On the role of dendritic cells in HIV-1 infection

<p>Dendritic cells (DCs) are antigen-presenting cells with the capacity to initiate primary T cell responses against pathogens such as HIV-1. In addition, DCs express the receptors required for HIV-1 infection and as DCs are prevalent in the mucosa, they encounter the virus early after sexual transmission. DCs also express additional receptors able to bind and capture intact HIV-1 without becoming infected.</p><p>Normally, DCs capture antigen in the periphery and migrate to draining lymph nodes to present the antigen to T cells to start immune responses. HIV-1 may utilize this process as, DCs can collect and carry HIV-1 and facilitate spread to CD4+ T cells. To optimize the T cell activation, DCs mature by upregulation of MHC and co-stimulatory molecules and induction of cytokine production. However, another consequence of efficient interaction between DCs and T cells is that it provides an optimal milieu for HIV-1 transmission and replication.</p><p>We studied the effects of HIV-1 infection on DC function. We found that monocyte-derived DCs (MDDCs) were productively infected by HIV-1 after in vitro exposure (as measured by intracellular production of HIV-1 p24). HIV-1 infected MDDCs upregulated co-stimulatory molecules in response to CD40ligand stimulation, comparable to uninfected MDDCs. However, intracellular cytokine staining revealed that while the HIV-1 infected DCs were able to produce TNFalpha, they failed to express IL-12 p70. This may impact the ability of DCs to induce optimal HIV-1 specific immune responses, as IL-12 is vital for the induction of cellular immune responses.</p><p>Next, we expanded the studies by examining isolated primary myeloid DCs (MDCs) and plasmacytoid DCs (PDCs). MDCs and PDCs became productively infected by different HIV-1 isolates. The DC subsets displayed differential susceptibility to HIV-1. HIV-1 exposure induced some maturation in the DCs. However, TLR ligation induced full maturation and TNFalpha production in both uninfected and infected DCs. Productively infected MDCs and PDCs efficiently transferred HIV-1 to autologous CD4+ T cells, and antigen-reactivated T cells were more frequently infected than non-responding T cells. This suggests that induction of DC-dependent antigen-specific T cell responses, crucial to the immune defence, also can lead to preferential HIV-1 infection of responding T cell clones in infected individuals.</p><p>DCs can present antigens derived from apoptotic cells. We investigated whether apoptotic HIV-1 infected cells were capable of eliciting HIV-1 specific immune responses in vivo. Immunization of mice with apoptotic HIV-1/MuLV infected cells resulted in induction of HIV-1 specific T cell and antibody responses. Moreover, immunized mice handled challenge with live HIV-1/MuLV infected cells more effectively than nonimmunized mice. These data show that immunization of mice with apoptotic HIV-1 infected cells can induce high levels of HIV-1 specific systemic immunity and prime for mucosal immunity that could provide means for the mice to cope with challenge.</p><p>Collectively, our findings demonstrate that DCs are under certain conditions impaired by HIV-1 infection but that they efficiently transfer HIV-1 to CD4+ T cells. Taken together, an increased understanding of DC immunobiology may help us develop more effective HIV-1 therapy and/or an HIV-1 vaccine.</p><h3>List of scientific papers</h3><p>I. Smed-Sorensen A, Lore K, Walther-Jallow L, Andersson J, Spetz AL (2004). HIV-1-infected dendritic cells up-regulate cell surface markers but fail to produce IL-12 p70 in response to CD40 ligand stimulation. Blood. 104(9): 2810-7. Epub 2004 Jul 01 <br><a href="https://pubmed.ncbi.nlm.nih.gov/15231570">https://pubmed.ncbi.nlm.nih.gov/15231570</a><br><br></p><p>II. Smed Sorensen A, Lore K, Vasudevan J, Louder MK, Mascola JR, Andersson, Spetz AL, Koup RA (2004). Differential susceptibility to HIV-1 infection of myeloid and plasmacytoid dendritic cells. [Submitted] </p><p>III. Lore K, Smed Sorensen A, Vasudevan J, Mascola JR, Koup RA (2004). Productively infected myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells. [Manuscript]</p><p>IV. Spetz AL, Smed Sorensen A, Walther-Jallow L, Wahren B, Andersson J, Holmgren L, Hinkula J (2002). Induction of HIV-1-specific immunity after vaccination with apoptotic HIV-1/murine leukemia virus-infected cells. J Immunol. 169(10): 5771-9. <br><a href="https://pubmed.ncbi.nlm.nih.gov/12421957">https://pubmed.ncbi.nlm.nih.gov/12421957</a><br><br></p>