Tag Archives: AIDS

COVID19 will be with us for a long time

Feast your eyes on this video of hundreds of maskless  people partying in the streets of Queens NYC 18 July.  It has to be seen to be believed.  Unfortunately, you’ll have to sit through some ads, but it’s worth the wait.

https://nypost.com/2020/07/18/video-shows-people-in-queens-flooding-streets-without-masks/.   Reports of COVID19 parties have been critized as being urban legends, with no specifics as to time or place or people being given.  Here’s Queens NYC one night — It may not be a COVID19 party in name, but it is in fact.

Much has been made of the spread of the pandemic in the South, notably Florida and Texas.  It has been laid to premature lifting of restrictions with Trump leading the charge.

Well New York City hasn’t, and the people shown partying are unlikely to take the President’s words as holy writ.   Two questions arise

l. Are these people insane or rational?

2. Is what they are doing likely to cause a similar surge in cases?

It’s time to deal with the world as it is, rather than the world as we’d like to be (enter the world of docs confronting any new disease — think Everett Koop and the early days of AIDS).

Forgetting the second question for a time, viewed from their perspective, their behavior is rational — which is not to say I condone it.

Here is data from Florida through yesterday (from their department of health) — http://ww11.doh.state.fl.us/comm/_partners/covid19_report_archive/state_reports_latest.pdf

Age  Range     Number of Cases  Number of Hospitalizations Deaths

14 – 24              54,815                                503                                    12

25 – 34             70,030                              1,315                                    34

This is age range of most of folks in the video

So the risk of death for 14 – 24 is .02% or under 1/1,000 — ditto for the 25 – 34 age group.   And that’s if the revelers actually acquire the virus.  So from a selfish perspective, their behavior is rational.

Is their behavior harmful to society at large?  You’d think so.

Well maybe not.  Here’s some work from 3 months ago.

https://www.nytimes.com/2020/07/09/nyregion/nyc-coronavirus-antibodies.html–https://www.cnbc.com/2020/04/23/new-york-antibody-study-estimates-13point9percent-of-residents-have-had-the-coronavirus-cuomo-says.html.

The State randomly tested 3,000 people at grocery stores and shopping locations across 19 counties in 40 localities to see if they had the antibodies to fight the coronavirus, indicating they have had the virus and recovered from it. With more than 19.4 million people residents, according to U.S. Census data, the preliminary results imply that at least 2.7 million New Yorkers have been infected with Covid-19.

With more than 19.4 million residents, according to U.S. Census data, the preliminary results indicate that at least 2.7 million New Yorkers have been infected with Covid-19.  They weren’t all hospitalized.

Here’s some work this month from Queens — https://www.nytimes.com/2020/07/09/nyregion/nyc-coronavirus-antibodies.html

At a clinic in Corona, a working-class neighborhood in Queens, more than 68 percent of people tested positive for antibodies to the new coronavirus. At another clinic in Jackson Heights, Queens, that number was 56 percent. But at a clinic in Cobble Hill, a mostly white and wealthy neighborhood in Brooklyn, only 13 percent of people tested positive for antibodies.

So the disease has already to spread to half the population in some neighborhoods in Queens. If even 10% of them were sick that would have been 140,000 hospitalizations.  It didn’t happen.

So some parts of Queens may be close to herd immunity.

 

When is the AIDs virus really dead?

When should we regard an AIDs virus lurking in the genome of a white blood cell as dead (or at least harmless).  Such proviruses are called defective, and commonly formed, because the process of reverse transcription (of RNA into DNA) is quite error prone.

Most would say an HIV1 provirus in the genome is dead  if can’t reproduce and get outside the cell carrying it.  Not so fast says Proc. Natl. Acad. Sci. vol. 117 pp. 3704 – 3710 ’20.  They show that such defective proviruses can be transcribed into RNA and these RNAs can produce proteins (when translated).

