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Posted: 23 May 2012
Journal Club: Review of latest publications - 22 May 2012

Latest research highlights: rAd5/rLCMV vaccine protects against heterologous challenge in NHPs, HIV adapts to foil antigen processing, role of autophagy in HIV infection, NeutNet Phase II report, microbicide/vaccine combination tested in NHPs, NIH reports on October 2011 carbohydrate workshop.

Flatz, Nabel et al. (J Virol, PMID 22593152) compared immunogenicity of several prime-boost combinations using DNA, rAd5, or rLCMV vectors to deliver either env or gag in mice and rhesus macaques. They chose the rAd5/rLCMV regimen to test for efficacy and observed statistically-significant protection against repeated low-dose rectal challenge with a heterologous virus (SIVsmE660). Somewhat ironically, none of the immunologic assays used to select this particular combination showed correlation with protection. Instead, protection correlated only with neutralization activity of sera from vaccinated protected animals on the challenge stock in human PBMCs (authors checked that the responses were indeed against the virus and not against human proteins).

HIV proteins have to be properly processed and presented in order to be recognized by CTLs. The cleavage of proteins into peptides is not a random process, but depends on specificities of multiple peptidases present in the proteasome and can vary from one cell type to another. Zhang, Le Gall et al. (J Immunol, PMID 22586036) characterized peptidase cleavage preferences in primary human PBMCs. Using pre-designed substrates they showed that amino acids outside of a restricted epitope affect processing and, therefore, efficiency of presentation. Using virus sequence data from >1000 patients, they show that HIV adapts on a population level, evolving to reduce the efficiency of processing of several known HLA epitopes. The information on processing preferences is critical not just to understand virus immune escape, but also to design better vaccines, which are able to present antigens in the most effective manner.

Autophagy is an important antiviral mechanism, limiting viral replication and spread from infected cells. Borel, Espert and Biard-Piechaczyk (Front Immunol, PMID 22586428) review the current understanding of the role of autophagy in HIV infection, identifying unique features of macrophages and CD4 T cells. The interaction is complex, with HIV inhibiting autophagy, but also borrowing some of those processes to augment its replication.

Heyndrickx, Scarlatti, et al. (PLoS ONE, PMID 22590544) report on the second stage of the NeutNet collaboration, which aims to define the most relevant and reproducible HIV neutralization assays. Previous work by this collaboration found significant sensitivity differences between assays and large variations in the PBMC assays when conducted in different laboratories. No single assay was able to capture the entire spectrum of neutralization activities. Similar to previous findings, this study found that results from different labs frequently differ, depending on both the virus and the inhibitory reagent used, and without the knowledge of what correlates with protection it is impossible to tell, which assay is “right”.

There are ongoing discussions about the benefits of combining different prevention modalities, such as microbicides and vaccines. Barouch, Moore et al. (PNAS, PMID 22586094) studied the effects of combining a T cell based vaccine, which lowers viral load, and a microbicides that blocks transmission and looked if protection was reinforced when combining approaches. Not surprisingly the vaccine + microbicide combination protected more animals than the individual approaches. It remains to be determined if the result would be similar when using an env-based vaccine which like a microbicides would block transmission.

We reported on the ”Functional Glycomics in HIV Vaccine Design” workshop, which took place at NIH on 31 May - 1 June. Now Taylor, Schreiber, et al. (Vaccine, PMID 22575168) developed a report on a similar meeting held by NIH “Carbohydrate Moieties as Vaccine Targets” that was held on 3-4 October 2011. The meeting discussed immune responses to carbohydrate antigens in infectious diseases and cancer, latest glycomics tools, as well as implications for HIV vaccine design.