Debunking myths on genetics and DNA

Sunday, April 28, 2013

And finally... spring! (And a plea for the bees)

A few days ago I complained about spring being late this year, so I thought I'd follow up with an update. :-)

Yup. I think it's here now. :-)

Sadly, I didn't see as many bees as I'd wished I did, and I fear it may not be a coincidence. Last year, my friend and colleague Bette Korber wrote a beautiful post on her blog and how we should all do our part to preserve these precious tireless workers:
"Bees are in trouble, and wild bees are disappearing. It's possibly caused by a lethal combination of virus and fungus, thought better able to take hold when bees are stressed and weakened. And stress them we do, with our pesticides, agricultural monoculture, and habitat loss. We can help the bees in a simple joyful way by planting native wildflowers in our gardens, different kinds, in abundance. Pesticide-free bee habitat restoration, one yard at a time. Spring is coming – get busy."

Friday, April 26, 2013

North Korea and the USA can indeed unite: in the battle against TB.

Tuberculosis (TB) is an infectious disease caused by a bacterium. It spreads through cough or sneeze from subjects with an active infection. While in most cases the disease is asymptomatic, a minority of latent infections does become active (i.e. the subject develops symptoms), and when it does, if left untreated, the disease can be deadly.

According to the CDC one third of the world's population are infected with TB, and while in the US the incidence of the disease has been declining over time, it is still a huge problem in parts of the world like Asia and sub-saharan Africa. While normally the chance of a latent TB infection becoming active is one in ten, the chance is much higher for HIV-positive subjects because their immune system is already debilitated by the HIV virus. As the CDC reports:
"TB is a leading killer of people living with HIV (PLHIV)."
A regimen of 3-4 drugs has been available for years to keep latent infections from becoming active. Sadly, TB infections from multidrug resistant strains (MDR) have been steadily increasing, setting back the progress made in the past decades.

From the World Health Organization:
"Drug resistance arises due to improper use of antibiotics in chemotherapy of drug-susceptible TB patients. This improper use is a result of a number of actions including, administration of improper treatment regimens and failure to ensure that patients complete the whole course of treatment. Essentially, drug resistance arises in areas with weak TB control programmes. A patient who develops active disease with a drug-resistant TB strain can transmit this form of TB to other individuals."
One of the countries plagued by MDR TB strains is North Korea, where the incidence of TB has dramatically advanced over the past years, reaching one of the highest incidences outside sub-saharan Africa.

In this week's issue, Science Magazine describes a joint effort between two countries that, according to the recent news, you'd least expect to pair up: North Korea and the United States. In collaboration with Stanford University, the Korean ministry of Public Health opened in 2010 a National Tuberculosis Reference Laboratory (NTRL).
"NTRL researchers can now diagnose TB cases that are resistant to first-line drug combinations, making it possible to spot patients who need more aggressive therapy. And the lab will soon add capacity to screen for extensively drug-resistant TB, known as XDR—the worst strains, some of which are close to impossible to treat."
The Science report covers stories of hope in the midst of desperation. It points to pressing issues the North Korean government has to address within its borders, and focusing on them would seem a more reasonable and logical strategy than polishing nuclear arsenals. Let's hope that the roots of this collaboration grow deeper than any political discrepancies. Let's hope that the battle against a common enemy (TB) will put an end to the empty, unfounded threats and pave the way to a broader, more civilized way of communication between countries.

Stone, R. (2013). Public Enemy Number One Science, 340 (6131), 422-425 DOI: 10.1126/science.340.6131.422

Thursday, April 18, 2013

Can we functionally cure HIV?

Last March, Dr. Deborah Persaud, from the John's Hopkins Children Center, presented a stunning finding at the conference CROI, receiving great resonance across several newscasts: Persaud reported the first case of infant functionally cured of HIV. You can watch Persaud's presentation by downloading the podcast here, it's the seventh talk of the session "Is there hope for HIV eradication?"

Up until this finding, the only living person cured from HIV was the Berlin Patient, who was cured after receiving gene therapy for his underlying leukemia condition. Despite this one successful case, gene therapy is not a feasible way to cure HIV.

What does it mean to be functionally cured?

Once in the host, the HIV virus establishes reservoirs of latent virus: these are viral particles that stay dormant in cells and tissues and have the ability to quickly rebound in the event that therapy is discontinued. That's why it's so important for an HIV infected person to never discontinue the drug regimen, as the rebound virus may be drug resistant. HIV is so efficient at escaping the immune system and therapy that standard practice these days is a lifetime of not just one, but a cocktail of 3-4 antiretroviral drugs.

To be functionally cured means that drugs are no longer needed to keep the viral load (amount of virus in the blood) in check (close or below detection), something that until now had only been achieved by an extremely low number of HIV-positive individuals (less than 1% of infected adults), the so-called "elite controllers." In all other subjects, the reservoirs are never completely weakened and they enable the virus to bounce back once therapy is interrupted.

