Saturday, March 23, 2013

HIV's Penicillin Moment?

In 1979, an immunodeficient 5 year old girl died in a New Jersey hospital.  Baffled by their inability to administer any successful treatments from 6 months of age, the doctors had nothing left to do but perform an autopsy and carefully record the results.  Four years later, retrospective consideration of the child’s medical history and the mother’s lifestyle appeared to be consistent with the epidemic that had emerged in the meantime.  This may have been the first recorded fatality of a person who contracted HIV via birth.  Now, 34 years later, it appears that there may be a hope for newborn infants similarly afflicted.

On March 3 this year, an announcement was made at the 20th Conference on Retroviruses and Opportunistic Infections: A two year old child appeared to be functionally cured of AIDS.  To elaborate more plainly, a woman with HIV who never received treatments during her pregnancy gave birth to an infant who was consequently HIV infected.  Treatments began directly with the infant 30 hours after birth – which is the moment when transmission of HIV from mother to child often occurs.  The decision was made to treat with a more aggressive combination of drugs than infants are usually given.  However, the series of treatments was halted prematurely and unexpectedly by the mother, who abruptly left town much to the frustration of the doctors.  This aberration in the treatment procedure proved to be an unexpected breakthrough.  When the mother finally returned with her baby, a relapse of HIV in the absence of treatment was expected.  Instead, the virus was physically undetectable – only traces of HIV genes could be detected.  This observation may have been a penicillin moment – if the mom had continued the prescribed treatment process as usual, the doctors may have not realized that a functional cure could be possible rather than the expected decades of treatments intended to keep the virus at bay.

In first-world nations, in the year 2013, newborns with HIV are rare.  The diagnosis is often made with the mother during pregnancy and preventative treatments can be effectively administered before birth.  But diagnosis doesn’t happen this way in less developed regions where HIV has a more ubiquitous presence and health clinics do not.  This is where this discovery matters the most.  The details of exactly how the cured 2 year old was treated are not yet available, but will likely be published soon.  From there, attempts will be made to reproduce it using the same combination of drugs, at the same point in time, etc.  Time will provide data, data will provide conclusions, and conclusions will provide parameters for future experiments that can refine the practice.  We will probably hear about this again.  Until then, here is a look at three common classes of HIV drugs that are often used in combination and how they work.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
All viruses are essentially genes packaged inside a ball of proteins.  In the case of the HIV virus, the genes are in the form of RNA.  If DNA is like a zipper, then RNA is like one side of that zipper.  In order for the zipper to be useful, you obviously need both sides.  And so the HIV virus also has an enzyme packaged inside of it along with its genes.  That enzyme is called reverse transcriptase, and its job is to convert the virus RNA into DNA after infection by completing the other half of the ‘zipper’ with compounds called nucleotides (the modified form of nucleosides).  Nucleotides are the elemental components of DNA and RNA, and they are abundantly found within any cell.  Once the DNA has been produced, the virus blueprints are copied en masse within the infected cell and the production of millions of new HIV viruses begins.  NRTIs are compounds that are similar enough to natural nucleotides to be used by the reverse transcriptase enzyme, but different enough to prevent the production of useful DNA (Figure 1).  These drugs inhibit the replication of HIV genes at the point of the reverse transcriptase enzyme function.

Non-nucleoside Reverse Transriptase Inhibitors (NNRTIs)
As with NRTIs, the target of NNRTIs is also the reverse transcriptase enzyme.  The difference is in how they block the function of the enzyme.  As implied by the name, these compounds are not false surrogates for nucleosides like NRTIs.  These compounds instead bind directly to the reverse transcriptase enzyme near the active site, which is to say where the enzyme chemistry happens.  Once bound to the enzyme, the chemistry is inhibited and the entire function is blocked (Figure 1).  The end result is that HIV genes cannot be replicated.

Figure 1. NRTI and NNRTI drugs interfere with the function of the HIV reverse transcriptase enzyme in two different ways.
HIV Protease Inhibitors
Further on down the line of HIV infection, another enzyme called HIV protease comes into play.  After the RNA of HIV is converted into DNA by the reverse transcriptase enzyme, the cell’s natural enzymes use the HIV DNA as a blueprint for producing a long ‘poly-protein’.  ‘Poly’, because it is a series of distinct HIV proteins (or enzymes) that do not become functional until they are severed from one another.  This is the job of the HIV protease enzyme – it cuts the ‘poly-protein’ up into its constituent proteins, which thereafter assemble to become a slew of newly formed viruses ready to spread their infection.  HIV protease inhibitors are compounds that work in the same way as the non-nucleoside reverse transcriptase inhibitors.  They bind to the HIV protease enzyme where the chemistry takes place, rendering the protease enzyme without function (Figure 2).  The result is that new virus particles (Figure 3) are never assembled because their individual components are all tied up together in a useless string of proteins.

Figure 2. HIV 'poly-proteins' are cut into constituent proteins by HIV protease.  Protease inhibitor drugs block this process.
A variety of other drugs are also used to suppress HIV by other mechanisms.  As we know, this is difficult to do and the virus tends to find ways around it.  And so we have learned that combinations of drugs are usually necessary to plug all the holes.  What we may learn from the case of this HIV-free 2 year old is that it is apparently much easier to plug those holes immediately after the infection takes place.

Figure 3. Simplified anatomy of HIV, assembled from the products of cleaved 'poly-proteins'.