The flaws of HIV

 

HIV is a complex virus. Though research carried out over the past 30 years has helped to understand most of its biology, its infectious process still contains grey areas. One of these has to do with the exact role played by Nef, an HIV accessorye protein, during infection. Without it, the weakened HIV virus loses much of its pathogenic ability. It was therefore necessary to identify the exact mechanism by which HIV infectivity is destroyed, and which cell protein is responsible. Researchers from the Universities of Geneva (UNIGE) and Trento have deciphered this important flaw in the virus arsenal of attack by identifying the SERINC5 protein. This discovery can be read in Nature.

To defend themselves against viral infections, our cells use a variety of biological weapons. But viruses mutate faster than the eukaryotic cells we are made of, reason why they have so-called "countermeasure" proteins that allow them to divert the effectiveness of our immune system. The Nef protein appears to be one of them and, it is known to play a fundamental role in its replication and the development of AIDS. Multifunctional, Nef is particularly capable of altering the activation state of T lymphocytes and macrophages, cells essential to our immune mechanism. However, these regulatory functions do not explain another role of Nef: its ability to enhance the infectivity of viral particles.

"When the virus replicates in a cell, it utilizes Nef in order to neutralize a specific protein whose function is to protect this cell against HIV. Our goal was therefore to identify this unknown protein to understand why some cells are more susceptible to HIV than others," explains Federico Santoni, co-author of the study, bioinformatician and computational biologist within Prof. Stylianos Antonarakis' research group at the Faculty of Medicine of the University of Geneva (UNIGE).

Finding the protein that defends our cells

The researchers examined cell lines coming from different organs in order to identify those that were most and least likely to be infected with HIV. To do so, they removed Nef from the virus -- the manipulated virus is called HIV?Nef -- to determine which microbiological elements, usually inhibited by Nef, could explain this greater or lesser sensitivity to infection. Thanks to large-scale bio-statistical calculation techniques developed at UNIGE, the scientists were able to measure, in each cell line, the levels of correlation between its receptivity to HIV?Nef and the amount of protein transcription (in other words the level of expression of tens of proteins present on the cell surface), in order to identify those which would enable cells to effectively fight against HIV. The scientists found that in the cell lines the least sensitive to HIV?Nef, a membrane protein, called SERINC5, was highly expressed, while it was not -- or almost not -- expressed in cell lines susceptible to the virus.

Massimo Pizzato, a HIV specialized virologist at the University of Trento and coordinator of the study, details how Nef is able to inhibit this protein and favor HIV infection: "This mechanism takes place in two stages. When HIV, stripped of the Nef protein, penetrates a cell to infect it, it succeeds without any problem. The virus then replicates normally. But when it comes out again to continue its destructive work in another cell, it takes a part of the infected cell membrane to build its own membrane. With it, it also carries the SERINC5 protein found on the membrane of the attacked cell. From then on, when the virus tries to infect a second cell, SERINC5 acts as an alarm signal and warns the cell that the pathogen is coming. The virus is therefore no longer able to penetrate." Nef, by inhibiting SERINC5, is therefore a crucial element for HIV infectivity.

Strengthening SERINC5

Usually, Nef is able to neutralize SERINC5. Nevertheless, the study shows that if SERINC5 is highly expressed, Nef is no longer able to counteract it, which greatly reduces the virus infection ability. The goal is therefore to reverse the balance of power to favor SERINC5. "SERINC5 is not the first antiretroviral factor discovered. For sure, we have identified a new element, but, most importantly, we deciphered a mechanism that works very differently from the others. Moreover, contrary to the antiretroviral factors previously discovered, which are activated by interferon (a protein substance produced by certain cells of the immune system in response to a pathogen), SERINC5 is expressed continuously in all cells of our immune system" states Federico Santoni.

"We now need to carry on working on this defensive mechanism to evaluate how to exploit this flaw in new therapeutic strategies, either by strengthening the presence of SERINC5 in all cells, or by modifying its structure to enable it to escape Nef inhibition. Long-term research!"

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Story Source:
The above post is reprinted from materials provided by Université de Genève. Note: Materials may be edited for content and length.

