WHO approves three Mylan ARV therapies to treat HIV/AIDS

http://www.futurity.org/top-stories/compound-dissolves-hiv-on-contact/

Scientists have discovered a compound that dissolves the HIV virus, as well as other lentiviruses, and also hepatitis C virus, on contact. It works not by attacking the viral envelope protein, but rather by attacking some internal component of the virus and thereby causing the virus to rupture and spill out its RNA, which is very fragile and is therefore quickly destroyed once it becomes unprotected. Since the viral envelope is not involved, it may be quite difficult for the viruses to evolve defenses against this attack. The compound is called "PD 404, 182".

I suspect the work of this Scripps Scientist may be even more important than the first appended article suggests. TAT seems to play a key role in HIV's ability to cause HIV related dementia and thrombocytopenia (a serious blood disorder). Crippling TAT could take out HIV's ability to trigger dementia/brain damage, and thrombocytopenia all at once.

http://www.bio-medicine.org/biology-news-1/Sc...y-news+%28Biology+News%29

"Date:11/30/2011

JUPITER, FL -- A scientist at The Scripps Research Institute has been awarded $3.4 million from the National Institutes of Health to study the mode of action and the therapeutic potential of a new compound that blocks a step of HIV replication not targeted by current therapies.

Susana Valente, an assistant professor at Scripps Florida, is the principal investigator of the five-year grant. Valente will lead research into the viral protein known as Tat, a potent activator of HIV gene expression, and a Tat inhibitor that is extremely effective at reducing viral output from acutely and chronically infected cells in culture. Most antiretroviral compounds only block new infections; a Tat inhibitor can reduce viral replication from cells already infected...."

http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2010.04168.x/full

"Article first published online: 1 MAR 2011

HIV-1 Tat-induced platelet activation and release of CD154 contribute to HIV-1-associated autoimmune thrombocytopenia

Summary. Background: Enhanced platelet activation in human immunodeficiency virus (HIV)-1-infected patients has been reported and shown to strongly correlate with plasma viral load. Activated platelets are known to express and to release a variety of proteins that can modulate the immune system. Specifically, platelet-derived CD154 has been shown to be directly involved in the development of autoimmune thrombocytopenia (ITP). The mechanism by which HIV-1 infection leads to platelet activation and the effect of this activation on the development of HIV-1 ITP, however, is not fully understood. Objective: We have investigated the effect of HIV-1 Trans activating factor (Tat) on platelet activation. Results: We report that HIV-1 Tat directly interacts with platelets and induces platelet activation resulting in platelet micro-particle release. This activation by Tat requires the chemokine receptor CCR3 and β3-integrin expression on platelets, as well as calcium flux. Tat-induced activation of platelets releases platelet CD154, an immune modulator. Enhanced B-cell activity is found in mouse spleen B cells co-cultured with platelets treated with Tat in vitro. An early antibody response against adenovirus is found in Tat-injected mouse immunized with adenovirus, suggesting an enhanced immune response in vivo. Conclusions: We have described a role of Tat-induced platelet activation in the modulation of the immune system, with implications for the development of HIV-1-associated thrombocytopenia..."

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003731

"HIV-1 Tat Activates Neuronal Ryanodine Receptors with Rapid Induction of the Unfolded Protein Response and Mitochondrial Hyperpolarization

Neurologic disease caused by human immunodeficiency virus type 1 (HIV-1) is ultimately refractory to highly active antiretroviral therapy (HAART) because of failure of complete virus eradication in the central nervous system (CNS), and disruption of normal neural signaling events by virally induced chronic neuroinflammation. We have previously reported that HIV-1 Tat can induce mitochondrial hyperpolarization in cortical neurons, thus compromising the ability of the neuron to buffer calcium and sustain energy production for normal synaptic communication. In this report, we demonstrate that Tat induces rapid loss of ER calcium mediated by the ryanodine receptor (RyR), followed by the unfolded protein response (UPR) and pathologic dilatation of the ER in cortical neurons in vitro. RyR antagonism attenuated both Tat-mediated mitochondrial hyperpolarization and UPR induction. Delivery of Tat to murine CNS in vivo also leads to long-lasting pathologic ER dilatation and mitochondrial morphologic abnormalities. Finally, we performed ultrastructural studies that demonstrated mitochondria with abnormal morphology and dilated endoplasmic reticulum (ER) in brain tissue of patients with HIV-1 inflammation and neurodegeneration...

Of the many HIV-induced neurotoxins, Tat is remarkable because it is actively released into the extracellular space by infected microglia, macrophages and astrocytes [10; 19–21]. Unbound Tat has been detected in the sera of HIV+ patients, reaching concentrations as high as 40 ng/mL [22]. It should be noted that this measurement is probably a gross underestimate of Tat's local concentration; Tat in vivo can be sequestered by endogenous glycosaminoglycans and heparin sulfates effectively lowering the detectable amounts of Tat circulating unbound. This observation lends credence to the notion that infiltrating microglia/macrophage adjacent to a synapse would have greatly increased local concentrations of Tat. However, once released from a cell Tat can enter virtually all neural cell types via its arginine-rich basic domain, termed the protein transduction domain (PTD) [23]–[26]..."

http://www.sciencecodex.com/read/no_more_free...iggybacking_viruses-83879

Scientists have determined the [3-dimensional] structure of the enzyme endomannosidase, significantly advancing our understanding of how a group of devastating human viruses including HIV and Hepatitis C hijack human enzymes to reproduce and cause disease. [...]

In the past the problem has been that this group of viruses including HIV, Hepatitis C, Dengue Fever and West Nile virus, are able to bypass the main pathway if inhibited and replicate via a second pathway using this enzyme. Thus for a treatment to be effective, both pathways need to be blocked.

"It was already known how to block the main pathway for these viruses [...] Combining international resources and expertise, we were able to determine the endomannosidase structure and this has revealed how we can block the bypass route, stopping the viruses from hijacking human enzymes." [...]

Mechanisms for HIV Persistence on ART


"There are different -but non-mutually exclusive- hypotheses to explain why HIV persists despite ART:
- Residual replication in cells located in sanctuary sites where drug levels are suboptimal,
- Long-lived HIV-infected cells that produce virus,
-Proliferation of latently infected cells with regeneration of a stable reservoir of slowly dividing infected cells."

"...Collectively, this suggests the presence of a chronic viral reservoir in which there is stochastic release of infectious virus and in which there are limited rounds of de novo infection. This could be explained by the existence of different reservoirs with unique pharmacological accessibility properties, which will require strategies that improve drug penetration/retention within these reservoirs in order to minimize maintenance of the viral reservoir by de novo infection...

...The ACTG 5301 trial will test the hypothesis that inhibition of PD-1 activates in a relatively specific manner cells containing HIV while simultaneously causing enhancement of HIV-specific immunity ..."


http://www.hiv-reservoir.net/index.php/the-ne...v-persistence-on-art.html