There is some evidence for this as the Nef protein of HIV1 can be detected in cells and plasma even when HAART (Highly Active Anti Retroviral Therapy) has knocked plasma viremia down to a level of under   50 copies/milliLiter.

How could this cause trouble ? Easy.  This would be chronically stimulating the immune system and in effect wearing it out.

This is very new stuff, and the fate of white cells containing replication incompetent proviruses which are still producing proteins isn’t known (but I’m sure this isn’t far off).

What to do about the Wuhan flu

This was published 27 Jan ’20.  Nothing has been altered (other than this).

What to do about the Wuhan flu?  The short answer is to lay in a month or two of dried food and drink, and have plenty of bottled water around.

The long answer depends on whether the new corona virus (called 2019-nCOV) becomes a pandemic and if the (symptomatic) case fatality rate continues at 3.5% (based on 80 deaths in 2,800 cases as of yesterday).

With a son, Chinese daughter in law and two grandchildren living in Hong Kong, I’ve followed the outbreak ever since hearing of it 1 January.

The best and most current source of info about the outbreak is the South China Morning Post — https://www.scmp.com.  It is in English and is not a government mouth piece.

Here’s the bad news

(1) As of a few days ago the virus had been found in 29/31 Chinese provinces.  This means that confining the virus to China is nearly impossible — how do you cut off a billion or so people from the rest of the world?

(2) Here’s more from today

  • Hong Kong University  faculty of medicine dean Gabriel Leung says research shows self-sustaining human-to-human transmission is already happening in all major mainland cities.   Here’s a link
  • https://www.scmp.com/news/hong-kong/health-environment/article/3047813/china-coronavirus-hong-kong-medical-experts-call
  •  Why is this significant?  You have to know how docs operate.  When I wanted information about some issue or disease, I’d call a doc whose opinion and background I respected.  It is likely that Leung made this statement after calling med school deans he personally knew in major mainland cities.

(3) There is no treatment, in the sense of stopping the virus in its tracks.  All we have is supportive care, oxygen rest, medication for fever, bronchodilators.  This is true for the vast majority of viruses.  Remember the joke that modern medical science can cure a cold in 14 days, but otherwise it takes two weeks.

(4) We know that you don’t have to be clinically ill to transmit the disease.  Screening new arrivals for fever is well and good but that won’t totally prevent spread.

(5) Some individuals are what is called ‘superspreaders’ — one individual infected 15 hospital personnel.

(6) I wouldn’t hope for a specific treatment any time soon — look how long it took to get any treatment for AIDS, despite the huge amount of resources devoted to it.

Here is some good news. It is quite possible that there are many more cases out there with people who were either asymptomatic or  just mildly ill.  The classic example is polio, in which for every case with paralysis there were 99 cases with mild GI illness or nothing at all.

This will need to wait until we can test people for antibodies to 2019-nCOV to find out how many people have had it.  This is probably at least a month away

Vaccines (if they can be made) are even more months away.  We’ll just have to hunker down and hope for the best.

Why lay in dried food ?– in a pandemic people will panic and clear out all food they can get their hands on.  There were pictures of empty bins in a Wuhan food market last week.

People are getting serious about it.  From Reuters -“U.S. President Donald Trump offered China whatever help it needed on Monday”.  It would be nice to have some of our people from the Center for Disease Control over there. Hopefully the Chinese won’t be too proud to accept the offer.

Addendum 28 Jan — apparently the US (in the form of the CDC) is begging China to let them help out — sad — why should they have to beg?  Apparently the first overture was 3 weeks ago ! ! ! ! — https://www.scmp.com/news/china/article/3047967/china-coronavirus-washington-asks-beijing-permission-send-health-team

Vaping — don’t do it until we know more

If you have kids, I’d advise them to stop vaping entirely until we know more. Here’s why — granted that there have been ‘only’ several hundred cases of ‘lung injury’ and a few deaths  in a 300+ million population, but in any new illness (AIDs, SARs, Legionnaire’s diseases) only the most severe cases are seen first.  

