Dendritic cells (DCs) play important roles in orchestrating host immunity against invading pathogens, representing one of the first responders to infection by mucosal invaders. From their discovery by Ralph Steinman in the 1970s followed shortly after with descriptions of their in vivo diversity and distribution by Derek Hart, we are still continuing to progressively elucidate the spectrum of DCs present in various anatomical compartments. With the power of high-dimensional approaches such as single-cell sequencing and multiparameter cytometry, recent studies have shed new light on the identities and functions of DC subtypes. Notable examples include the reclassification of plasmacytoid DCs as purely interferon-producing cells and re-evaluation of intestinal conventional DCs and macrophages as derived from monocyte precursors. Collectively, these observations have changed how we view these cells not only in steady-state immunity but also during disease and infection. In this review, we will discuss the current landscape of DCs and their ontogeny, and how this influences our understanding of their roles during HIV infection.

/pdf/human-dendritic-cell-subsets-ontogeny-and-impact-on-hiv-30s1b33t2r.pdf

Human Dendritic Cell Subsets, Ontogeny, and Impact on HIV Infection.

Passive transfer of neutralizing antibodies is effective in protecting rhesus macaques against simian/human immunodeficiency virus (SHIV) challenge. In addition to neutralization, effector functions of the crystallizable fragment (Fc) of antibodies are involved in antibody-mediated protection against a number of viruses. We recently showed that interaction between the Fc fragment of the broadly neutralizing antibody IgG1 b12 and cellular Fc receptors (FcRs) plays an important role in protection against SHIV infection in rhesus macaques. The specific nature of this Fc-dependent protection is largely unknown. To investigate, we generated a panel of 11 IgG1 b12 antibody variants with selectively diminished or enhanced affinity for the two main activating FcRs, FcRIIa and FcRIIIa. All 11 antibody variants bind gp120 and neutralize virus as effectively as does wild-type b12. Binding studies using monomeric (enzyme-linked immunosorbent assay [ELISA] and surface plasmon resonance [SPR]) and cellularly expressed Fc receptors show decreased (up to 5-fold) and increased (up to 90-fold) binding to FcRIIa and FcRIIIa with this newly generated panel of antibodies. In addition, there was generally a good correlation between b12 variant affinity for Fc receptor and variant function in antibody-dependent cell-mediated virus inhibition (ADCVI), phagocytosis, NK cell activation assays, and antibody-dependent cellular cytotoxicity (ADCC) assays. In future studies, these b12 variants will enable the investigation of the protective role of individual FcRs in HIV infection.

A panel of IgG1 b12 variants with selectively diminished or enhanced affinity for Fcγ receptors to define the role of effector functions in protection against HIV.

HIV antibody (Ab) functions capable of preventing mucosal cell-free or cell-to-cell HIV transmission are critical for the development of effective prophylactic and therapeutic vaccines. In addition to CD4+ T cells, other potential HIV-target cell types including antigen-presenting cells (APCs) (dendritic cells, macrophages) residing at mucosal sites are infected. Moreover, the interactions between APCs and HIV lead to HIV cell-to-cell transmission. Recently discovered broadly neutralizing Abs (NAbs) are able to neutralize a broad spectrum of HIV strains, inhibit cell-to-cell transfer and efficiently protect from infection in the experimentally challenged macaque model. However, the 31% protection observed in the RV144 vaccine trial in the absence of detectable NAbs in blood samples pointed to the possible role of additional Ab inhibitory functions. Increasing evidence suggests that IgG Fcγ receptor (FcγR)-mediated inhibition of Abs present at the mucosal site may play a role in protection against HIV mucosal transmission. Moreover, mucosal IgA Abs may be determinant in protection against HIV sexual transmission. Therefore, defining Ab inhibitory functions that could lead to protection is critical for further HIV vaccine design. Here we review different inhibitory properties of HIV-specific Abs and discuss their potential role in protection against HIV sexual transmission.

