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Posted: 22 Jun 2012
Journal Club: Review of recent publications - 22 June 2012

Latest research highlights: Better nanoparticles for mucosal delivery, breast milk antibodies mediate ADCC, certain T cell clonotypes are better at protection, B cells facilitate T cell responses, reviews of elite controllers and of the MF59 adjuvant mode of action

Some viruses evolved mechanisms to effectively diffuse through mucosal layers.  In their latest work Ensign, Hanes, et al. (Sci Transl Med, PMID 22700955) utilize one of those mechanisms to improve delivery of nanoparticles to mucosal tissues.  They coated nanoparticles with a high density of low molecular weight PEG, which led to deep penetration of mucous layers and a more effective delivery of anti-HSV drugs, resulting in improved protection against viral challenge. The technology may be applicable for the development of anti-HIV microbicides and for designing mucosal HIV vaccines.

Mabuka, Overbaugh, et al. (PLoS Pathog, PMID 22719248) investigated the functional properties of antibodies found in breastmilk.  While a recent paper from Friedman et al. found highly-potent neutralizing antibodies in milk, the current article shows that for most women, breastmilk contians little to no neutralizing antibodies.  Instead, researchers found that all 19 studied women had non-neutralizing antibodies to HIV, which mediated antibody-dependent cytotoxicity (ADCC).  Moreover, the level of ADCC inversely correlated with infant’s risk of infection, reinforcing the current thinking that non-neutralizing antibodies play a role in protection.

In their review article, Gaardbo, Nielsen, et al. (AIDS Res Treat, PMID 22693657) compare and contrast immunological features and responses to HIV in long-term non-progressors and controllers, looking for factors that may explain the differences in immunological control of viral replication.

O’Hagan, Seubert, et al. (Vaccine, PMID 22682289) review studies on the adjuvant MF59 and propose a mechanism on how it enhances immune responses induced by protein-based vaccines.  They argue that MF59 leads to transient up-regulation of cytokines at the site of injection, which both attract and stimulate immune cells, including granulocytes and monocytes, which further boost the local micro-environment.  Antigen-presenting cells, attracted to this immunocompetent environment, more readily absorb the antigen and effectively traffic it to lymph nodes.

The human leukocyte antigens HLA-B*27 and HLA-B*57 are associated with protection against progression of HIV, yet most people with alleles encoding HLA-B*27 and HLA-B*57 are unable to control HIV.  In their recent study, Chen, Walker, et al. (Nat Immunol, PMID 22683743), compare HIV-infected individuals (five per group) that express HLA-B*2705 that either control (elite controllers) or do not control (progressors) viral replication.  Viruses from all individuals contained the KK10 epitope targeted by HLA-B*2705.  Compared to responses in progressors, CD8 responses from controllers were more potent in inhibiting HIV replication ex-vivo and better recognized escape variants of KK10.  The CD8 T cell clonotypes that are most effective in mediating viral inhibition are abundant in controllers whereas they are rare or absent in progressors.

Leon, Lund, et al (Nat Immunol, PMID 22634865) looked at initiation and modulation of cellular immune responses after infection with Heligmosomoides polygorus.  Contrary to the belief that naive T cells are first primed by antigen-bearing DCs in the T cell zone of lymph nodes, they show that optimal development of TFH and TH2 happens adjacent to B cell follicles. It seems that B cells facilitate recruitment of mature antigen-presenting DCs and CD4 T cells to regions close to B cell follicles. The researchers demonstrate that the generation of TH2 and TFH occurs in a manner dependent on B cells, lymphotoxin, CXCL13 and CXCR5.