"Bringing the drug closer to the cell" could improve both treatment and PrEP
A combination of particle formulations of the atazanavir and ritonavir drugs, increased of an immune buffer designed to induce drugs into the right cells in order to keep the drug longer in the body, produced a decline of 100 times in the number of CD4 T cells in the lymph nodes of HIV-infected mice and a further reduction of the amount of new viruses produced by cells. Pre-treatment with the drug also generates infections produced with considerably lower viral loads, suggesting from this concept that it may be used in pre-exposure prophylaxis (PrEP) as well as in the treatment of HIV infection or AIDS. The drug combination has largely prevented the uptake of HIV into T lymphocyte cells and thus has considerable potential to prevent or suppress the infection in the long run.
Editor's note: I understand the last sentence a modest but clear of a call to attention for a possible "cure" a treatment medium or long term or a "functional cure" with fewer visits to the hospital, improving even more the quality of life of PLWHA
The discovery of the potential of the drug combination was made almost in a casuistic way. The experimental immune drug cushion, URMC-099, was being investigated as a suppressor of possible treatment for HIV-induced inflammation of the brain and nervous system in the long and chronic process of HIV infection. It works by suppressing B-kinase, a family of proteins that act as switches to inflammatory genes (aspirin is also a suppressor of kinase).
From Wikipedia, the free encyclopedia. (Redirected from kinase) Em biochemistry, One kinase ou kinase, is a type of enzyme which transfers phosphate groups of high-energy donor molecules (such as ATP) To specific target molecules (substrates). The process is called phosphorylation.   The target molecule may be activated or inactivated by phosphorylation. All kinases require a ion divalent metal as the Mg2+ or Mn2+ to transfer the phosphate group. These enzymes are activated by cyclic AMPWhich catalyzes the phosphorylation of certain proteins. A protein kinase catalyzes the addition of phosphate reaction of this grouping and this reaction is unidirectional, with the ATP being broken for producing the energy needed for the reaction. A protein phosphatase, does exactly the reverse reaction of kinases, it removes a phosphate grouping, ie does dephosphorylation. The cells contain several proteins kinases and protein phosphatases each being responsible for acting in a specific group or a specific protein. The protein kinases belong to a large family of enzymes that share a sequence of amino acids 290. Some specific amino acid sequences that allow specific kinases recognizing groups on the protein to be phosphorylated. Source: Widepedia. To read the full article, click here
The same team also investigated a new method of delivery to the drug's body for the protease inhibitor atazanavir, boosted by ritonavir. Both of these drugs were formulated as nanoparticles - thousands of drug particles, small enough to pass into cells and even to cellular components. These nano particles were then attached to folic acid, a common micronutrient, whose molecules are also used by cells of the immune system, with the result that, arriving in lymph nodes, the drug was elaborated proactively in T cells.
Adding to the nano-formulated URMC-099-driven atazanavir (nano ATV) cells were induced in mice - which were genetically adapted to have human immune systems - to maintain intracellular drug levels for up to ten days in a single dose , especially at sites in the cells where viral HIV particles are constructed.
This first resulted in a considerable decline in the number of CD4 cells infected with HIV. In untreated mice, the CD4 count, expressed as the percentage of T lymphocytes that were CD4 cells, decreased from 75 to 40% - as seen in most courses of HIV infection. Using nano ATV, the percentage of CD4 was maintained at 60% - within the range of uninfected mice.
However the nano ATV achieved this feat by itself, probably due to a specific particularity of it that had not been noticed before (always remember the history of penicillin). The URMC-099, although without generating any effect on its own structure produced a considerably above-predicted reduction and in addition to the effect of atazanavir when dosed as nano ATV. The viral load in treated mice was about 100.000 copies / ml; in mice treated only with increased atazanavir potency was 1600 copies / ml and with URMC-099 was 284 copies / ml. The effect persisted a little after the dose was withdrawn. Mice were infected and not treated first for a period of nine weeks; then nanoATV was injected once a week and URMC-099 administered daily in this way for three weeks. CD4 counts remained stable when measured a week later.
What was unprecedented, however, was that the addition to atazanavir URMC-099 had produced a considerably larger decline in the number of HIV-infected cells of both T lymphocyte cells and macrophages in the spleen and lymph nodes and especially the actual viral production by infected cells.
