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Posted: 13 Jul 2012
Journal Club: Review of recent publications - 13 July 2012

Latest research highlights: New microbicide delivery system, EAT-2 is a powerful gene-based adjuvant, infection with a harmless virus improves HIV prognosis, escape from bNabs, and immunization of newborns

Microbicides

Currently, the use of antiviral drugs as microbicides is limited to gel formulations, which require coitus-dependent application. Embedding these drugs into matrices that provide continuous and prolonged release would make them more reliable and much easier to use. Such matrices usually rely on slow diffusion of the embedded small molecules or on water-based dissolution of the matrix. Gunaseelan, Maskiewicz et al. (Pharm Res, PMID  22736232) propose a new approach, which is to create the matrix from several solid compounds that turn directly into gas at physiologic temperatures. The rate of release can be accurately controlled by creating a mixture of compounds with different sublimation rates. The researchers provide the proof-of-concept data by monitoring the release and the antiviral activity of TDF and FTC in cell cultures and in ectoservical explants.

Adjuvants

EAT-2 is the only known adapter protein for signaling lymphocyte activation molecule (SLAM) receptors in DCs and macrophages. Previous work from the Amalfitano lab showed that artificial expression of EAT-2 as part of a vaccine platform leads to activation of innate responses during vaccination and improves adaptive responses. Now Aldhamen, Amalfitano et al. (J Immunol, PMID 22745373) show that the stimulatory effect of EAT-2 is strong enough to improve responses to rAd5-delivered antigens in the presence of pre-existing anti-Ad5 immunity. Given the safety concerns raised in the face of increased infection observed in Ad5-positive uncircumcised men in the Step trial, it is unlikely that this exact approach will be implemented in future HIV efficacy trials, but the work demonstrates the power of EAT-2-expressing constructs as adjuvants boosting Ag-specific immune responses.

Co-infections and pathogenesis

GB virus C is a flavivirus known to infect humans through transfused blood products and sex. It’s not known to cause any diseases in humans and considered to be completely non-pathogenic. It has been observed previously that HIV patients coinfected with GBV-C tend to have lower viral loads and improved disease prognosis, but the sequence of infection events and the presence of active GBV-C viremia was not known. Vahidnia, Custer et al. (Clin Infect Dis, PMID 22752515) looked at the samples from the 1996-1997 Viral Activation Transfusion Study and found that, in HIV-infected patients with advanced disease, acute GBV-C infection was associated with significantly decreased mortality. The study supports the idea that GBV-C infection is somehow responsible for better control of HIV. If confirmed, these results can lead to the development of new therapeutic approaches, either by using GBV-C directly or through understanding the mechanisms behind protection and their utilization in therapeutic vaccines.

Antibodies

A number of recently-identified bNabs target V1-V2 region of Env. Doria-Rose, Mascola et al. (J Virol, PMID 22623764) show that mutations in a short segment of that region make the virus resistant to most of these antibodies. This indicates that the recognition mechanism is shared between V1-V2-targeting bNabs and that HIV can become cross-resistant.

Pediatric vaccines

Is it possible to use a vaccine to prevent infection in infants born to HIV-positive mothers? Liu, Barouch et al. (J Virol, PMID 22593160) show that a single dose of rAd26 carrying SIV gag on the day of birth is poorly immunogenic in newborn monkeys. However, quickly boosting rAd35-based prime with rAd26 (both carrying gag) improves both cellular and humoral immune responses and makes them last longer, suggesting that this approach may be effective. The researchers did not look for efficacy in this study.