The value of repetition

One of the most important things I heard while in college came from one of my favorite biology professors. It happened in an early intro class half-filled with bio majors, half-filled with people looking for a course with a lab. He was covering the basics of science itself, speaking to the value of repetition:

Science is all about reproducibility. If you can’t reproduce your data, it’s all a load of horseshit.

That isn’t to say a person can automatically discredit some new piece of research simply because it’s new and has therefore not yet been reproduced. What it means is that when scientists do attempt to reproduce previously found results, they need to be successful in order for the results to be accepted. An unfortunate side effect of human nature means that we don’t see negative results published as often as we should – unless, of course, they disprove what someone else has already published – but these results do still happen every single day. That’s just science.

This all brings me to a recent piece of news:

Scientists have managed to repeat one of the biggest medical breakthroughs of the last few years.

Almost exactly one year ago, Johns Hopkins researchers made national headlines when they announced that they’ve vanquished the AIDS-causing virus from a child born to an HIV-positive mother in Mississippi. They began antiretroival treatment before the baby was 30 hours old. She’s now 3.5 years old and still virus-free, even without treatment in the last two years. Researchers have puzzled over how it happened, and many remain skeptical. The child was only the second person ever to be “cured” of HIV; the first was an adult through a stem-cell transplant. Since it’s difficult to prove that the body has been completely cleared of HIV, Nature explains, being “functionally cured” means the virus is effectively controlled and the immune system stays healthy without treatment.

Just yesterday, doctors announced that they have cleared the virus from a second baby infected with HIV. This girl was born in Los Angeles last April to a mother with advanced AIDS who had not been taking her medication. With aggressive treatment beginning just four hours after her birth, the virus was undetectable within 11 days, the New York Times reports.

A sample size of 2 does not scientific fact make (though there are upwards of 8 other unconfirmed cases around the world), but it cannot be understated how much this bolsters the legitimacy of attacking HIV in infants this way. It could turn out that the virus is still living somewhere in the bodies of these children – adults who have been functionally cured have had the virus return shortly after certain surgeries such as bone marrow transplants – so this remains a game of wait-and-see. However, if this proves to be an effect method for curing HIV, then not only will there be immediate benefits to HIV-positive newborns, but some insight may be spread into how we can better detect the hidden HIV in adults patients who are functionally cured.

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Cell type, HIV transmission, and circumcision

This is taken from a paper I did in a capstone course for my undergrad studies. I happened to come across it recently and I thought it would be interesting to post here.

Cell type matters in HIV infection. Transmission is higher amongst homosexual men who engage in rectal intercourse where the cells there are different as compared to cells on the genitals. Thin columnar epithelium that lines the rectum is assumed to facilitate the transmission of HIV; thick stratified squamous epithelium lines the vaginal and oral mucosa and appears to transfer protective properties against HIV acquisition. Video image analysis has shown that the latter is nine to twelve times thicker than the former [2]. In addition, intercourse causes more severe trauma to the former, thus allowing viruses better access not only beyond the mucosa, but, for the rectum, a richer bed of blood vessels.

Keratinized cells are a known protector against HIV. Like the body surface of a scorpion, they prevent attachment and entry of foreign agents. In both circumcised and uncircumcised men a keratinized, stratified squamous epithelium covers the penile shaft and outer surface of the foreskin. This acts as a protective barrier against HIV. However, the inner mucosal surface of the foreskin is not keratinized [1]. Furthermore, this surface is rich with Langerhans’ cells, cells which have been associated with higher rates of HIV infection due to their expression of CD4 glycoprotein which bind directly to gpl20 on the surface of HIV [2]. Since the foreskin is pulled back during intercourse, the surface area containing Langerhans’ cells is increased, thus giving HIV more opportunities to infect a host.

Observational studies back up the hypothesis that circumcised men are less susceptible to HIV infection. A 1989 study found uncircumcised men to be over 8 times more likely to be infected versus circumcised men [3]. A 1996 Ugandan study compared HIV infection between religious groups. Once abstinence, alcohol consumption, and number of sexual partners were accounted for, it was found that the likely reason Muslim men had lower rates of HIV infection versus other religious groups was due to higher rates of circumcision [4]. A 1999 study found that circumcision amongst rural Ugandans provided significant protection against HIV infection, but only if it occurred prior to the age of 20 [5].