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Journal Reference:

1. Annachiara Rosa, Ajit Chande, Serena Ziglio, Veronica De Sanctis, Roberto Bertorelli, Shih Lin Goh, Sean M. McCauley, Anetta Nowosielska, Stylianos E. Antonarakis, Jeremy Luban, Federico Andrea Santoni, Massimo Pizzato. HIV-1 Nef promotes infection by excluding SERINC5 from virion incorporation. Nature, 2015; DOI: 10.1038/nature15399

Read more articles like this here: http://www.sciencedaily.com/news/health_medicine/hiv_and_aids/

New drugs reawaken latent HIV to eradicate virus

A new study suggests a class of drugs already being tested in clinical trials for the treatment of cancer may also hold the key to complete eradication of HIV.

 

 

 Researchers used a class of drugs called Smac mimetics to reawaken latent HIV in cells of patients treated with antiretroviral drugs, allowing suppression of the virus.

 

In the journal Cell Host & Microbe, a team led by researchers from the Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla, CA, reveals how drugs called Smac mimetics suppress dormant HIV (human immunodeficiency virus) cells among patients treated with antiretroviral therapy (ART).

ART is a combination of at least three antiretroviral drugs that slows the progression of HIV. While the treatment has led to significant reductions in death rates from HIV around the globe, the search continues for a way to eliminate the disease once and for all. 

Antiretroviral drugs work by preventing HIV cells from multiplying, reducing levels of the virus in the body and giving the immune system the opportunity to stave off other infections.

However, HIV is never completely eradicated in patients treated with ART; the virus can lay dormant in cells, escaping detection by the immune system. 

"If you take people off their antiretroviral therapies, some of these dormant cells reawaken to make more virus and re-establish disease," explains lead study author Lars Pache, PhD. "The key for a cure for HIV is to purge these cells that have dormant HIV."

 

This type of strategy is referred to as a "shock-and-kill" approach, but although it is a method that has been widely investigated by researchers in recent years, it has yet to see success. 

Pache and colleagues explain this is because candidate drugs used to reawaken dormant HIV - such as latency reversing agents (LRAs) - are not potent enough or can trigger immune system overactivity, which can be deadly.

A 'one-two punch' for HIV

After searching for genes within host cells that aid in the suppression of HIV, the team identified one gene - called BIRC2 - that when absent, increases HIV activity. 

Because Smac mimetics work by blocking BIRC2 and molecules related to the gene, they investigated whether the drugs could reawaken dormant HIV, allowing it to be identified and attacked by the immune system. 

The team notes that one of the reasons why HIV can hide from the immune system is because it is covered by "tightly wound" DNA. They hypothesized Smac mimetics may work well with another class of drugs called histone deacetylase inhibitors, which can unwind this DNA, revealing the HIV underneath.

The researchers tested a Smac mimetic called SBI-0637142 combined with a histone deacetylase inhibitor called panobinostat on cells from HIV-infected patients undergoing ART. They found that the drug combination reawakened HIV in the cells without activating the immune system.

They also tested another Smac mimetic called LCL161 - currently being tested in phase 1 and 2 clinical trials for the treatment of cancer - combined with panobinostat, finding that the treatment produced similar results.

Based on their findings, the team suggest Smac mimetics - in combination with other drugs such as histone deacetylase inhibitors - could be potential candidates for an HIV cure.

Study co-author Sumit Chanda, PhD, adds:

"This is a one-two punch for HIV. Our internal drug possesses about 10-100 times more potent LRA activity than the small molecules currently in clinical development, making it a promising next-generation candidate to tackle HIV latency."

The researchers say they now hope to team up with a pharmaceutical company in order to develop Smac mimetics for assessment in clinical models of HIV latency, before moving to human trials if they are deemed safe and effective. 

Because the drugs are already being tested in clinical trials, the team says the approval process for their use in the treatment of HIV is likely to be shorter. 

In July, Medical News Today reported on a study published in PLOS Pathogens in which researchers found HIV cells awaken much less frequently than previously thought following ART.

While latent HIV cells were believed to awaken around four to five times a day once ART had ceased, the new study found they actually only awaken once a week. 

Written by Honor Whiteman

Read more articles like this here: http://www.medicalnewstoday.com/categories/hiv-aids

Targeting semen proteins to prevent HIV infection

Research led by investigators from the Perelman School of Medicine at the University of Pennsylvania describes two novel approaches that could prevent HIV infection by targeting proteins in semen that boost transmission of the virus.

HIV (human immunodeficiency virus) is commonly spread through sexual contact with an HIV-infected partner. The virus can be transmitted via infected blood, semen or vaginal secretions, with semen being the primary vector for the virus.

 

Researchers found a molecule called CLRO1 interfered with semen polymers called amyloid fibrils, reducing the likelihood of HIV transmission.

