Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques

Prevention of mother-to-child transmission (MTCT) of HIV remains a major objective where antenatal care is not readily accessible. We tested HIV-1–specific human neutralizing monoclonal antibodies (NmAbs) as a post-exposure therapy in an infant macaque model for intrapartum MTCT. One-month-old rhesus macaques were inoculated orally with the simian-human immunodeficiency virus SHIVSF162P3. On days 1, 4, 7 and 10 after virus exposure, we injected animals subcutaneously with NmAbs and quantified systemic distribution of NmAbs in multiple tissues within 24 h after antibody administration. Replicating virus was found in multiple tissues by day 1 in animals that were not treated. All NmAb-treated macaques were free of virus in blood and tissues at 6 months after exposure. We detected no anti-SHIV T cell responses in blood or tissues at necropsy, and no virus emerged after CD8+ T cell depletion. These results suggest that early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs.Fil: Hessell, Ann J.. Oregon Health and Science University; Estados UnidosFil: Jaworski, Juan Pablo. Oregon Health and Science University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Epson, Erin. Oregon Health and Science University; Estados UnidosFil: Matsuda, Kenta. National Institutes of Health; Estados UnidosFil: Pandey, Shilpi. Oregon Health and Science University; Estados UnidosFil: Kahl, Christoph. Oregon Health and Science University; Estados UnidosFil: Reed, Jason. Oregon Health and Science University; Estados UnidosFil: Sutton, William F.. Oregon Health and Science University; Estados UnidosFil: Hammond, Katherine B.. Oregon Health and Science University; Estados UnidosFil: Cheever, Tracy A.. Oregon Health and Science University; Estados UnidosFil: Barnette, Philip T.. Oregon Health and Science University; Estados UnidosFil: Legasse, Alfred W.. Oregon Health and Science University; Estados UnidosFil: Planer, Shannon. Oregon Health and Science University; Estados UnidosFil: Stanton, Jeffrey J.. Oregon Health and Science University; Estados UnidosFil: Pegu, Amarendra. National Institutes of Health; Estados UnidosFil: Chen, Xuejun. National Institutes of Health; Estados UnidosFil: Wang, Keyun. National Institutes of Health; Estados UnidosFil: Siess, Don. Oregon Health and Science University; Estados UnidosFil: Burke, David. Oregon Health and Science University; Estados UnidosFil: Park, Byung S.. Oregon Health and Science University; Estados UnidosFil: Axthelm, Michael K. Oregon Health and Science University; Estados UnidosFil: Lewis, Anne. Oregon Health and Science University; Estados UnidosFil: Hirsch, Vanessa M.. National Institutes of Health; Estados UnidosFil: Graham, Barney S.. National Institutes of Health; Estados UnidosFil: Mascola, John R.. National Institutes of Health; Estados UnidosFil: Sacha, Jonah B.. Oregon Health and Science University; Estados UnidosFil: Haigwood, Nancy L.. Oregon Health and Science University; Estados Unido

Reversing Established Sepsis in Rats with Human Vasoactive Hormone Adrenomedullin and its Binding Protein

We recently demonstrated that early administration of rat adrenomedullin (AM), a vasoactive peptide, in combination with its binding protein (human AMBP-1) produces various beneficial effects in sepsis. Human AM is a 52–amino acid peptide, but rat AM differs from human AM, having only 50 amino acid residues, with two amino acid deletions and six substitutions. It remains unknown whether a combination of human AM and human AMBP-1 (AM/AMBP-1) is also beneficial in sepsis and, if so, whether human AM/AMBP-1 reverses established sepsis in rats. To test the effects of human AM/AMBP-1, we induced sepsis in male adult rats by cecal ligation and puncture (CLP). At 10 h after CLP (i.e., severe sepsis), human AM (12–48 μg/kg body weight) was administered in combination with human AMBP-1 (40–160 μg/kg body weight). Vehicle-treated animals received a nonspecific human plasma protein (albumin). Blood and intestinal samples were collected at 20 h for various measurements. In additional groups of septic animals, the gangrenous cecum was surgically excised at 20 h after CLP. The 10-day survival was recorded. Our results showed that tissue injury, as evidenced by increased levels of transaminases and lactate, was present at 20 h after CLP. Proinflammatory cytokines tumor necrosis factor-α and interleukin-6 were significantly elevated. Gut barrier dysfunction, manifested by increased mucosal permeability to hydrophilic macromolecules and increased bacterial translocation to mesenteric lymph nodes, also occurred at 20 h after CLP. Administration of human AM/AMBP-1 in established sepsis markedly attenuated tissue injury, reduced proinflammatory cytokine levels, ameliorated intestinal-barrier dysfunction, and improved the survival rate from 47% to 67%–80%. Thus, human AM/AMBP-1 can be further developed as a safe and effective therapy for patients with established sepsis

Adhesion G protein-coupled receptors: opportunities for drug discovery

The seminal discovery of the novel activation mechanism of Adhesion GPCRs (aGPCRs)1,2, together with their strong and growing links to disease from human genetics and pre-clinical research, has prompted a rapid reconsideration of this unique family of receptors for classical drug discovery. However, while acknowledged as a sub-family of GPCRs by the IUPHAR3, these receptors are anything but classical with their complex gene structures, large multi-domain N-termini, autocatalytic cleavage and tethered ligands. Initially thought to have a purely structural role, the increasing functional complexity of this GPCR sub-family and the many, potentially unique mechanisms of modulation challenges the way we have perceived this protein class until now. Significantly, if 50% of non-sensory GPCRs are unexploited as drug targets4, this figure reaches 100% for aGPCRs so the potential to develop novel therapies could be substantial5. Here, we discuss the unique opportunities and challenges brought by aGPCRs in the context of drug discovery programs naturally starting with target identification then extending to target validation, assay building and safety considerations

Chimeric Rhinoviruses Displaying MPER Epitopes Elicit Anti-HIV Neutralizing Responses

<div><p>Background</p><p>The development of an effective AIDS vaccine has been a formidable task, but remains a critical necessity. The well conserved membrane-proximal external region (MPER) of the HIV-1 gp41 glycoprotein is one of the crucial targets for AIDS vaccine development, as it has the necessary attribute of being able to elicit antibodies capable of neutralizing diverse isolates of HIV.</p> <p>Methodology/Principle Findings</p><p>Guided by X-ray crystallography, molecular modeling, combinatorial chemistry, and powerful selection techniques, we designed and produced six combinatorial libraries of chimeric human rhinoviruses (HRV) displaying the MPER epitopes corresponding to mAbs 2F5, 4E10, and/or Z13e1, connected to an immunogenic surface loop of HRV via linkers of varying lengths and sequences. Not all libraries led to viable chimeric viruses with the desired sequences, but the combinatorial approach allowed us to examine large numbers of MPER-displaying chimeras. Among the chimeras were five that elicited antibodies capable of significantly neutralizing HIV-1 pseudoviruses from at least three subtypes, in one case leading to neutralization of 10 pseudoviruses from all six subtypes tested.</p> <p>Conclusions</p><p>Optimization of these chimeras or closely related chimeras could conceivably lead to useful components of an effective AIDS vaccine. While the MPER of HIV may not be immunodominant in natural infection by HIV-1, its presence in a vaccine cocktail could provide critical breadth of protection.</p> </div