Addendum 19 Mar — from PNAS – When exposed to high temperatures in a vaping device , vitamin E acetate can release the very toxic gas ketene CH2 = C = O which has been shown (in animal studies, dosage not given) to damage the lungs and impair the central nervous system

This is exactly the way it was with AIDs, the first few cases seroconverting (showing they’d been infected with the virus) had their immune system collapse almost immediately after infection.  As time wore on, we’d see seroconverters who remained healthy for 1 year, 2 years, 5 years, because (for reasons we still don’t understand) they were resistant to the virus or had a stronger immune system.  But eventually they got sick and died as well.

So it is with vaping related lung illness.  How many more cases we’ll see in  more resistant individuals in the coming years isn’t known. Will we have a nation of 30 year olds crippled with chronic lung disease?  Unlike AIDS, SARS or Legionnaire’s disease where there is a single organism, there are thousands of vaping products, and what people are putting into the machines is completely unknown.  Perhaps it’s just one drug.  Perhaps it’s a contaminated drug.  Perhaps its the particular machine.  At this point we don’t know.  It’s just like the early days of the AIDs epidemic — plausible theories abound and reliable data is scarce.  I was practicing medicine when AIDs came out in the late 70s and it was scary as hell, not knowing what was causing it.  At least with this we’re pretty sure it’s the vaping, given the age distribution and the positive histories in all.

We have one excellent example of a genetic condition predisposing to lung disease — alpha1 antitrypsin deficiency predisposes to emphysema and chronic obstructive pulmonary disease  — https://en.wikipedia.org/wiki/Alpha1_antitrypsin.  It would be useful  to see how many of the vaping cases have this deficiency.

This just in – according to the Wall Street Journal 2 hours ago 31 October ’19 ago the CDC says there have been 1,888 cases with 37 deaths.  Hopefully this is NOT the tip of the iceberg  — but probably it is.

Addendum 1 Nov ’19 I wrote this to a niece who has an 18 year old daughter entering college.  She is a teacher in a standard American high school (not in the ghetto, not filthy rich).  If any one has boots on the ground she does. Her response:  “Yes it’s very common in high school” — scary.

Addendum 8 Nov ’19  — The following comment by Peter Shenkin is so important that it belongs in the body of the blog proper —

It’s pretty impressive, but these are early times in the investigation.

If you have kids, I’d advise them to stop vaping entirely until we know more. Here’s why — granted that there have been ‘only’ …

You wrote: “Vaping — don’t do it until we know more”

We now know more; source of the following quote is at the end.

“CDC Announces “Major Breakthrough” that I Recognized and Reported Two Months Ago; Outbreak is Almost Certainly Not Associated with Legal Nicotine Vapes
Minutes ago, the Centers for Disease Control and Prevention (CDC) announced what they called a “major breakthrough” in its investigation of the vaping-associated respiratory illness outbreak. They tested lung tissue samples from 29 case patients and all 29 (100%) were found to contain vitamin E acetate oil.

This finding does represent a major breakthrough for four reasons:

1. The vitamin E acetate oil was detected in the actual lung tissue of the case patients.

2. The vitamin E acetate oil was detected in every single one of the lung tissue samples from these 29 case patients.

3. The samples came from 10 different states, confirming that the outbreak seems to have a common cause, rather than geographic variation.

4. Three of the patients whose lung samples revealed vitamin E acetate had reported using only nicotine-containing products, thus confirming that there is significant under-reporting which may explain why about 11% of the patients do not report vaping THC.”

The above quote is from: https://tobaccoanalysis.blogspot.com/2019/11/cdc-announces-major-breakthrough-that-i.html.

Full disclosure: Michael Siegel, a Public Health and Epidemiology doc who writes this blog, is my first cousin once removed. In another blog entry, he lambasts the FDA for disallowing mint vaping liquids while giving cigarette companies a pass on mint-flavored cigarettes.