So, what was different with this child?

The mother went into labor without prenatal care. An HIV test was done during labor and normally, when the test is positive, antiretroviral drugs are administered. This is highly effective in preventing mother-to-infant infections as the only moment when the infant is exposed to the mother's blood is at birth. The antiretroviral drugs keep the viral load so low that the risk of infection becomes very small (around 2%). Unfortunately, in this particular case, the birth was so precipitous that there was no time to administer such drugs. The newborn baby was immediately tested for HIV.

This is my understanding of what was unique about this case: normally a first test is done and, if positive, a second follow-up test is performed and prophylaxis is started once the infection is confirmed. In this case, though, two independent tests were done at the same time and, since both confirmed the HIV infection, prophylactic treatment was started very early, when the baby was 31 hours of age. Also, unique to this case was the fact that a regimen of three drugs, of which one at the therapeutic level instead of the standard prophylactic dosage, was administered during the first week of life. After that, the baby was switched to a standard treatment of antiretroviral drugs (again, my understanding from the CROI talk).

Such regimen successfully brought the child's viral load down to undetectable, which is normal in these cases. Despite this, because of HIV's ability to establish reservoirs, antiretroviral therapy is never discontinued. Like I said before, it is a lifetime therapy. So called "drug holidays" result in more virulent and drug-resistant HIV quasispecies. However, this child was lost to follow-up at 18 months of age and was once again seen by the doctors at 25 months of age, when the caregiver reported discontinuing the therapy. Immediate testing was done to assess the child's viral loads. The child was tested not once, but many times. Genetic testing was also done to make sure it was the same child treated before. The doctors must have been in disbelief as for the first time they were seeing the incredible: after 5 months since discontinuing antiretroviral therapy, the viral load in this child was still undetectable.

What are the consequences? As Dr. Persaud repeated many times during her talk, this is a single case and a proof of concept. We need more cases to be able to generalize (as statistics teach us). However, it points to something that indeed needs to be explored: how early in the infection can we (and should we) intervene? In a 2012 paper [1], Persaud and colleagues studied the dynamics of the latent HIV reservoirs in 17 infants on very early antiretroviral drug therapy (median start age 8 weeks) and found that the size of the reservoirs at age 2 was associated to how early undetectable viral loads were achieved during therapy. The earlier viral load was suppressed through therapy, the smaller the HIV reservoir at age 2. Is there a point, very early into the infection, when the virus is vulnerable and all reservoirs can be not just reduced in size, but actually completely eradicated through potent and prompt intervention?

In rare cases, HIV-infected patients are able to spontaneously maintain their viral load at a very low level without the need of drugs, the so called "elite controllers." What if, when administered early enough, antiretroviral drugs could transfer this type of spontaneous protection to every HIV-infected person?

Shortly after the CROI conference, a French study published in PLoS Pathogens [2] reported 14 cases of what they call "post-treatment controllers," in other words, people whose viral loads remained very low after interrupting treatment. With the exception of mother-to-infant transmissions at birth, it's extremely hard to catch this virus early because people often don't realize they've been infected: symptoms, if any, appear 3-4 weeks later and are often mistaken for a common cold. Twelve of the 14 cases reported in [2] had symptoms that prompted early intervention and start of therapy during the primary infection.
"Post-treatment controllers (PTCs) had a more severe primary infection with higher viral loads and were frequently symptomatic, which may have prompted the early treatment in some cases [. . .] Therefore, our results strongly suggest that the infection control in the PTCs was not achieved spontaneously and was favored by the early onset of therapy. Because the interruption of long-term antiretroviral therapy initiated early during primary infection is not recommended, only a very small proportion (~2%) of the patients in the French Hospital Database on HIV Infection experienced such an interruption, which may explain the rarity of PTCs worldwide [2]."

[1] Persaud, D., Palumbo, P., Ziemniak, C., Hughes, M., Alvero, C., Luzuriaga, K., Yogev, R., Capparelli, E., & Chadwick, E. (2012). Dynamics of the resting CD4+ T-cell latent HIV reservoir in infants initiating HAART less than 6 months of age AIDS, 26 (12), 1483-1490 DOI: 10.1097/QAD.0b013e3283553638

[2] Sáez-Cirión, A., Bacchus, C., Hocqueloux, L., Avettand-Fenoel, V., Girault, I., Lecuroux, C., Potard, V., Versmisse, P., Melard, A., Prazuck, T., Descours, B., Guergnon, J., Viard, J., Boufassa, F., Lambotte, O., Goujard, C., Meyer, L., Costagliola, D., Venet, A., Pancino, G., Autran, B., Rouzioux, C., & , . (2013). Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study PLoS Pathogens, 9 (3) DOI: 10.1371/journal.ppat.1003211

Tuesday, April 16, 2013

Waiting for spring...

No sign of spring here in Northern New Mexico, so I brought in some flowers from Southern California. I didn't have the macro with me, these are all shot at 200mm, two stops down to make the background dark.