Image credit: James Shorter

Semen contains proteins that form polymers called amyloid fibrils. These polymers help the HIV virus attach to the membranes of human cells, boosting transmission of the virus by up to 10,000 times.
Senior study author Prof. James Shorter, associate professor of biochemistry and physics at the Perelman School of Medicine, and colleagues propose that reducing amyloid fibril levels in semen could reduce HIV transmission. They reveal how this could be done in two separate studies.
The first - published in the journal Chemistry & Biology in 2012 - describes how a heat shock protein called Hsp104 attacks amyloid fibrils, converting them into non-amyloid forms.
In addition, the team reveals how they developed inactive Hsp104 scaffolds that disrupt the organization of amyloid fibrils, leading to the assembly of non-threatening protein structures. The researchers also modified Hsp104, allowing it to team up with an enzyme to weaken amyloid fibrils in semen.
According to Prof. Shorter, each of these strategies reduced amyloid fibrils' ability to boost HIV transmission, "so this approach has potential as a therapeutic."

'Tweezer-shaped' molecule reduces likelihood of HIV transmission by 100-fold

For the second study - recently published in eLife - Prof. Shorter and colleagues teamed up with researchers from the Ulm University Medical Center in Germany to reveal how a small molecule called CLRO1 not only interferes with amyloid fibrils' ability to enhance HIV transmission, but attacks the HIV virus itself.
The researchers describe CLRO1 as a "tweezer-shaped" molecule that impairs the formation of amyloid fibrils in semen and dismantles pre-formed fibrils.

In addition, CLRO1 interferes with membranes surrounding HIV virus particles, disarranging particles that have already attached to amyloid fibrils.

On exposing human cells to HIV-infected semen, the researchers found CLRO1 reduced the likelihood of HIV transmission by more than 100-fold.
 
The researchers say because CLRO1 has no negative impact on other cell membranes, it could be used to develop safer vaginal and anal gels that prevent HIV infection. Prof. Shorter adds:

"We think that CLR01 could be more effective than other microbicides that are in development because of its dual action, its safety in terms of side effects and its potential broad application."

The team notes that CLRO1 has proven safe in zebrafish and mice, and the next step is to test the molecule in non-human primates.

Last month, Medical News Today reported on the first case of prolonged remission in an HIV-infected child. Researchers revealed that an 18-year-old woman who was infected with HIV at birth was in remission, even though she had not received antiretroviral therapy for the past 12 years.

Written by Honor Whiteman

More articles like this can be found here: http://www.medicalnewstoday.com/categories/hiv-aids

My Continued Journey Living With HIV

Today is the third day on my once again new regimen of HIV Medication. I am back to taking the drug that I started with six long years ago. Yes, I am taking Atripla again. I would have never dreamed I would be taking this drug again after all the horrible side effects, but on October 2, 2015 this is once again my medication.

I have gone through so much grief this past year with HIV medications that sometimes I just want to give up. I know that giving up is NOT the answer so I will once again try working with Atripla. I just pray this time around I do not go through all the horrible side effects I did before.

Why am I back on Atripla? Well let me explain what has happened. Since I got off of Atripla and been on Triumeq for four months then being on Tivicay and Truvada since then, I have gained 50 plus pounds, been constipated and basically miserable for the past year. I had to switch the medication that kept my headaches under control because the one I was on was causing kidney stones that put me in the hospital twice this past year. After going through all my medications my PCP figured out that the ingredients in the HIV medication I had been on was causing me to gain weight. God knows I do not need to be this big!!! Now talking with my HIV doctor there was a war because she was convinced that I could not have possibly be gaining weight because of the HIV medication, because {here is where the fight started} none of the other people on the medication where gaining weight. I just sat there in awe and disbelief. How can a doctor think they can lump you in with a group of people when we ALL have different body chemistries and our bodies react differently to medication than the next person. The fight was on but I told her I would quit medication therapy for good if she did not get me on something else. Her answer – THE ONLY thing I will put you on is ATRIPLA. She knew all the hell I went through before on ATRIPLA but because she is the “Specialist” it was her way or the highway. Since I obviously do not want to get sick and die I chose to go back on Atripla. It really sucks when you are on Medicare and state assistance, therefore, having NO choice of doctors but the ones they send you too. If I still had my private insurance I would be switching doctors. I know there are so many new drug regimens that she could have put me on, but she was going to “show me”. So here I am back on the first line of therapy I was on for 5 years. I pray it actually gets me back to undetectable, since the last one I was on was no longer keeping me undetectable. I also pray my CD4 count does not continue to drop. I trust God will take care of me, He always has.