Bad news on the AIDs front

Bad news for those hoping for an AIDs cure. As you know, the active virus (HIV1) has a genome made of RNA. However, thanks to an enzyme it possesses called reverse transcriptase (which has led to Nobel prizes), it copies itself into DNA and integrates into the genome of lymphocytes. There it sits presumably doing nothing, but it’s always capable of activating and producing more infectious virus.

We seem to have fought the virus to a draw, using a cocktail of drugs which attack different aspects — HAART (Highly Active Antiretroviral Therapy). Success is usually considered being unable to detect viral RNA in the blood (see later). However blood cells are short-lived. What about the longer living lymphocytes found in the lymph nodes and spleen.

That’s what was studied in a current paper [ Nature vol. 530 pp. 5` – 45 ’16 ] but in only 3 people. All had no detectable virus in the blood (under 48 copies/milliLiter — an incredibly tiny amount — see later). What they did was to biopsy lymph nodes in the groin on study entry and at 3 and 6 months.

Then they sequenced the genomes of the lymphocytes from the nodes, to study the HIV1 DNA integrated into the genome. They found that the genome changed with time. This is very bad. Why?

Because it implies that, even though you the virus in the blood, the virus was not staying latent in the lymph nodes, but coming out of the lymphocytes and forming infectious virus which then mutated. Subsequently the mutated virus integrated into the genome of another lymphocyte. So even with what we consider excellent control, the virus is not purely latent. Drug resistance could arise from mutations (although they didn’t see it in this study).

Clearly, more people need to be studied this way (but serial biopsies? It will probably be done in prisoners, if such things are still done).

It’s worthwhile thinking about how incredibly selective and accurate our methods of analysis are. 48 copies of the viral RNA per milliLiter of blood is the lower limit of detection. Remember that water has a molecular weight of 18, so a liter of distilled water is 1000 grams / 18 grams = 55.5 Molar. A mole has 6 x 10^23 molecules. A milliLiter is 10^-3 liters. So 1 milliLiter of distilled water has 55 * 6 * 10^23 * 10^-3 == 3 * 10^22 molecules of water in it so the assay is finding 48 or more molecules of HIV1 RNA in the water haystack. Even figuring that the concentration of water in blood is 1/10 that of distilled water, this is still impressive.

Microexons, great new drugable targets

Some very serious new players in cellular and tissue molecular biology have just been found. They are very juicy drugable targets, not that targeting them will be easy. If you don’t know what introns, exons and alternate splicing are, it’s time to learn. Go to https://luysii.wordpress.com/2010/07/07/molecular-biology-survival-guide-for-chemists-i-dna-and-protein-coding-gene-structure/ read and follow the links forward. It should be all you need to comprehend the following.

The work came out at the tail end of 2014 [ Cell vol. 159 pp. 1488 – 1489, 1511 -1523 ’14 ]. Microexons are defined as exons containing 50 nucleotides or less (the paper says 3 – 27 nucleotides). They have been overlooked, partially because their short length makes them computationally difficult to find. Also few bothered to look for them as they were thought to be unfavorable for splicing because they were too short to contain exonic splicing enhancers. They are so short that it was thought that the splicing machinery (which is huge) couldn’t physically assemble at both the 3′ and 5′ splice sites. So much for theory, they’re out there.

What is a cell and tissue differentially regulated alternative splicing event? It’s the way a given mRNA can be spliced together one way in tissue/cell #1 and another in tissue/cell #2 producing different proteins in each. Exons subject to tissue specific alternative splicing are significantly UNDERrepresented in well folded domains in proteins. Instead they are found in regions of protein disorder more frequently than one would expect by chance. Typically these regions are on the protein surface. The paper found that the microexons code for short amino acid motifs which typically interact with other proteins and ligands. 3 – 27 nucleotides lets you only code for 1 – 9 amino acids.

