HIV/AIDS–What’s Preventing the Cure?

Amy Fabian (11 AM Micro) worked for a period of time in a research lab, learning about the pathogenesis of Human Immunodeficiency Virus, and our current ability to protect individuals from infection by this virus. Here is Amy’s story:

A few summers ago I spent some time working in a medical lab at John’s Hopkins Hospital and my primary focus during this time was to learn as much as I could about the pathology of HIV/AIDS.   It is a popular area of study for pathologists in Baltimore City because this fatal illness rears its ugly head at a rate that is much more pronounced than the infection rate in my hometown of Hanover, PA.  I worked with a Pathologist by the name of Dr. Stephen Houk and when I asked Dr. Houk why we haven’t been able to find a cure yet and how this one virus (HIV/AIDS) has been able to continually evade some of the most brilliant minds in science across the globe—his answer was simple, “It mutates too rapidly, which in turn causes the development of too many different strains of the virus for us to effectively vaccinate against.”  I have a problem accepting that answer for several reasons.

First, let’s look at the medical definition of cancer, “A rapid alteration (mutation) to the DNA molecule can disrupt the genes in the body causing the affected cells to lose their restraints on growth and to begin to produce quantities of abnormal cells.  The abnormal cells begin to divide uncontrollably and eventually form a new growth known as a “tumor” or neoplasm (Concise Dictionary of Modern Medicine).”  Cancer is a rapid mutation to the DNA molecule.  In the medical profession we see several people who enter into and come out of remission from cancer every single day.  In fact, recent studies show that the US has the highest survival rate out of 31 different countries for the following four kinds of cancer—breast, colon, rectum, and prostate.  So, science has developed a cure for cancer—a potentially fatal disease that rapidly mutates.  Scientists have successfully dealt with mutation factors relating to the cause of cancer in the human body, so why is it seemingly impossible to combat this same issue concerning the pathology of the HIV/AIDS virus?

My second reason for not wanting to accept Dr. Houk’s answer is because when I take into consideration that scientists have been able to all but eradicate the Bubonic Plague from the face of the earth, successfully vaccinate against Polio, and develop an effective anti-serum to Ebola—a virus which is infinitely more virulent than HIV/AIDS will ever be—it makes little sense to me that modern medicine still remains unable to develop at least a vaccination for the HIV/AIDS epidemic.   It just does not add up.  Let’s use Ebola for example.  In terms of viruses, Ebola Hemorrhagic Fever (EHF) makes HIV seem like child’s play.  The incubation period for Ebola ranges from 2 to 21 days—with 4 to 6 days being the average—and the fatality rates range from 68% all the way up to 91% in the more under-developed countries.  Death usually occurs in the second week of symptoms and is more than likely the result of severe blood loss from associated Ebola symptoms.  HIV, on the other hand, has an incubation period of three to six months, possibly longer and the fatality rate will at some point reach 100% because there is no cure—HIV will eventually kill every person it infects.  However, an HIV+ person can live 20+ years with the advancements science has been able to make in the area of anti-retroviral medications and other life sustaining treatments.  Ebola is virulent enough to kill a large majority of the patients it infects within a 14-day period.  Viral virulence that allows 20+ years until death compared to 14 days from onset of symptoms until death is a pretty significant difference.  Yet science has been able to develop a passive antibody transfusion obtained from a previous human Ebola survivor that is shown to be effective in the treatment of Ebola in humans.  On the subject of mutation, we could safely assume that Ebola mutates as well, simply because it’s a virus and many viruses do mutate during replication.  So what I really don’t understand is this: how is it that science has been able to get a grip on something extremely deadly like Ebola, but remain clueless in terms of a vaccine or cure concerning the much less virulent HIV/AIDS virus?  Further, since attenuated vaccines inject a portion of a virus into the person receiving the immunization in order to give their body a chance to produce antibodies, will it EVER be possible to even get to medical trials for an HIV/AIDS vaccine due to ethical concerns over injecting a healthy human with any portion of a fatal, non-curable virus?

  1. McGraw-Hill Concise Dictionary of Modern Medicine—online medical dictionary.
  2. article: Cancer Survival Rates Vary by Country.  By Kathleen Doheny.
  3. Medical Research Paper Search Engine: Title of paper—The Ebola Virus and the Challenges to Health Research in Africa.  Authored by Daniel Bausch.
  4. Hard copy book:  Ebola, by William T. Close, MD. Published by Ivy Books, June 27, 1995.