I will be seeing my heart doctor this week for tests to see how my heart is doing. My PCP thinks I have the beginning stages of Congestive Heart Failure. I will also be seeing the dermatologist this week to get rid of the Skin Cancer on my face. I will post updates as I get them the next couple of weeks.

For now I pray that all who read my journey can learn from my experiences. Be well – stay safe – and always - always - always PROTECT YOURSELF.

David Moorman

10-5-2015

Treat all people living with HIV

Treat all people living with HIV, offer antiretrovirals as additional prevention choice for people at "substantial" risk

New policies could help avert more than 21 million deaths and 28 million new infections by 2030

News release
 

30 SEPTEMBER 2015 ¦ GENEVA - Anyone infected with HIV should begin antiretroviral treatment as soon after diagnosis as possible, WHO announced Wednesday. With its "treat-all" recommendation, WHO removes all limitations on eligibility for antiretroviral therapy (ART) among people living with HIV; all populations and age groups are now eligible for treatment.

The expanded use of antiretroviral treatment is supported by recent findings from clinical trials confirming that early use of ART keeps people living with HIV alive, healthier and reduces the risk of transmitting the virus to partners. 

 

WHO/A. Fitrianto

 

WHO now also recommends that people at "substantial" risk of HIV should be offered preventive antiretroviral treatment. This new recommendation builds on 2014 WHO guidance to offer a combination of antiretroviral drugs to prevent HIV acquisition, pre-exposure prophylaxis (PrEP), for men who have sex with men. Following further evidence of the effectiveness and acceptability of PrEP, WHO has now broadened this recommendation to support the offer of PrEP to other population groups at significant HIV risk. PrEP should be seen as an additional prevention choice based on a comprehensive package of services, including HIV testing, counselling and support, and access to condoms and safe injection equipment. 

New recommendations on early use of ART and expanded offer of PrEP are contained in WHO’s "Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV.” The new guideline stresses that, in order to effectively implement the recommendations, countries will need to ensure that testing and treatment for HIV infection are readily available and that those undergoing treatment are supported to adhere to recommended regimens and are retained in care.

The recommendations were developed as part of a comprehensive update of the "WHO consolidated guidelines on the use of antiretroviral drugs for preventing and treating HIV infection". This early release guideline is shared ahead of the full publication, slated for release later this year, because of their potential for public health impact. 

Based on the new recommendations, the number of people eligible for antiretroviral treatment increases from 28 million to all 37 million people who currently live with HIV globally. Expanding access to treatment is at the heart of a new set of targets for 2020 with the aim to end the AIDS epidemic by 2030. These targets include 90% of people living with HIV being aware of their HIV infection, 90% of those receiving antiretroviral treatment, and 90% of people on ART having no detectable virus in their blood.
According to UNAIDS estimates, expanding ART to all people living with HIV and expanding prevention choices can help avert 21 million AIDS-related deaths and 28 million new infections by 2030.

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For media inquiries, please contact:

Christian Lindmeier
Communications Officer, WHO
Telephone: +41 22 791 1948
Mobile: +41 79 5006552
E-mail: lindmeierch@who.int

Discovering an Antibody With Refined Abilities to Combat HIV

Researchers have found a so-called broadly neutralizing antibody (BNA) that can identify a key, shape-shifting portion of HIV when it is in multiple forms, possibly indicating this naturally occurring immune response could be manufactured to become a part of a future treatment for the virus. Publishing their findings in the journal Cell, researchers published the results of an X-ray crystallography and electron microscopy study of interactions between a BNA called 8ANC195 and what is known as the envelope spike on HIV’s surface.

The HIV envelope spike is made up of a series of proteins that bind to the surface proteins on immune cells. The spike can be in an open or closed position. In the event that HIV is floating independently through the body, the spike would typically be closed. But research has shown that HIV tends to spread directly from an infected immune cell to another immune cell, in which case the viral spike would likely be open. 

According to this new research, 8ANC195 can recognize and attach to the viral spike when the spike is either closed or partially open, ultimately neutralizing the effects of the virus.

The researchers hope that 8ANC195 may one day become a component of combination HIV therapy.

To read the study abstract, click here.

To read a press release about the study, click here.

Search: Broadly neutralizing antibody, BNA, 8ANC195, Cell.

Find more stories like this here: http://www.poz.com/

My Continued Journey – Living With HIV

September 15, 2015



__________________________________________________________________________________

Well today I saw my ID Doctor and things did not go as well as planned.