One well known example of a short interaction motif is RGD (for Arginine Glycine Aspartic acid in the single letter amino acid code). The sequence is found in a family of surface proteins (the integrins) with at least 26 known members. These 3 amino acids are all that is needed for the interns to bind to a variety of extracellular molecules — collagen, fibrin, glycosaminoglycans, proteoglycans. So a 3 amino acid sequence on the surface of a protein can do quite a bit.

Among a set of analyzed neural specific exons (e. g. they were only spliced that way in the brain) found in known disordered regions of the parent protein, 1/3 promoted or disrupted interactions with partner proteins. So regulated exon splicing might specify tissue and cell type specific protein interaction networks (Translation: they might explain why tissues look different even when they express the same genes). The authors regard microExon inclusion/exclusion as protein surface microsurgery.

The paper has found HUNDREDS of evolutionarily highly conserved microexons from RNA-Seq data sets (http://en.wikipedia.org/wiki/RNA-Seq) in various species. Many of them impact neurogenesis and brain function. Regulation of microExons changes significantly during neuronal differentiation. Although microexons represent only 1% of the alternate splice sites seen, they constitute ‘up to’ 1/3 of all evolutionarily conserved neural-regulated alternative splicing between man and mouse.

The inclusion in the final transcript of most identified neural microExons is regulated by a brain specific factor nSR100 (neural specific SR related protein of 100 kiloDaltons)/SRRM4 which binds to intronic enhancer UGC motifs close to the 3′ splice sites, resulting in their inclusion. They are ‘enhanced’ by tissue specific RBFox proteins. nSR100 is reduced in Autism Spectrum DIsorder (really? all? some?). nSR100 is strongly coexpressed in the developing human brain in a gene network module M2 which is enriched for rare de novo ASD assciated mutations.

MicroExons are enriched for lengths which are multiples of 3 nucleotides (implying strong selection pressure to preserve reading frames). The microExons are also enriched in charged amino acids. Most microExons show high inclusion at late stages of neuronal differentiation in genes associated with axon and synapse function. A neural specific microExon in Protrudin/Zfyve27 increases its interaction with Vesicle Associated membrane protein associated Protein VAP) and to promote neurite outgrowth. A 6 nucleotide neural microExon in Apbb1/Fe65 promotes an interaction with Kat5/Tip60. Apbb1 is an adaptor protein functioning in neurite outgrowth.

So inclusion/exclusion of microExons can alter the interactions of proteins involved in neurogenesis. Misregulation of neural specific microexons has been found in autism spectrum disorder (what hasn’t? Pardon the cynicism).

Protein interaction domains haven’t been studied to nearly the extent they need to be, and we know far less about them than we should. All the large molecular machines of the cell (ribosome, mediator, spliceosome, mitochondrial respiratory chain) involve large numbers of proteins interacting with each other not by the covalent bonds beloved by organic chemists, but by much weaker forces (van der Waals,charge attraction, hydrophobic entropic forces etc. etc.).

Designing drugs to interfere (or promote) such interactions will be tricky, yet they should have profound effects on cellular and organismal physiology. Off target effects are almost certain to occur (particularly since we know so little about the partners of a given motif). Showing how potentially useful such a drug can be, a small molecule inhibitor of the interaction of the AIDs virus capsid protein with two cellular proteins (CPSF6, TNPO3) it must interact with to get into the nucleus has been developed. (Unfortunately I’ve lost the reference)

My cousin married a high school dropout a few years ago. Not to worry — he dropped out of high school to go to college, and has a PhD in Electrical Engineering from Berkeley and has worked at Bell labs. He was very interested in combining his math and modeling skills with my knowledge of neurology to make some models of CNS function. I demurred, as I thought we knew too little about the brain to come up with models (which I generally distrust anyway). The basic problem was that I felt we didn’t know all the players in the brain and how they fit together.