Another 1999 study looked interviewed close to 200 uncircumcised men and close to 200 circumcised men. Amongst non-Muslims, circumcised men were found to have a greater risk profile than uncircumcised men. That is, those who were circumcised engaged in riskier behavior and had more partners on average. However, particular sex practices and hygienic behaviors were not notably different, and so they did not account for the higher risk of HIV infection amongst uncircumcised men [6].

~~~

The paper continues with a discussion germane to the requirements for the particular assignment, so I won’t reproduce any more here. However, it should be noted that the science on the matter does continue into more recent years, resulting in most major health organizations (WHO, UNAIDS, etc) supporting male circumcision in developing nations as one valuable method in the fight against HIV/AIDS.

Citations:

1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1127372/?tool=pubmed

2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1383923/pdf/immunology00069-0131.pdf

3. http://www.sciencedirect.com/science/article/pii/S0140673689905898
4. Kiwanuka, Noah; Gray R., Sewankambo N.K., Serwadda D., Wawer M., Li C. (7–12 July 1996). “International Conference AIDS.”. Religion, behaviours, and circumcision as determinants of HIV dynamics in rural Uganda. Vancouver, British Columbia. Retrieved 2008-09-25

5. Kelly R, Kiwanuka N, Wawer MJ, et al (February 1999). “Age of male circumcision and risk of prevalent HIV infection in rural Uganda”. AIDS 13 (3): 399–405.

6. Bailey RC, Neema S, Othieno R (November 1999). “Sexual behaviors and other HIV risk factors in circumcised and uncircumcised men in Uganda”. J Acquir Immune Defic Syndr. 22 (3): 294–301.

Breakthrough study of 2011 and the tools for curbing HIV

The journal Science has named the HPTN 052 clinical trial, a study looking at the ability of antiretroviral medication to prevent HIV transmission, as the 2011 Breakthrough of the Year:

Led by study chair Myron Cohen, M.D., director of the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill, HPTN 052 began in 2005 and enrolled 1,763 heterosexual couples in Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, the United States and Zimbabwe. Each couple included one partner with HIV infection. The investigators randomly assigned each couple to either one of two study groups. In the first group, the HIV-infected partner immediately began taking a combination of three antiretroviral drugs. The participants infected with HIV were extensively counseled on the need to consistently take the medications as directed. Outstanding compliance resulted in the nearly complete suppression of HIV in the blood (viral load) of the treated study participants in group one.

In the second group (the deferred group), the HIV-infected partners began antiretroviral therapy when their CD4+ T-cell levels—a key measure of immune system health—fell below 250 cells per cubic millimeter or an AIDS-related event occurred. The HIV-infected participants also were counseled on the need to strictly adhere to the treatment regimen.

It was found that those taking the medication while their immune system was still highly healthy were 96% less likely to transmit HIV to their partners. This result was so stupendous that, even though the trial is still ongoing, an early public release of the findings was ordered. It is important that people know how to best combat transmission. That spread of information is what is needed to prevent the spread of infection:

“On its own, treatment as prevention is not going to solve the global HIV/AIDS problem,” said Dr. Fauci. “Yet when used in combination with other HIV prevention methods—such as knowing one’s HIV status through routine testing, proper and consistent condom use, behavioral modification, needle and syringe exchange programs for injection drug users, voluntary, medically supervised adult male circumcision, preventing mother-to-child transmission, and, under some circumstances, antiretroviral use among HIV-negative individuals—we now have a remarkable collection of public health tools that can make a significant impact on the HIV/AIDS pandemic.”

“Scale-up of these proven prevention methods combined with continued research toward a preventive HIV vaccine and female-controlled HIV prevention tools places us on a path to achieving something previously unimaginable: an AIDS-free generation,” Dr. Fauci added.

I added the emphasis to the above excerpt because I am reminded of the utter irresponsibility displayed by PZ Myers on this issue in the past. While I still very much like what the guy has to say on many subjects, he was dead wrong to dismiss any one of the listed tools. In this case, he specifically dismissed the notion that there is any evidence whatsoever that circumcision has any impact on HIV infection rates. As I’ve documented elsewhere, he is absolutely wrong on the facts. That evidence does exist and it is important that it is known. That is why Dr. Fauci noted it amongst all the other ways we must use to combat this disease. HIV/AIDS is one of the most serious epidemics facing the developing world today; no one should be proud to exacerbate the problem, especially when the motivation is ideological in nature – we’re talking about god damned human lives here.

