Dendritic cell and IgA responses in SIV and HIV-1 pathogenesis

Sammanfattning: Simian immunodeficiency virus (SIV) as well as human immunodeficiency virus (HIV-1) can infect different subsets of dendritic cells (DC). Such cells may therefore not only be involved in the generation of recruitment of naïve T and B lymphocytes in induction of SIV/HIV-1 specific adaptive responses but also transmit virus from port of entrance to the secondary lymphoid compartment generating systemic viral spread. DC express both CD4 as well as chemokine receptors, particular CCR5, allowing these cells to be susceptible for infection. However, SIV/HIV-1 I may also bind in trans to lectins, such as DC-SIGN, which may provide a tool for viral dissemination without need for viral replication in targeted DC. Here we have investigated functional and maturational aspects of DC both in SIV infected monkeys as well as in HIV- I infected patients. First we demonstrated that ex vivo recruitment of myeloid DC from SIV infected monkeys by addition of exogenous cytokines was intact despite a low virus replication in these cell cultures. However, in vivo the SIV infection was associated with a sustained recruitment of myeloid DC to the lymph nodes, but dysfunctional maturation of such cells with lack of phenotypic markers of maturation such as CD83 and DC-LAMP but retained CD1a expression. By assessing humoral responses during primary HIV-1 infection at the time of HIV-1 seroconversion we could demonstrate an early HIV-1 neutralizing IgA response in infected individuals. We also examined the humoral response in highly exposed persistently seronegative individuals (HEPS) both at mucosal sites as well as in plasma. These individuals lacked HIV-1 specific IgG, but secreted HIV-1 specific IgA, both at the mucosal level and in plasma. However, in contrast to HIV-1 neutralizing sera from infected patients, this IgA activity could not inhibit transfer of HIV-1 cell-bound virus. This was analyzed in an assay where we used HIV- I exposed DC expressing DC-SIGN and co-cultured with PBMC in the presence or absence of Ig. Based on our previous studies, this may indicate that HEPS are protected against further HIV-1 dissemination at the luminal side of mucosal sites or during viral transport through the mucosal epithelia, at least prior to viral interaction with DC-SIGN expressing DC. These data indicate that DC as well as IgA has important immune regulatory roles in the innate as well as in the adaptive response to early HIV-1 infection. Assessing antibody-mediated inhibition of cell associated HIV-1 transfer will be of importance for evaluating novel HIV- I vaccine candidates.