MicroExons show this in spades.

The incredible information economy of frameshifting

Her fox and dog ate our pet rat

H erf oxa ndd oga teo urp etr at

He rfo xan ddo gat eou rpe tra t

The last two lines make no sense at all, but (neglecting the spaces) they have identical letter sequences.

Here are similar sequences of nucleotides making up the genetic code as transcribed into RNA

ATG CAT TAG CCG TAA GCC GTA GGA

TGC ATT AGC CGT AAG CCG TAG GA.

GCA TTA GCC TAA GCC GTA GGA ..

Again, in our genome there are no spaces between the triplets. But all the triplets you see are meaningful in the sense that they each code for one of the twenty amino acids (except for TAA which says stop). ATG codes for methionine (the purists will note that all the T’s should be U). I’m too lazy to look the rest up, but the ribosome doesn’t care, and will happily translate all 3 sequences into the sequential amino acids of a protein.

Both sets of sequences have undergone (reading) frame shifts.

A previous post https://luysii.wordpress.com/2014/10/13/the-bach-fugue-of-the-genome/ marveled about how something too small even to be called a virus coded for a protein whose amino acids were read in two different frames.

Frameshifting is used by viruses to get more mileage out of their genomes. Why? There is only so much DNA you can pack into the protein coat (capsids) of a virus.

[ Proc. Natl. Acad. Sci. vol. 111 pp. 14675 – 14680 ’14 ] Usually DNA density in cell nuclei or bacteria is 5 – 10% of volume. However, in viral capsids it is 55% of volume. The pressure inside the viral capsid can reach ten atmospheres. Ejection is therefore rapid (60,000 basepairs/second).

The AIDS virus (HIV1) relies on frame shifting of its genome to produce viable virus. The genes for two important proteins (gag and pol) have 240 nucleotides (80 amino acids) in common. Frameshifting occurs to allow the 240 nucleotides to be read by the cell’s ribosomes in two different frames (not at once). Granted that there are 61 3 nucleotide combinations to code for only 20 amino acids, so some redundancy is built in, but the 80 amino acids coded by the two frames are usually quite different.

That the gag and pol proteins function at all is miraculous.

The phenomenon is turning out to be more widespread. [ Proc. Natl. Acad. Sci. vol. 111 pp. E4342 – E4349 ’14 ] KSHV (Kaposi’s Sarcoma HerpesVirus) causes (what else?) Kaposi’s sarcoma, a tumor quite rare until people with AIDS started developing it (due to their lousy immune system being unable to contend with the virus). Open reading frame 73 (ORF73) codes for a major latency associated nuclear antigen 1 (LANA1). It has 3 domains a basic amino terminal region, an acidic central repeat region (divisible into CR1, CR2 and CR3) and another basic carboxy terminal region. LANA1 is involved in maintaning KSHV episomes, regulation of viral latency, transcriptional regulation of viral and cellular genes.

LANA1 is made of multiple high and lower molecular weight isoforms — e.g. a LANA ladder band pattern seen in immunoblotting.

This work shows that LANA1 (and also Epstein Barr Nuclear antigen 1` ) undergo highly efficient +1 and -2 programmed frameshifting, to generate previously undescribed alternative reading frame proteins in their repeat regions. Programmed frameshifting to generate multiple proteins from one RNA sequence can increase coding capacity, without increasing the size of the viral capsid.

The presence of similar repeat sequences in human genes (such as huntingtin — the defective gene in Huntington’s chorea) implies that we should look for frame shifting translation in ourselves as well as in viruses. In the case of mutant huntingtin frame shifting in the abnormally expanded CAG tracts rproduces proteins containing polyAlanine or polySerineArginine tracts.

Well G, A , T and C are the 1’s and 0’s of the way genetic information is stored in our genomic computer. It really isn’t surprising that the genome can be read in alternate frames. In the old days, textual information in bytes had parity bits to make sure the 1’s and 0’s were read in the correct frame. There is nothing like that in our genome (except for the 3 stop codons).