Nope, wrong

PZ has a post about circumcision where he goes through the arguments in favor of the procedure based upon a video. (I haven’t watched the video nor will I because from what I gather it’s just a hack piece which does not focus on circumcision as performed by medical professionals in a medical setting.) Two of the arguments he quotes are apparently from a single guy and should just be boiled down to one: ’cause religion says to do it. Another one appeals to tradition, which is also a bogus argument, but then PZ has this last one:

The health benefits. Total bullshit. As one of the speakers in the movie explains, there have been progressive excuses: from it prevents masturbation to it prevents cancer to it prevents AIDS. The benefits all vanish with further studies and are all promoted by pro-circumcision organizations. It doesn’t even make sense: let’s not pretend people have been hacking at penises for millennia because there was a clinical study. Hey, let’s chop off our pinkie toes and then go looking for medical correlations!

PZ is wrong. The evidence has not suddenly vanished that circumcision prevents the transmission of HIV in high risk groups. Furthermore, it is blatantly invalid to dismiss this evidence because it may be used by pro-circumcision organizations, whatever those are.

If PZ wants to argue that circumcision holds little to no health benefits in places like the United States and other low risk nations for certain diseases, he can do that and be perfectly accurate. But if he wants to argue that circumcision has zero benefits in all circumstances, then he is in denial of the preliminary evidence.

HIV: It’s still all about shape

The last time I wrote about HIV, I made the point that biology is all about shape; keep that idea in mind and a lot of things will suddenly start making a lot of sense. In that instance, I was writing about antibodies that were able to nearly universally attack HIV based upon one particular location on the virus which did not change shape. In this post I want to talk about a new study concerning protein differences.

To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and analyzed the effects of individual amino acids within the classical HLA proteins

HIV controllers are just what you probably think they are: they are people whose bodies are able to control the impact of HIV. They maintain healthy levels of helper T Cells. Progressors, on the other hand, are people who follow the expected course after they contract HIV. In this study, a large group of controllers were taken and had their genomes compared to progressor genomes. Researchers found more than 300 (313, to be exact) SNPs on the chromosome 6 that separated these two groups.

This is a pretty specific area with a small amount of difference. In fact, on the HLA-B protein, a difference of just 5 amino acids makes all the difference in a single groove. It appears as though this is one of the most important differences between controllers and progressors, constituting a significant region which enables the immune system to control and limit the proliferation of HIV. The amino acid sequence changes the shape of the groove in controllers as compared to progressors. This change protects the controller against HIV and its deadly consequences.

Precisely how this change in shape keeps HIV from turning into AIDS has not yet been made clear, but it is very promising. Given the current state of research, I’m willing to predict we’ll see a cure for HIV before we see a cure for cancer.

The fight against HIV

In biology, it’s all about shape. Enzymes, proteins, antibodies, blood vessels, cells, everything. They work best when they fit best or match in shape best. That’s why two new HIV antibodies have such potential.

Scientists report they’ve discovered possible new weapons in the war against HIV: antibody “soldiers” in the immune system that might prevent the AIDS virus from invading human cells.

According to the researchers, these newly found antibodies connect with and neutralize more than 90 percent of a group of HIV-1 strains, involving all major genetic subtypes of the virus.

That breadth of activity could potentially move research closer toward development of an HIV vaccine, although that goal still remains years away, at best, experts say.

HIV molecules evolve at a rapid pace. This makes it nearly impossible to produce antibodies at rates and in quantities sufficient to combat the disease on a long-term basis. However, there is one part of an HIV virus which remains virtually unchanged. This is important because it means there is a site with a consistent shape on the virus. That’s where these antibodies are being directed, thus offering a potentially powerful new tool in the fight against HIV.