/pdf/which-antibody-functions-are-important-for-an-hiv-vaccine-4p3l8we3mf.pdf

Which Antibody Functions are Important for an HIV Vaccine

Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection

Antibodies that mediate killing of HIV-infected cells through antibody-dependent cellular cytotoxicity (ADCC) have been implicated in protection from HIV infection and disease progression. Despite these observations, these types of HIV antibodies are understudied compared to neutralizing antibodies. Here we describe four monoclonal antibodies (mAbs) obtained from one individual that target the HIV transmembrane protein, gp41, and mediate ADCC activity. These four mAbs arose from independent B cell lineages suggesting that in this individual, multiple B cell responses were induced by the gp41 antigen. Competition and phage peptide display mapping experiments suggested that two of the mAbs target epitopes in the cysteine loop that are highly conserved and a common target of HIV gp41-specific antibodies. The amino acid sequences that bind these mAbs are overlapping but distinct. The two other mAbs were competed by mAbs that target the C-terminal heptad repeat (CHR) and the fusion peptide proximal region (FPPR) and appear to both target a similar unique conformational epitope. These gp41-specific mAbs mediated killing of infected cells that express high levels of Env due to either pre-treatment with interferon or deletion of vpu to increase levels of BST-2/Tetherin. They also mediate killing of target cells coated with various forms of the gp41 protein, including full-length gp41, gp41 ectodomain or a mimetic of the gp41 stump. Unlike many ADCC mAbs that target HIV gp120, these gp41-mAbs are not dependent on Env structural changes associated with membrane-bound CD4 interaction. Overall, the characterization of these four new mAbs that target gp41 and mediate ADCC provides evidence for diverse gp41 B cell lineages with overlapping but distinct epitopes within an individual. Such antibodies that can target various forms of envelope protein could represent a common response to a relatively conserved HIV epitope for a vaccine.

/pdf/identification-of-hiv-gp41-specific-antibodies-that-mediate-4ch4oc5j20.pdf

Identification of HIV gp41-specific antibodies that mediate killing of infected cells.

Langerhans cells (LCs) and interstitial dendritic cells (IDCs) may be among the first human immunodeficiency virus type 1 (HIV-1) targets after sexual transmission. We generated cells of these types by differentiation of purified CD34 cord blood cells. After in vitro infection with R5-tropic strains, we obtained similar percentages of infected cells for both dendritic cell (DC) subsets. Moreover, LC infection was not increased by blockage of langerin by antilangerin. These results indicate that, under our experimental conditions, there was no evidence of any preference of HIV replication in LCs versus IDCs. The inhibitory activity of HIV-1-specific IgAs and IgGs against HIV-1 replication in LCs and IDCs was analyzed. We found that neutralizing antibodies inhibit HIV-1 infection of both DC subsets. Interestingly, HIV-1 was inhibited more efficiently by the IgGs than the corresponding IgA, due to an Fc receptor-dependent mechanism. Moreover, nonneutralizing inhibitory IgGs were able to inhibit infection of both LCs and IDCs. These results underline the importance of HIV-1 inhibition by the binding of the Fc part of IgGs to Fc receptors and suggest that the induction of neutralizing and nonneutralizing inhibitory IgGs in addition to neutralizing IgAs at mucosal sites may contribute to protection against sexual transmission of HIV-1.

http://www.dendritics.net/files/documentation/Peressin_M,_DCGM4,_2011.PDF

HIV-1 replication in Langerhans and interstitial dendritic cells is inhibited by neutralizing and Fc-mediated inhibitory antibodies.

Background Dendritic cells (DCs) present on the mucosa site are considered as one of the first target cells of HIV-1 following sexual transmission. It has been demonstrated that immature DCs could transfer infectious HIV-1 particles to CD4 T-lymphocytes via a virological synapse in trans. The aim of this study was to investigate the capacity of monoclonal neutralizing antibodies to inhibit HIV-1 transfer from immature DCs to CD4 T-lymphocytes.

/pdf/p04-27-monoclonal-neutralizing-antibodies-inhibit-hiv-1-3169d8h2gd.pdf

P04-27. Monoclonal neutralizing antibodies inhibit HIV-1 transfer from immature dendritic cells to human primary CD4 T-lymphocytes

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HIV-1 replication in Langerhans and interstitial dendritic cells is inhibited by neutralizing and Fc-mediated inhibitory antibodies.

P04-27. Monoclonal neutralizing antibodies inhibit HIV-1 transfer from immature dendritic cells to human primary CD4 T-lymphocytes