What is truly suprising it that reading in alternate frame produces ‘meaningful’ proteins. This gets us into philosophical waters. Clearly

Erf oxa ndd oga teo urp etr at

Rfo xan ddo gat eou rpe tra t

aren’t meaningful to us. Yet gag and pol are quite meaningful (even life and death meaningful) to the AIDS virus. So meaningful in the biologic sense, means able to function in the larger context of the cell. That really is the case for linguistic meaning. You have to know a lot about the world (and speak English) for the word cat to be meaningful to you. So meaning can never be defined by the word itself. Probably the same is true for concepts as well, but I’ll leave that to the philosophers, or any who choose to comment on this.

An experiment of nature

Yesterday’s post https://luysii.wordpress.com/2014/10/15/ebola/ concerned the fact that 2 nurses taking care of a patient in Texas had been infected (presumably even after taking all the recommended precautions). Given that, I was concerned about the possibility of airborne spread.

Bryan wrote in to say the following:

“It seems doubtful airborne spread was involved. Remember, the Texas patient was initially sent home after showing symptoms, yet none of his family members were infected. Only those health workers directly involved in his care (and thus exposed to infected bodily fluids) have been infected, consistent with the idea that the disease can be transmitted only though contact with infected bodily fluids.”

I certainly hope he is right.

In something right out a novel, the possibility of airborne spread is now going to be empirically tested, as one of the two infected nurses flew to Cleveland, and then back to Texas in the 24 hours prior to her diagnosis. She apparently had a slight fever on boarding. So 100+ people were in a confined space with her for a few hours.

It’s why I don’t read fiction — reality is far more fantastic than anything writers can produce.

One more bizarre development. Here in Massachusetts, legislators today are scheduled to hear about the readiness of the state’s hospitals to handle Ebola. Amazingly, they will only get input from hospital CEOs. No nurses, thank you. Naturally the nurses are pissed as they should be (and so should you if you live in the state). If there were ever a time to hear from boots on the ground about Ebola readiness, it is now.

Addendum 17 Oct ’14

The Obama administration has just appointed a former chief of staff for former vice-president Gore and present vice-president Biden as the “Ebola czar”. Presumably, not for his medical expertise but for his ability to coordinate various governmental agencies, which was hardly the problem in the CDC’s response to the Texas cases. Hopefully, this will not be another case of “Brownie, you’re doing a heck of a job,” but I’m not optimistic — http://en.wikipedia.org/wiki/Michael_D._Brown

Now for some molecular biology. The genome of Ebola is RNA which mutates much more rapidly than DNA genomes. It does this so quickly that at death from AIDS (another RNA virus), there are so many viral variants present that the infecting ensemble is called a quasiSpecies. With a large population infected in Africa there is more Ebola virus extant than at any time in the past. There is some reason to hope that natural selection for a more transmissible form of Ebola in the large infected human population will not occur (the AIDS virus hasn’t become more infectious over the years). This is only a hope.

Never stop thinking, never stop looking for an angle

Derek Lowe may soon be a very rich man if he owns some Vertex stock. An incredible pair of papers in the current Nature (vol. 505 pp. 492 – 493, 509 – 514 ’14, Science (vol 343 pp. 38 – 384, 428 – 432 ’14) has come up with a completely new way of possibly treating AIDs. Instead of attacking the virus, attack the cells it infects, and let them live (or at least die differently).

Now for some background. Cells within us are dying all the time. Red cells die within half a year, the cells in the lining of your gut die within a week and are replaced. None of this causes inflammation, and the cells die very quietly and are munched up by white cells. They even send out a signal to the white cells called an ‘eat me’ signal. The process is called apoptosis. It occurs big time during embryonic development, particularly in the nervous system. Neurons failing to make strong enough contacts effectively kill themselves.

