Inactivation of HIV-1 by neutralizing antibodies at the time of initial exposure would provide a potent mechanism to inhibit HIV infection in vivo and would be a desirable feature of an immune response elicited by a highly effective AIDS vaccine, but HIV has evolved a number of mechanisms to evade broadly neutralizing antibodies. For example, HIV Env can evade this response through carbohydrate and variable loop masking, conformational changes that protect highly conserved, receptor binding structures, and its high degree of genetic variability (47
). Here we report that immunoglobulin G neutralizing antibodies can block CCR5-tropic HIV-1 entry into myeloid DCs, but once the virus is internalized through DC-SIGN by the antigen-presenting cell, it provides a previously unrecognized mechanism of immune evasion to neutralizing antibodies that may also be integral to the strategy of HIV spread and persistence. The enhancement of infection and the protection from neutralizing antibodies provided by the DCs help the virus to efficiently infect host T cells (Fig. ).
Recently, McDonald et al. have described the formation of an infectious synapse, which provides both a structure and a mechanism to explain the enhancement of T-cell infection by DCs (31
). The present study is consistent with this model and further suggests that such a synapse is poorly accessible to neutralizing antibodies (Fig. ). In the seven viruses tested (two CXCR4-tropic, three CCR5-tropic, and two dualtropic), it was found that once CCR5-dependent viruses establish DC infection, even the most potent broadly neutralizing antibodies are limited in their ability to prevent the T-cell spread of infection (Fig. ). This phenomenon is likely reflective of primary HIV-1 strains that are also generally resistant to antibody neutralization (34
). These findings suggest that in infected individuals, mDCs may serve as a reservoir and immune therapies for HIV will need to prevent or reduce the infection of these cells to be highly effective.
Several groups have shown that DC-mediated trans
-infection can be inhibited by both neutralizing antibodies and fusion inhibitors with different R5 isolates (18
). The findings here are consistent with previous work; however, there has been no analysis of the effect of DCs on neutralizing antibodies in long-term DC-T-cell cocultures. The present study shows that even in the continuous presence of neutralizing antibodies, mDCs confer resistance to HIV-1 inactivation by known, broadly neutralizing antibodies. This finding contrasts with the effect of peptide-based fusion inhibitors, which inhibit viral replication during trans
), suggesting that these lower-molecular-weight, more-diffusible antagonists are able to gain access to virus in DCs. The present study also points to at least two additional mechanisms by which mDCs may enhance HIV infection and transmission. The ability of CCR5-tropic viruses to infect immature DCs, although not highly productive (Fig. ), allows the development of a reservoir of infected mDCs that infect T cells efficiently upon maturation (Fig. , , and ). Although previous studies have addressed the infectivity of monocyte-derived DCs by HIV (13
), it has not been evident why CCR5-tropic virus remains more highly transmissible than the CXCR4-tropic virus. One explanation is suggested by preferential infection of immature mDCs by CCR5-tropic virus, which may serve as a cellular “Trojan horse” that initiates a persistent infection (Fig. ). This property, as well as the enhanced infectivity, suggests that DCs may play a major role in HIV pathogenesis and transmission. These findings also suggest that a preventive vaccine should be able to elicit robust antibodies to inactivate the virus before the antigen-presenting cell can internalize it. Finally, it has been recognized that DC bind to other viruses, such as Ebola virus (2
), dengue virus (41
), cytomegalovirus (24
), and severe acute respiratory syndrome virus (48
), through DC-SIGN or related receptors; this mechanism of viral uptake and protection from antibodies may be relevant to other infectious diseases.