On the role of dendritic cells in HIV-1 infection

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.

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.

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.

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.

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.

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.

List of scientific papers

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
https://pubmed.ncbi.nlm.nih.gov/15231570

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]

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]

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.
https://pubmed.ncbi.nlm.nih.gov/12421957