About ycpmicro

My name is David Singleton, and I am an Associate Professor of Microbiology at York College of Pennsylvania. My main course is BIO230, a course taken by allied-health students at YCP. Views on this site are my own.

Posted on April 18, 2012, in Guest Post. Bookmark the permalink. 11 Comments.

  1. Dr. Saverio Monachino

    Sorry, not sure if the comment I tried to post actually went through, so I’ll try again.

    Amy asks some good questions but to make comparisons between one infectious disease and another (or between a virus infection and tumor progression) is extremely difficult due to the simple fact… all systems are not equal.

    HIV has a problem and that is: It has a mutation rate we have not encountered before. Polio (and other viruses) does not and hence vaccination for this disease works. Of course FLU vaccine has to be changed every year b/c that virus too has the ability to change, though in this case it is on a yearly basis. HIV changes or has the ability to change on a daily basis and this is because there is no real ‘proof reading’ mechansm affiliated with the HIV RT. Ergo changes in the nucleoside sequence occur all the time -selective pressure or no selective pressure. In any 6 to 8 hour replciation cycle for the virus you will get over 1 million new virus particle per infected cell. They become a ‘pool’ from which a selection can occur. This selection will help it resist both immune regulation (host response or vaccine development) or therapeutic efforts (triple drug combination is the only thing which gives an infected individual a chance to keep virus production low).

    Changes within the virus occur to help the virus resist treatment or immune response as mentioned but also it helps the virus seek the ideal breading environment. In this way new infections brought about via a CCR5 (macrophage) tropic virus which occurs during sexual contact change to CXCR4 (T cell) tropic virus within days/weeks of initial infection (as infected cells migrate to the lymph nodes) without any external selctive pressure.

    • Sorry Dr. Monachino, the comment system automatically approves comments for any email address that is already in the system, but if the address is seen as new, it gets held in moderation until I release it.

      We are currently going over virus biology right now in class, and are just now getting to HIV. The other difficulty with developing a vaccine against HIV infection is also the need to develop both a cellular and humoral immune response for effective protection. The other problem as you point out is one in equivalence: the appearance of mutation in cancers occurs at a rate dependent upon the number of cancer cells and their replication rate in an individual, but the appearance of mutation in a virus population such as HIV will be dependent on the many orders of magnitude higher number of virions in comparison to host cells. Viruses and bacteria outnumber us many fold, even in our own bodies. Virus mutation, like antibiotic resistance acquisition (see the next posting!) is not a matter of “if,” but a matter of “when!”

      • Dr. Saverio Monachino

        i’m not on wordpress that often and so I just happened upon your reply from weeks ago. so, thanks for the reply and… I liked the posting on ‘House’ (second to last episode). It isn’t my favorite show but I do like Hugh Laurie and the cast. I really liked Hugh when he played alongside Rowan Atkinson (Mr. Bean) in ‘Black Adder’ (yeah, I’m an old guy).

        • Black Adder series 2 was airing when I spent my junior year of college in England. That was the one set in Elizabeth’s reign. I didn’t recall Hugh Laurie being in it, but just checked He was in two of the 6 episodes as Prince Ludwig.

  2. I’d like to discuss mRNA editing, and protein inhibition:

    mRNA editing– Can changes be introduced into the genome of cDNA to cause a mutation to occur–such as cytidine to uridine and adenosine to inosine? The result would be an alteration to the amino acid sequence of the protein so it differs from the sequence that the DNA predicts. That would then prohibit the synthesis of the 2nd strand of DNA. (After both cDNA and the complement form double stranded viral DNA, its transported into the cell nucleus by integrase.) But if there arent two strands to form the viral DNA, can the genetic info still get transported into the host’s cell?

    protein inhibition- If we were to use a drug such as Enfuvirtide to inhibit the functions of gp120 and gp41 adhesion proteins and if we facilitated changes in the amino acid sequence of the capsid protein p24 and the matrix protein p17, would that cause DECREASED virulence, replecation function, or capsid/matrix function?

    What about it all 4 things were happening at the same time: 1. gp120 and gp41 adhesion proteins inhibited by Enfuvirtide, 2. p24 inhibited by amino acid sequence change, 3. p17 inhibited by amino acid sequence change and 4. mRNA editing… would the combination of those 4 alterations have any effect on blocking adhesion or entry of the HIV virus into a host cell?

