Secondary Logo

Research Highlights

Muller, Elmi MBChB, MMED1

doi: 10.1097/TP.0000000000001980
In View: Research Highlights
Free

1 Groote Schuur Hospital, Observatory Cape Town, Western Cape, South Africa.

Received 9 October 2017. Revision received 10 October 2017.

Accepted 12 October 2017.

The author declares no funding or conflicts of interest.

Correspondence: Elmi Muller, MS, Groote Schuur Hospital Main Road, Observatory Cape Town, Western Cape 7925, South Africa. (elmi.muller@uct.ac.za).

Back to Top | Article Outline

Defining Total-body AIDS Virus Burden With Implications for Curative Strategies

Estes JD, Kityo C, Ssali F, et al. [published online October 2, 2017]. Nat Med. doi: 10.1038/nm.4411.

Human immunodeficiency virus (HIV) reservoirs have an important impact on the potential cure for the disease and will continue to be important in HIV transplant practices, especially when using HIV-positive donors. Despite having undetectable viral loads in serum, patients carry a significant amount of virus in lymphoid tissue (LT) which could result in reactivation of latent viral pools, thus making it very difficult to eradicate the virus. Furthermore, anti-retroviral therapy (ART) penetration into LT is poor. Therefore, viral load may be undetectable in serum; however, a significant amount of virus may still exist in LT, solid organs, and the brain. Interestingly, the penetration for ART into the brain is also limited, and many patients who have undetectable levels of virus in the serum will have high viral loads in the brain.

The authors examined HIV reservoirs in humans as well as in rhesus macaques and looked for the virus in LT, gut, brain, heart, kidney, liver, lung, and spleen. To diagnose reservoirs, they looked for DNA, RNA, as well as virus-producing cells. They illustrated that the primary reservoir site was LT, where 98% of the RNA cells resided. Another organ with a high frequency of RNA-positive cells was the lung.

Interestingly, the levels of ART in LT were significantly less than that in peripheral blood mononuclear cells and well below optimal concentration for viral suppression. Furthermore, there was a very large residual reservoir of DNA cells in individuals on ART, even in the presence of undetectable plasma viral loads. In the gut, there was almost no decrease of the DNA cell reservoir subsequent to ART.

The authors demonstrated that even during effective ART, virus-producing cells persisted in the tissue, despite plasma viremia being less than 50 copies/mL. Ongoing viral production or reactivation of latently infected cells could be potential sources of virus that may reignite infection after treatment interruption.

Back to Top | Article Outline

Inhibition of Y1 Receptor Signaling Improves Islet Transplant Outcome

Loh K, Shi YC, Walters S, et al. Nat Commun. 2017;8(1):490.

Clinical outcomes of pancreatic islet cell transplantation remain unsatisfactory with low survival rate of donor islets and compromised efficiencies of these cells. The authors investigated the effect of Y1 receptor blockers on islets after transplantation. Moreover, they tested the functional capacity of native beta cells at a time when type 1 diabetes becomes apparent, although patients are not yet fully insulin dependent, a condition referred by many as the “honeymoon period” for type 1 diabetics. The addition of Y1 receptor antagonists not only extended the period of normoglycemia in autoimmune-prone diabetic mice in their “honeymoon period,” but also improved outcomes in mice who received an islet cell transplant.

Mechanistically, Y1 receptor stimulation reduced the intracellular cyclic adenosine monophosphate level resulting in reduced insulin secretion of pancreatic islet cells. Therefore, Y1 receptor blockers have the potential to increase insulin production, not only in transplanted islet cells but also in native pancreatic beta cells.

The authors also investigated whether Y1 deficient islet transplants had a better outcome than wild type islet transplants in diabetic mice by manipulating Y1 receptors in islet cells before transplantation. Mice were either transplanted with a sufficient or a suboptimal number of islets (300 vs 60, respectively). An additional group of mice were transplanted with a minimal number of islets (60) where the Y1 receptor had been deleted. In the last group, the outcome was just as good as in the group of mice who received an adequate number of islets. In the other group who received a deficient number of islets, the outcome was poor, and the mice never became normoglycemic.

This finding was repeated by blocking the Y1 receptor with a pharmacological agent (BIB03304). Interestingly, a transient inhibition over 5 days resulted in glycemic control in mice with a minimal islet mass (60). In mice receiving a minimal islet transplant (60) with an absent initial glycemic control could not be obtained initially, normoglycemia had been restored with a delayed Y1 receptor blockade starting from day 9.

Similarly, human islet cultures enhanced insulin secretion when BIBO3304 was added to the culture, significantly improving glucose control.

Thus, adding Y1 antagonists to the clinical treatment of islet cell transplants may reduce the number of beta cells to achieve normoglycemia.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.