Apoptosis is also called programmed cell death — the cell literally kills itself using enzymes called caspases to break down proteins, and other proteins to break down DNA.

We have evolved other ways for cell death to occur. Consider a cell infected by a bacterium or a virus. We don’t want it to go quietly. We want a lot of inflammatory white cells to get near it and mop up any organisms around. This type of cell death is called pyroptosis. It also uses caspases, but a different set.

You just can’t get away from teleological thinking in biology. We are always asking ‘what’s it for?’ Chemistry and physics can never answer questions like this. We’re back at the Cartesian dichotomy.

Which brings us to an unprecedented way to treat AIDS (or even prevent it).

As anyone conscious for the past 30 years knows, the AIDS virus (aka Human Immunodeficiency Virus 1 aka HIV1) destroys the immune system. It does so in many ways, but the major brunt of the disease falls on a type of white cell called a helper T cell. These cells carry a protein called CD4 on their surface, so for years docs have been counting their number as a prognostic sign, and, in earlier days, to tell them when to start treatment.

We know HIV1 infects CD4 positive (CD4+) T cells and kills them. What the papers show, is that this isn’t the way that most CD4+ cells die. Most (the papers estimate 95%) CD4+ cells die of an abortive HIV1 infection — the virus gets into the cell, starts making some of its DNA, and then the pyroptosis response occurs, causing inflammation, attracting more and more immune cells, which then get infected.

This provides a rather satisfying explanation of the chronic inflammation seen in AIDS in lymph nodes.

Vertex has a drug VX-765 which inhibits the caspase responsible for pyroptosis, but not those responsible for apoptosis. The structure is available (http://www.medkoo.com/Anticancer-trials/VX-765.html), and it looks like a protease inhibitor. Even better, VX-765 been used in humans (in phase II trials for something entirely different). It was well tolerated for 6 weeks anyway. Clearly, a lot more needs to be done before it’s brought to the FDA — how safe is it after a year, what are the long term side effects. But imagine that you could give this to someone newly infected with essentially normal CD4+ count to literally prevent the immunodeficiency, even if you weren’t getting rid of the virus.

Possibly a great advance. I love the deviousness of it all. Don’t attack the virus, but prevent cells it infects from dying in a particular way.

Never stop thinking. Hats off to those who thought of it.

Why Drug Discovery Is So Hard – Reason #22b — Drugs aren’t always doing the things we think they are

One of the things the AIDS virus does to make ‘curing’ AIDS so difficult is hiding. It integrates a DNA copy of its RNA genome into the genome of immune cells (and God knows what else) where it just sits quietly. Activation of the immune cell to fight infection often leads to emergence and production of more virus. One promising mode of therapy is preventing the DNA copy from entering our genome in the first place. The AIDS virus (aka HIV1) produces a protein called Integrase which does that. This has led to the development of integrase inhibitors.

[ Proc. Natl. Acad. Sci. vol. 110 pp. 8327 – 8328, 8690 – 8695 ’13 ] THe HIV1 integrase is targeted to sites in chromatin by the host protein LEDGF (Lens Epithelium Derived Growth Factor, aka p75). This work shows that the integrase inhibitors blocking the interaction of LEDGF/p75 (a translational coactivator) with the integrase cause something else — they cause AIDS viruses under construction within the cell. to assemble into a noninfectious structure. This happens long after integration and expression of viral RNA and protein. It is they thought that the integrase inhibitors inappropriately stabilize integrase dimers in the viral assembly process.

Who knew? They weren’t designed to do that.

For two more examples along these lines please see

https://luysii.wordpress.com/2012/03/18/why-drug-discovery-is-so-hard-reason-22-drugs-arent-doing-what-we-think-they-are/

https://luysii.wordpress.com/2011/02/02/medicinal-chemists-do-you-know-where-your-drug-is-and-what-it-is-doing/