Instead of trying to help me understand my questions, the Doctor just kept shutting me down.

I left her office very frustrated.

Unfortunately she is the top ID Doctor here in Oklahoma City.

I had concerns about the medication causing me all the weight gain. Her initial and very strong response was that she has over 1000 patients and NONE of them that she has on the Truvada/Tivcay combo has gained any weight. Basically telling me that I am WRONG, even though I have researched for myself and have found that one of the common ingredients in Triumeq and Tivacy is known to cause weight gain. I have gained 50 pounds since going on and then off of Triumeq. I initionally gained 30 pounds while on Triumeq for 4 months. I was taken off Triumeq and put on the Truvada/Tivcay combo and have gained 20 more pounds. But hey, she is right it has NOTHING to do with the medication. Whatever!!!! Since coming off of Atripla and going on these other pills I have gained all this weight. I even had a home health care nurse tell me the foods I am eating are fine and she could not understand why I am gaining even while exercising. 

Here is the kicker. When I asked her to put me on something different she skirted the issue I am having and said the only option she would give me at this time would be to go back on Atripla. I have prayerfully decided to go back on Atripla and just deal with the side effects. Those side effects where not as bad as gaining 50 pounds. I will post results of going back on Atripla in a few weeks.

I am posting here my results of my last two visits. I am so thankful for the wonderful CD4 but I am not happy about this little rise in HIV. I know it is not much but it just goes to show that the VIRUS is always there doing damage to our bodies even when the CD4 is good.  

9/8/2015 HIV-1 RNA VIRAL LOAD

Patient: DAVID ALAN MOORMAN ID: HCA_LAB L001150177 Note: All result statuses are Final unless otherwise noted. Tests: (1) HIV-1 RNA VIRAL LOAD (VPHIV) HIV-1 RNA VIRAL LOAD 33 copy/mL Linearity is 20 copies/ml to 10,000,000 copies/ml. 

Method: ROCHE, COBAS AmpliPrep/TaqMan HIV-1 Test, version 2.0, FDA approved. HIV-1 RNA VIRAL LOAD-LOG 10 1.52 copy/mL

9/8/2015 CD4 ONLY

Patient: DAVID ALAN MOORMAN
ID: HCA_LAB L001150177
Note: All result statuses are Final unless otherwise noted.

 Tests: (1) CD4 ONLY (CD4)
  WHITE BLOOD CELL     [H]  12.31 K/mm3 (C)             4.0-11.0         
    Previously reported result: 12.31 K/mm3
    Edited by: ELAB.RIJ on 09/09/15:1033
  LYMPHOCYTE %              30.7 %                      15.0-46.0        
  TOTAL LYMPHOCYTES         3779 CELLS/uL                                
  CD4 ABSOLUTE COUNT        2192 CELLS/uL               200-3390         
  CD 4 HELPER/INDUCER       58 %                        31-67            

 

2/23/2015 HIV-1 RNA VIRAL LOAD

Patient: DAVID ALAN MOORMAN ID: HCA_LAB L001150177 Note: All result statuses are Final unless otherwise noted. Tests: (1) HIV-1 RNA VIRAL LOAD (VPHIV) HIV-1 RNA VIRAL LOAD NO HIV DETECTED copy/mL Linearity is 20 copies/ml to 10,000,000 copies/ml. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Method: ROCHE, COBAS AmpliPrep/TaqMan HIV-1 Test, version 2.0, FDA approved.

2/23/2015 CD4 ONLY 

Patient: DAVID ALAN MOORMAN
ID: HCA_LAB L001150177
Note: All result statuses are Final unless otherwise noted.

Tests: (1) CD4 ONLY (CD4)
  WHITE BLOOD CELL     [H]  11.68 K/mm3                 4.0-11.0         
  LYMPHOCYTE %              42.6 %                      15.0-46.0        
  TOTAL LYMPHOCYTES         4976 CELLS/uL                                
  CD4 ABSOLUTE COUNT        2986 CELLS/uL               200-3390         
  CD 4 HELPER/INDUCER       60 %                        31-67            

I still have to see the dermatologist about the skin cancer and the heart doctor

about the heart issues and inflamation in my body. I will continue to update as I 

see the different Doctors.

Take care, be blessed and KEEP FIGHTING!!!

I REFUSE to LET HIV control my LIFE!!!

Just because we may have HIV-

Does NOT mean HIV has us!!!

Blessings and Peace,

David Moorman