HIV entry mechanism into immune cell nucleus revealed

Once HIV enters an immune cell, it has to make its way into the nucleus to fuse with the cell’s DNA. Most viruses wait until the cell divides to do this, but HIV is too impatient. Instead, the virus hijacks a protein and makes it enlarge pores in the membrane surrounding the nucleus that the cell uses to pass materials to and from the nucleus.
This was the main finding of new research published in the journal PLOS Pathogens by a team from Loyola University, Chicago, IL.

Senior author Edward M. Campbell, associate professor in the Department of Microbiology and Immunology at Loyola’s Stritch School of Medicine, says the discovery could lead to new drugs to treat HIV/AIDS.

Viruses cause disease by invading cells and changing how they behave. Different viruses target different cells. HIV targets cells in the immune system.

As HIV impairs and destroys infected people’s immune cells, their defense against disease and infection weakens. The most advanced stage of infection – which can take from 2-15 years to develop – is called AIDS.

According to the World Health Organization (WHO), there are around 37 million people living with HIV worldwide, and around 2 million become newly infected every year.

HIV-1 is the predominant strain of HIV that causes the vast majority of HIV infections worldwide. When people talk about HIV, they usually mean HIV-1.

Without host cells, viruses cannot sustain themselves and reproduce. They have no energy source or metabolic engine of their own; they have to enter the host cell, penetrate its nucleus, and fuse with its DNA to take control of cell machinery to make their own proteins and replicate.

HIV-1 hijacks cell protein to enlarge nuclear pores

Most viruses take the opportunity to enter the nucleus when the host cell divides and the nuclear membrane or envelope – the wall that protects the nucleus and its precious cargo of DNA – breaks down. But HIV-1 does not wait for this; somehow, it manages to enter the nucleus of non-dividing cells. Exactly how it does this has been a mystery for years.

What has been especially baffling is that the HIV-1 capsid – the protein shell that protects the genetic material of the virus – is some 50 percent larger than the pores in the nuclear envelope. These pores normally allow proteins and other materials in the host cell to travel to and from between the nucleus and the cell body.

The discovery that Prof. Campbell and colleagues make in their study surrounds a protein called KIF5B that normally transports various materials inside the cell away from the nucleus.

They found that HIV-1 hijacks KIF5B and induces it to tear off pieces of the nuclear envelope and transport them away from the nucleus, causing the pores to become big enough to allow HIV-1 to pass through. The pieces that are torn off are proteins called Nup358.

In cells that have no KIF5B or Nup358, the authors note that HIV-1 entry is much reduced, and the virus accumulates around the outside of the nuclear envelope.

Discovery could lead to new drug for HIV

The team suggests the finding could lead to a new type of anti-HIV drug that stops KIF5B from disrupting the pores in the nuclear envelopes of host cells.

Such a drug might slow HIV’s entry into the host cell nucleus long enough to give the immune system time to raise the alarm and destroy the virus.

Cells have natural mechanisms for detecting viruses in their cytoplasm – the fluid that fills the cell and surrounds the nucleus. But HIV-1 is able to enter the nucleus before these mechanisms have time to react.

Drugs that disable the hijacking of KIF5B would trap HIV-1 in the cytoplasm. This would not only prevent infection, but also increase the chance of HIV-1 being detected and eliminated

“It’s like making a bank vault harder to break into. In addition to making the money more secure, it would increase the chance of sounding the alarm and catching the burglars.”


Functional Cure For HIV Additional Trials Underway After Successful Cure Of Patient-Best Life Insurance Program

Barcelona – In what could be among the most sensational discoveries in modern day medicine, Doctors in Barcelona, Spain announced that believe they have found a massive breakthrough that could lead to a possible cure to HIV – {the AIDS-causing virus that affects the lives of more than 34 million people worldwide, according to WHO.}

Timothy Brown was the first patient to ever be cured of HIV after a bone marrow transplant to treat his leukemia received. He is known as the ‘Berlin patient’.

By using blood transplants from the umbilical cords of individuals with a genetic resistance to HIV, Spanish medical professionals believe they can treat the virus, having proven the procedure successful with one patient.

Now, a 37-year-old man from Barcelona, who had been infected with the HIV virus in 2009, was cured of the condition after receiving a transplant of blood.

While unfortunately the man later died from cancer just three years later, having developed lymphoma, the Spanish medical team is still hugely encouraged by what it considers to be a breakthrough in the fight against HIV and related conditions, according to the Spanish news source El Mundo.