    • The changes that occur in cDNA are the result of the lack of “proofreading” on the part of reverse transcriptase, the enzyme that makes a DNA copy of the HIV RNA genome. These mutations occur at a very high rate to begin with, so proposing to try and target and introduce specific detrimental mutations is not likely to be successful: the virus has likely already tried and discarded those mutations. RNA editing specifically refers to the rearrangement of exons to generate novel open reading frames. The HIV rev (p19) and tat (p14) genes are the only ones that demonstrate splicing. Blocking the ability of those two essential gene products to be spliced would slow down viral replication, but the splicing machinery is essential for every single host cell that carries out transcription, so I do not know how such a compound could be selectively toxic for viral replication.

      Enfuviritide does not specifically inhibit adhesion per se (at least not in the sense that we discussed it in a very limited sense in the classroom discussion), but instead blocks a very specific step in that process: the fusion of the viral envelope with the host cell plasma membrane. Its cost (about $25K per year) makes it currently a last-ditch drug for patients with multiply drug resistant isolates of HIV.

      Combination therapies (HAART) is currently state of the art for HIV treatment, however as noted in class it is expensive. Novel therapies to include (like your Enfuviritide example) help to address the observed mutation incidence, but drug discovery is a very time consuming, and quite frankly not very lucrative business (one promising drug out of many thousands of useless compounds) for biotech companies. I am sure that Dr. Monachino can speak authoritatively to that statement.

  3. It just seems like… whatever I come up with it’s not possible because of the intricate nature of the disease itself and the replication/mutation rate. Several thousands of scientists are still unable to provide an answer in terms of a cure or vaccine after decades of study and work with the virus. Reverse transcriptase seems to be a major player in the replication theory because without it, HIV doesnt exist, so that seems like a reasonable place to start.

    When I think about ….ok, how can we kill the virus inside of the human body? I ask myself the question- what is an ABSOLUTELY ESSENTIAL process that MUST happen before HIV can be introduced into the system and what HAS to happen in order for it to replicate within the body and what can be done to inhibit those processes? But everything I come up with, seems like HIV has already thought of it and has a way to get around it. It’s frusterating for me as well as the actual scientists studying it I’m sure.

    Do you ever think, in your opinion, that there will be a cure or vaccine knowing the info you know about how intricate HIV’s pathology is?

    Also, I was reading a book on HIV recently and it claimed that HIV is NOT cytotoxic. It claims that a molecule of HIV itself does not kill human cells, but the opportunistic infections as a result of the presence of HIV is what ultimately causes cell death. What insight can you provide for that book’s claim? You told us in class HIV was cytotoxic.

    In regards to Delta 32, I just dont understand why that gene can’t be introduced into a non carrier. People blessed with carrying Delta 32 essentially are immune to the most common form of HIV. If they were to unfortunately come into contact with HIV-wildtype they could be infected but if I can protect myself against the most common form of HIV that’s way better than nothing at all–which is what modern science has for us at this moment regarding a cure or vaccine. It just seems to me that we have a gene proven to block transmission and we’re not using it to our advantage.

    • It is scary that given the amount of money that has been put into HIV research, potential cures/vaccines are still somewhere in the future. The intractability of the problem in essence does come down to the mutability of the target, both from a therapeutic (existing infections) and preventative standpoint.

      So: cytotoxicity issues. HIV infection of CD4 T-helper cells does result in a very apparent decrease in the number of circulating and lymph-node associated T-helper cells as the viral load increases. It is the decrease in T-helper cells that results in the increasing susceptibility of the patient to opportunistic infections, and as you state, it is a random opportunistic infection that the patient will ultimately die from. However, T-helper cells are affected by viral infection. Although HIV is an enveloped virus, and enveloped viruses bud off of the infected cells which doesn’t result in immediate lysis of the host cell, these cells are significantly adversely affected by the virus and die from the infection. Interestingly, the cellular biology of HIV infection is not entirely clear on what the cytotoxic mechanism is. My quick search of Pubmed indicated that a couple of candidate hypotheses are currently in vogue, including the possibility that HIV infection of T-cells promotes the process of apoptosis (programmed cell death) in virally infected cells. On its own, apoptosis of virally infected cells would be a good thing as it would be a potent innate antiviral defense, but for a virus that continually is shed as an active infection is occurring means that continual reinfection of other T-cells would still be occurring.