Untreated infected mice had 40 cells by 1000 in their spleen producing HIV and 50,3 actively by 1000 in their lymph nodes. With nanoATV alone, it was reduced to 4,0 and 10,8 for 1000 in the spleen and lymph nodes respectively and less than 0,1 and less than 2.3 respectively when URMC-099 was added.
The researchers also conducted a series of experiments in which they mice infected with HIV after nanoATV and URMC-099 treatment, or as a way of preparing therapeutic modulation. They first dosed mice with atazanavir alone, ordinary nanoATV alone or this plus URMC-099. Then after the withdrawal of the drug, they mice infected with HIV.
Drugs not effectively present at the time of HIV infection do not prevent infection: but they reduced the number of cells with HIV DNA integrated into them after infection, from 11,471 DNA copies by 1000 cells with atazanavir (not ordinary better than 74 copies / 1000 cells with nanoATV alone and 33 / 1000 with URMC-099. Non-integrated viral RNA in cells decreased from 1100 copies by 1000 cells with atazanavir to 100 ordinary copies / 1000 cells over nanoATV alone to 19 copies / 1000 cells with addition of URMC-099.
Pre-treatment of infection with the two drugs has also produced deep breaks the number of cells producing new viruses. Only NanoATV produced 90,8, 94,2 and 95,7% decreases in active viral expression per cell depending on the dose (1, 10 and 100 micromols of nanoATV respectively). Adding to URMC-099 produced further decreases in HIV expression patients by 63,8, 81,7, 97,8 and 91,3% respectively for four doses of URMC-099 (0,1, 1,0, 10 and 100 nanograms / ml respectively). This means that production after viral infection was reduced by 94,1% when the two lower doses of nanoATV and URMC-099 were used, 99,6% when the two highest doses were used and 99,3% when the next two doses were used higher .
How do the two drugs claim to dye this effect? As stated above, by binding the formulated nano atazanavir to a folic acid molecule capable of effective drug penetration into cells; the nanoparticles were small enough even to enter organelles (cellular components) where viral cells and proteins are disassembled, copied and reassembled, but they would not be eliminated quickly, as they would be, if the drug molecules themselves would be if they were in the context
organelle From Wikipedia, the free encyclopedia. (Redirected from organelles) Em cell biology, organelles, organelles, or yet organelles( "Small bodies") are bounded by membrane compartments have specific roles to play in the overall function of a cell. Organelles work in an integrated way, each taking one or more cellular functions. The name "organelle" comes from the idea that these structures are the organs of the cell, as the organs are for the body (hence the name organelle, the suffix -she being one diminutive). The organelles are identified by microscopy and can also be purified bycell fractionation. There are many types of organelles, particularly in cells eukaryotic. While the prokaryotes do not have organelles per se, some of them contain micro- proteinsWhich are supposed to serve as primitive organelles.  Fonte Wikepedia. Pata learn more, click here.
Adding the URMC-099 interrupted the process from the cells by pressing their "self-destruction buttons" when stimulated by the inflammatory proteins of HIV, and lived longer. The drugs together suppressed the specific cellular proteins that function as activators of the immune response genes that in HIV infection, make viral replication possible.
Measurements of the amount of the HIV reverse transcriptase (RT) enzyme in cells showed that with the two highest doses of URMC-099, activity was still suppressing this process. for five days after the last dose of the drug!
"This is the first formulation known to date (09 / 02 / 2016) of combinations able to reach the lymph nodes of infected animals and reduce by more than 90%, the number of viral infectious particles," the researchers said. They aim to improve the targeting of nanoATV by attaching it to the protein components of the HIV protective envelope to perform further experiments on human cells.
Posted in: 05 February 2016
A note mine. Although to always be careful when I use that word to dream of 4 letters, I, the skeptic, I begin to see hope ****.
That's the most I can say
Translated and revised by Claudio Souza in the day dawn 09 February 2016 the original Combination nanotherapy angiograms drastically the amount of HIV produced by cells in mice
Tip of Carlos jackson
Zhang G et al. The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. Nanomedicine 12, 109-122. 2016