Human blood contains at least 2 subpopulations of antigen-presenting dendritic cells (DCs) that can be differentiated by their expression of CD11c. Myeloid DCs (myDCs), which are CD11c⁺, trap invading pathogens in the tissues and then migrate to lymphoid tissues where they stimulate pathogen-specific T-cell responses. Plasmacytoid DCs (pcDCs), which are CD11c⁻, secrete interferon-α in response to viral infections. This study reports that in HIV-1 infection there is a progressive depletion of both these DC populations and that this correlates with an increasing HIV-1 plasma virus load. The median numbers of myDCs and pcDCs were 6978/mL and 9299/mL, respectively, in healthy male controls and 2298/mL and 1640/mL, respectively, in patients with more than 10⁵ HIV-1 RNA copies/mL. Both DC populations expressed CD4, CCR5, and CXCR4. The findings suggest that loss of DCs in HIV infection may contribute to disease progression.

Recently it has been shown that the 2 populations of blood dendritic cells (DCs), termed plasmacytoid (pcDCs) and myeloid (myDCs), are reduced in HIV-1 infection. This study aimed to determine whether these 2 populations are targets for HIV-1 infection and whether their ability to stimulate T-lymphocyte proliferation is affected. Highly purified populations of myDCs and pcDCs were isolated from the blood of antiretroviral treatment–naive patients and assessed for the level of HIV provirus by polymerase chain reaction (PCR). We show that both populations are targets for HIV-1 infection as indicated by the presence of provirus in 12 of 14 pcDC and 13 of 14 myDC samples tested. A proportion of this provirus is integrated in myDCs. The ability of both myDCs and pcDCs from HIV-1–infected patients to stimulate allogeneic T-lymphocyte proliferation in a 6-day mixed leukocyte reaction was severely impaired, but was not mediated by secondary infection of T lymphocytes. Thus, in addition to depletion, both myeloid and plasmacytoid DCs are infected and show impaired functional capacity. These findings suggest that infection, depletion, and dysfunction of dendritic cells may contribute to the immunosuppression associated with HIV-1 disease.

Plasmacytoid dendritic cells (pcDC) and myeloid dendritic cells (myDC) are shown to express CD4 and low levels of CCR5 and CXCR4, but only myDC express DC SIGN, a C-type lectin that binds human immunodeficiency virus but does not mediate virus entry. Both DC types were more susceptible to infection with a macrophage than a lymphotropic strain of human immunodeficiency virus type 1, but pcDC were more readily infected than myDC.

In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5 vaccine. We propose that this was due to activation and expansion of Ad5-specific mucosal-homing memory CD4 T cells. To test this hypothesis, Ad5 and Ad11 antibody titers were measured in 20 healthy volunteers. Dendritic cells (DCs) from these individuals were pulsed with replication defective Ad5 or Ad11 and co-cultured with autologous lymphocytes. Cytokine profiles, proliferative capacity, mucosal migration potential, and susceptibility to HIV infection of the adenovirus-stimulated memory CD4 T cells were measured. Stimulation of T cells from healthy Ad5-seropositive but Ad11-seronegative individuals with Ad5, or serologically distinct Ad11 vectors induced preferential expansion of adenovirus memory CD4 T cells expressing α₄β₇integrins and CCR9, indicating a mucosal-homing phenotype. CD4 T-cell proliferation and IFN-γ production in response to Ad stimulation correlated with Ad5 antibody titers. However, Ad5 serostatus did not correlate with total cytokine production upon challenge with Ad5 or Ad11. Expanded Ad5 and Ad11 memory CD4 T cells showed an increase in CCR5 expression and higher susceptibility to infection by R5 tropic HIV-1. This suggests that adenoviral-based vaccination against HIV-1 in individuals with preexisting immunity against Ad5 results in preferential expansion of HIV-susceptible activated CD4 T cells that home to mucosal tissues, increases the number of virus targets, and leads to a higher susceptibility to HIV acquisition.

Stabilization of virus protein structure and nucleic acid integrity is challenging yet essential to preserve the transcriptional competence of live recombinant viral vaccine vectors in the absence of a cold chain. When coupled with needle-free skin delivery, such a platform would address an unmet need in global vaccine coverage against HIV and other global pathogens. Herein, we show that a simple dissolvable microneedle array (MA) delivery system preserves the immunogenicity of vaccines encoded by live recombinant human adenovirus type 5 (rAdHu5). Specifically, dried rAdHu5 MA immunization induced CD8 ⁺ T-cell expansion and multifunctional cytokine responses equipotent with conventional injectable routes of immunization. Intravital imaging demonstrated MA cargo distributed both in the epidermis and dermis, with acquisition by CD11c ⁺ dendritic cells (DCs) in the dermis. The MA immunizing properties were attributable to CD11c ⁺ MHCII ^hi CD8α ^neg epithelial cell adhesion molecule (EpCAM ^neg ) CD11b ⁺ langerin (Lang; CD207) ^neg DCs, but neither Langerhans cells nor Lang ⁺ DCs were required for CD8 ⁺ T-cell priming. This study demonstrates an important technical advance for viral vaccine vectors progressing to the clinic and provides insights into the mechanism of CD8 ⁺ T-cell priming by live rAdHu5 MAs.