      With introducing delta 32 into a non-carrier, this is a problem because the non-carrier actually has the wild type protein, which is the one that acts as a co-receptor for HIV entry. The delta 32 individual actually lacks the functional protein, which is why they are resistant to infection. In the wild-type individual, introducing the delta 32 allele would have no effect, as the wild type protein would still be there. You would have to have some way of replacing the chromosomal copy of the functional gene in every potentially infected cell in the body (presumably by targeting a stem cell population) with the delta 32 allele. Merely introducing the delta 32 allele doesn’t solve the problem, which is the presence of the wild-type receptor.

  4. Im confused on the delta-32 information. What is a “wildtype gene”? Carriers are resistant to the common form of HIV, but not resistant to HIV wildtype. If carriers arent resistant to HIV-wildtype, that would mean that they do carry the wildtype gene then right? Could you please re-explain the wildtype gene and wildtype receptor information to me? I’m not understanding how you’ve got it here.

    It seems like gene therapy or targeting certain stem cells is the most probable way to go with this. Another topic I dont understand how HIV has all the answers for is RNA editing. The point is to target, and change, an amino acid sequence within the DNA. That can be done with gene therapy– how would an alteration to the DNA sequence not have any effect at all on the strength of the virus?

    Is it fair to say that without the enzyme reverse transcriptase, there would be no way HIV could infect a human cell?

    • Many individuals have a gene for the full length, functional CCR5 protein. CCR5 acts in those individuals as a co-receptor along with CD4 for the binding of HIV, so that anyone who has the functional CCR5 gene is more at risk of infection by HIV. CCR5 functions in cells as a receptor for several chemokines, or signalling molecules that are transmitted between cells of the immune system. The CCR5delta32 version of the gene is a truncated version of the gene, so that the individual with that allele would have an incompletely functional CCR5 protein. By introducing a CCR5delta32 gene into a CCR5 containing cell, the functional CCR5 protein would still be there, and would be able to allow HIV infection into that cell, because the delta32 allele is recessive to the dominant CCR5 gene.

      Now that said, there is a case report in the literature of an individual who was HIV positive, who developed acute myeloid leukemia requiring whole body irradiation and bone marrow stem cell transplantation. The transplanted cells were of the CCR5delta32 phenotype and were resistant to HIV infection, and that cell population have replaced the HIV infected cells in his body, suggesting a possible therapeutic approach for HIV treatment. I would however suggest that whole body irradiation/bone marrow transplant as perhaps a radical approach.

  5. The concept I asked about makes much more sense now, thank you.

    About the Delta-32 bone marrow/full body irradiation patient- I KNEW delta-32 had to be able to serve SOME purpose in the hunt for a treatment of HIV–even if it was only in one person! What they’ve done is remarkable. I read the full case on the Discovery website after reading the abstract in your link. They did an update on the man’s condition–he’s still HIV free, 3-years post procedure, WITHOUT the use of HARRT drugs. I think science is losing sight of the fact that this procedure WORKED. Yes, it may have only been on one subject and it may be dangerous, but it WORKED. How are we ever going to find out if this approach is legitimate if we don’t continue to study it?

    More than 33 million people world wide are infected with HIV. There are infected people who are healthy enough to withstand this treatment. If they’re given full disclosure of the risks involved and they want to proceed…. there’s no reason in this world they should be told no. There’s a 30% chance they could die from having this procedure done. Ok, so either they have a 100% chance of eventually dying from the disease or they take a 30% chance of dying during a procedure that could potentially cure them. Out of the 33 million infected people, I’d be more than willing to bet that there would be plenty of healthy volunteers willing to partake in an experimental study of this procedure if it were ever started.

    In what ways is this approach radical? You have a disease here–100% fatality rate, no cure, no vaccine… up comes a procedure that could POSSIBLY be a substantial breakthrough. If we just let this go and chalk it up to a fluke– who knows what we’d be throwing away!? The world really isn’t in a position to negotiate with this matter. In the fight of Us (the whole world) against HIV– HIV is majorly kicking our butts; it’s got an answer for EVERYTHING. When a brilliant scientist comes up with something he thinks may work in this battle for a cure, HIV has already thought about it and has come up with 100 different ways to make sure whatever that scientist came up with won’t work. So if the other side shows a weakness, which it has by way of us now knowing latent HIV cells rest in bone marrow, we need to do everything we can to make sure it’s not wasted. This procedure NEEDS to be explored. To not explore it further would be a HUGE waste and it would do all infected people who pray every night for a cure a huge injustice.

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