Doctors in Barcelona initially attempted the technique using the precedent of Timothy Brown, an HIV patient who developed leukemia before receiving experimental treatment in Berlin, the Spanish news site The Local reported.

Brown was given bone marrow from a donor who carried the resistance mutation from HIV. After the cancer treatment, the HIV virus had also disappeared.

According to The Local, the CCR5 Delta 35 mutation affects a protein in white blood cells and provides an estimated one percent of the human population with high resistance to infection from HIV.

Spanish doctors attempted to treat the lymphoma of the so-called “Barcelona patient” with chemotherapy and an auto-transplant of the cells, but were unable to find him a suitable bone marrow.

“We suggested a transplant of blood from an umbilical cord but from someone who had the mutation because we knew from ‘the Berlin patient’ that as well as [ending] the cancer, we could also eradicate HIV,” Rafael Duarte, the director of the Haematopoietic Transplant Programme at the Catalan Oncology Institute in Barcelona, told The Local.

Prior to the transplant, a patient’s blood cells are destroyed with chemotherapy before they are replaced with new cells, incorporating the mutation which means the HIV virus can no longer attach itself to them. For the Barcelona patient, stem cells from another donor were used in order to accelerate the regeneration process.

Eleven days after the transplant, the patient in Barcelona experienced recovery. Three months later, it was found that he was clear of the HIV virus.

Despite the unfortunate death of the patient from cancer, the procedure has led to the development of an ambitious project that is backed by Spain’s National Transplant Organization.

March 2015 marked the world’s first clinical trials of umbilical cord transplants for HIV patients with blood cancers.

Javier Martinez, a virologist from the research foundation Irsicaixa, stressed that the process is primarily designed to assist HIV patients suffering from cancer, but “this therapy does allow us to speculate about a cure for HIV,” he added.

Despite the joy and ululation, those who think its time to celebrate may have not done their research. The process of curing HIV referred to by the doctors is called Stem Cell Transplant. Whilst it has worked on this one patient, there is a lot more information about its viability and use as a cure for all people affected with HIV / AIDS.
To begin with, getting a Stem Cell Transplant is much more dangerous than living with HIV.
To successfully complete an SCT you have to completely destroy the stem cells in your bone marrow using intense conditioning resulting in:
1. Low/No white blood cells – [no ability to fight off infection, meaning even something as small as flu could kill you]
2. Low Platelets – [heavy risk of uncontrollable bleeding- a nosebleed would most likely result in death)
3. Low hemoglobin – [you will need many, many blood transfusions]
4. Graft vs Host disease – [which can cause really poor quality of life or kill you]
5. A long time spent in hospital – [weeks to months, if not a year plus].
Stem Cell Transplants do save lives, but judging by the risks state above, they only make sense for people who have specific life threatening conditions such as acute leukemia. These conditions would imply that loss of life is almost guaranteed, and certain, leaving SCT as the last hope or only option.
From a sensible perspective, HIV is now a manageable chronic condition in most cases. This “CURE” is certainly interesting but probably not applicable for almost all HIV positive people.
HIV is a minor inconvenience in the world of modern medicine. It is easily controlled with 1 pill (ARVs) taken once a day, typically with no complications or side effects.
However, dying from a bone marrow transplant because of the risks mentioned before is, by comparison, a major inconvenience.
There is great reason to be excited however, discoveries like these are a major breakthrough and can allow medical personnel to build on them for a more constructive and less intensive cure.

Trials are already underway to gather more information. They started in March 2015.

To decide if it could be done or not a trial, it was necessary first to note that Spanish banks umbilical cord had samples that will carry a key mutation that is responsible for transferring protection against HIV. This is the genetic mutation CCR5 Delta 3 , a variation that acts as a shield against the AIDS virus. Cells carrying this variant areimpermeable to the pathogen.

That’s what was discovered, almost by chance, with the Berlin patient, ie, if a person receives bone (or cord blood) from another subject that carries this positive change, will renew your blood cells they are immune to HIV, the body that will end disappearing.

“We knew that Spain is a world power in number of cords and cellularity, because the collection protocol makes us samples with many cells needed for transplants in adults. So we decided to analyze those cells rich laces, 25,000 . To this end, we agreed with all the autonomous communities and cord banks, “he told WORLD Rafael Matesanz, director of the National Transplant Organization, which has funded the search with about 100,000 euros.

