-1 mucosal transmission and resting CD4+ T cells infection. Whether DC transfer minute amounts of virus for ‛resting’ CD4+ T cells to amplify or transmit signals necessary for infected ‛resting’ CD4+ T cells to produce more virions, it has become increasingly clear that DC-T cell interaction at the portal of entry must contribute significantly to systemic dissemination of the virus (Turville et al., 2006). Setting up a certain threshold of infection locally in resting CD4+ T cells, DC and macrophages seems to be a prerequisite for the systemic spread and massive viral replication in lymphoid tissues such as GALT. In this context, activated CD4+ T cells take over viral production later during the infection and increase the release of viral particles in the blood stream (Pope and Haase, 2003). In parallel, migrating HIV-1-infected DC on their own certainly contribute as well to viral dissemination to draining lymph nodes. Intense viral replication in GALT leads to the severe depletion in HIV-1-specific CD4+ T cells, the preferential target of HIV-1 (Brenchley et al., 2004; Douek et al., 2002;
Mehandru et al., 2004). In addition, HIV-1 promotes immune evasion in more subtle ways. When interacting with DC, HIV-1 prevents the DC it infects to properly go through maturation, veering DC from accurate antigen presentation towards the induction of regulatory or suppressive cells
(Granelli-Piperno et al., 2004; Patterson et al., 2005). Finally, HIV-1 also favors the mild activation of infected CD4+ T cells by modifying, in a potentially Nef-dependent manner, the composition of the immunological they form with APC. Contrary to fully activated CD4+ T cells (which die rapidly upon HIV-1 infection), intermediate CD4+ T cells activation would provide the virus a propitious environment for continued viral production (Fackler et al., 2007; Thoulouze et al., 2006).
Figure 15. Model of HIV-1 mucosal transmission. After overcoming the mucosal barrier, HIV-1viral particles infect CD4+ T cells, macrophages, LC and DC present at the mucosal and subepithelial level, establishing infection locally.
Subsequently, infected cells and virus reach the proximal draining lymph nodes where infection starts to spread systemically.Next, a massive and explosive replication cycle takes places in the GALT, amplifying the viral load. From (Nikolic et al., 2007).
8b. Fighting HIV-1 at the front door: microbicides and vaccines
Due to the very small time window at hand to prevent or at least contain HIV-1 infection, namely from HIV-1 exposure to before viral systemic dissemination and establishment in lymphoid tissues, the combination of microbicides and vaccines able to induce a fast and durable mucosal immunity are favored strategies (Belyakov and Berzofsky, 2004; Haase, 2005; Pope and Haase, 2003). In both cases, the sole objective is to reduce the number of infected cells at the portal of entry below a certain threshold required for a self-propagating HIV-1 infection.
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Efficient vaccines should be able to set up a rapid and intense mucosal immune response which, through an adequate CD8+ CTL response and specific neutralizing antibodies, should at least contain the viral infection in a small number of infected cells (Haase, 2005). However, one persistent challenge faces anti-HIV-1 vaccines. Due to HIV-1 error-prone replication cycle, escape mutants quickly appear along the course of infection, rendering antiretroviral antibodies and CTL useless or at least less effective (Pope and Haase, 2003). The recent failure of the promising replication-defective adenovirus serotype 5 (Ad5) vector-based HIV-1 vaccine (the STEP trial) further highlights the difficult task involved in designing a safe and effective vaccine (Steinbrook, 2007).
Microbicides against HIV-1, or topical anti-infective agents as they should more correctly be called, ought also to achieve reduction of early infected cells. In addition to directly inactivating viral particles and preventing entry of the virus into the mucosa and/or into cells, ideal anti-HIV-1 microbicides should additionally protect the integrity of the mucosal barrier. Concomitantly, it should as well avoid stimulating inflammation, thus helping strengthen the mechanical aspect of the barrier as well as preventing recruitment of activated CD4+ T cells, important vectors of HIV-1 systemic dissemination (Haase, 2005). First generation microbicides, comprising detergents, vaginal pH modifiers and polyanionic gels, have so far failed to protect from HIV-1 infection (Klasse et al., 2008; Nikolic et al., 2007). In the specific case of DC, it was clearly shown that compounds aiming at CD4, the co-receptors or at viral components involved in entry of virions into cells, inhibited direct infection of MDDC and their trans-enhancing infection property (Ketas et al., 2003). Similar results were obtained where CCR5 inhibitors prevented direct infection of cells in mucosal explants while a fusion inhibitor had the same impact on LC infection in addition to preventing viral transmission to co-cultured T cells (Sugaya et al., 2007). Taken together, these results highlight the fact that, although internalized through the interaction with other cell surface proteins, HIV-1 present within DC remains sensitive to such inhibitors. A recent study, using again a fusion inhibitor, describes how captured virions in DC fail to spread to target cells, while the ability of DC to induce virus-specific T cell responses are not hindered (Frank et al., 2008).
Additionally, C-type lectins (CLR) are potentially perfect candidates for HIV-1 microbicides, their strong presence at the cell-surface of DC and their involvement in DC-mediated trans-infection of T cells putting them at the center of DC-HIV-1 interactions. In vitro inhibition of HIV-1 gp120 binding to DC has been shown using mannans (Arrighi et al., 2004b; Geijtenbeek et al., 2000b). Disappointingly, in vivo experiments failed to confirm the potential protecting character of mannan (Veazey et al., 2005). In light of recent data discussed previously in this manuscript, altering HIV-1 interactions with some CLR, notably Langerin, could be detrimental
to the host due to the protective nature of certain lectins (de Witte et al., 2007; Klasse et al., 2008). Consequently, Langerin should be protected from microbicides targeting CLR such as DC-SIGN in order for it to fulfill its role (de Witte et al., 2008).
Although intricate and sometimes contradictory (Ruiz-Mateos et al., 2008; von Lindern et al., 2003), additional data gathered on the role of tetraspanins in HIV-1 life cycle, especially in primary cells such as DC or CD4+ T cells could perhaps lead to the development of microbicides.
A promising small peptide-inhibitor mimicking a portion of CD81 has been described to inhibit the HCV E2-CD81 interaction (Martin et al., 2005). A better understanding of the interactions, although potentially indirect, between HIV-1 viral proteins and tetraspanins would make possible the development of novel microbicides.
8c. Concluding remarks
Although difficult to asses the relevance of in vitro findings in the in vivo “real world”, in vitro studies of the interactions between HIV-1 and DC, often embodied by MDDC, are central in making those first steps towards the understanding of an increasingly complex situation.
Evaluation of the role of the tetraspanin-rich compartment in the sexual transmission of HIV-1 should now be investigated in other DC subtypes, i.e. subepithelial mucosal DC, as discrepancies between subtypes could certainly occur in this aspect. A clear description of the intricate processes at hand in mucosal transmission of HIV-1 and the role played by DC will, without a doubt, lead to better, more effective answers against HIV-1.
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