After one year evaluating cord by cord to see which of them carried the mutation , said Rafael Duarte, who was director of Hematopoietic Transplant Program at the Catalan Institute of Oncology (ICO) and is now head of Hematopoietic Transplantation Oncohematology and the Hospital Puerta Iron, “we have managed to identify this feature 157 units, representing 0.6% of the Spanish population.”

That elite cords, and a solution for those offers that require a transplant for hematologic problem, an option to cure HIV to those who, besides being HIV positive, develop a cancer of the blood. “This is not a therapy for any patient with HIV. Only is intended for those who in addition to the virus develop leukemia, lymphoma, etc,” explains Matesanz.

With antiretroviral treatments available, a general therapy umbilical cord blood is not viable. First, because there are few units worldwide who carry the mutation makes the infallible cells against the virus, and secondly because this type of transplantation is not without risks. According to overall figures in Europe the expected mortality from complications of transplant is between 20% and 25%.

This is only acceptable in patients with very serious blood disease , which if not treat them in a short time, to death. Furthermore, according a study of over 100 patients, those with HIV who have undergone a bone marrow transplant have a higher risk of complications than for people without HIV. Therefore, there is a therapy for all HIV-positive people but to very specific cases, “says Duarte.

For all this is important to test this treatment in the context of a clinical trial, said the hematologist, because the protocols are the same in the various hospitals where it is made, monitoring will be equal and once the results are available, allow you to learn from experience experts worldwide.

The trial, which will involve the Puerta de Hierro Hospital, the Gregorio Maranon (both in Madrid), the Catalan Institute of Oncology (ICO), and the Hospital La Fe de Valencia, along with cord blood banks and the ONT, It aims to recruit patients in two to five years. “The first patient is already in. It is discussed in Madrid not until later this year or early next, because previously required to go through a chemotherapy [to kill tumor cells in their bone] and a conditioner that take several weeks. This is a person with a type of lymphoma and HIV we do not want to give more information, “said Duarte, who is the principal investigator of this trial.

157 cords mutation CCR5 Delta 3 identified in Spain continue to be part of the international registration, REDMO, but is an advisory committee (formed by doctors in hospitals, banks cord and ONT) through a protocol established to decide what to do with them if they are claimed by researchers from another country well for an HIV-positive patient with a hematologic or problem for a person without carrying HIV, consistent with the cord and requires a medical problem as a leukemia or lymphoma.

The trial, scheduled for three years and with a budget of 150,000 euros provided by the Mutua Madrileña Foundation, is within an experimental framework. “It is looking for a high amount of healing but the proof of the hypothesis that this transplant can make HIV disappear. The implications are qualitative rather than quantitative.”

The same view Josep Maria Gatell, co-director of the XV European AIDS Conference being held these days in Barcelona, is shown “is interesting in terms of research, no practical way for the current treatment of patients with HIV.”



New HIV cases almost triple for first quarter 2016

Participants at the Ending Mother-to-Child Transmission of HIV workshop spent the day ensuring they are practising the same techniques. (Photo courtesy the Health Ministry)

Participants at the Ending Mother-to-Child Transmission of HIV workshop spent the day ensuring they are practising the same techniques. (Photo courtesy the Health Ministry)

New HIV cases have almost tripled in Antigua & Barbuda for the first quarter of 2016, with 21 new patients testing positive for the virus, over  eight for the same period last year.

The statistics collected from the Mount St John’s Medical Centre and submitted to the AIDS Secretariat indicate the cases were confirmed between January 1 and March 3.

AIDS Programme Manager Delcora Williams said the statistics suggest the messages of abstinence, protection and monogamy is not being heeded.

“It is still alarming for us, and that means that somehow or the other they are not (adhering) to the messages that have been going out in how to prevent themselves from testing positive with HIV and AIDS,” Williams said in an interview.

However, she said, the secretariat only received the statistics yesterday, and she has not had an opportunity to properly assess the findings.

Speaking from yesterday’s meeting with mid-wives to look at ways of ensuring all stakeholders are on the same path to eliminating the mother to transmission of HIV, Williams said the intention is to continue targeting those who are at risk for contracting the virus.

Williams added that HIV prevention messages and access to HIV testing, counselling and treatment is available to everyone.

Asked if the AIDS Secretariat feels defeated in its attempts to decrease the number of new infections, Williams said no.

“The numbers could show an increase in the number of persons accessing an HIV test, which is a good thing, because now they can actually access care and treatment to live a healthy and reproductive life,” she told OBSERVER.

Of the new infections, there are three pregnant women infected with the virus.

(More in the Daily Observer)