May 02 2013

HIV Cure Close?

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12 responses so far

12 Responses to “HIV Cure Close?”

  1. Halfdeadon 02 May 2013 at 11:06 am

    Whether this is a cure or not, I find the fact that HIV has been pushed back so far, so fast, by medical science to be rather amazing. To be honest I would have no idea that we had come so far if I did not read a lot of science blogs, many people, if not most, still consider HIV to be an automatic death sentence, it’s gratifying to see that this is not the case.

  2. evhantheinfidelon 02 May 2013 at 11:13 am

    Dr. Novella, evan though it presents a relatively low risk of transmission in this manner anyway, if the reservoir eradication method pans out, would it make intercourse safe for the recipients?

  3. evhantheinfidelon 02 May 2013 at 11:14 am

    My last comment was barely intelligible. Sorry about that!

  4. Lurking Virologiston 02 May 2013 at 2:22 pm

    After clicking around the press links (admittedly for only a few minutes) all I could come up with was a reference to HDAC inhibitors. These drugs have been used by a number of different research groups to address latency, with modest success in vitro and using mouse models, but my feeling is that these reagents are a long way from being ready for prime time. Certainly not months. I’d put it in the proverbial 5-10 year range.

    First off, there isn’t yet a ‘gold standard’ latency model. We haven’t completely defined the reservoir yet in people, so there’s no way to be sure we can replicate it in the lab. We know central memory CD4 cells are a big component, but there are other viable candidates (glial cells in the brain, for instance). These other candidates may have a very different response to the administered ‘purging’ drugs. While the Berlin Patient was a huge step forward, part of the problem (from a basic science standpoint) was that his entire hematopoietic system was destroyed and replaced, so there was no way to determine which compartment(s) the virus was hiding in.

    Second, in order to be useful a ‘purge and kill’ strategy has work at basically 100% efficiency. The only way to know if you’ve achieved functional cure is to take the patient off their ARVs and see if they get viral rebound. So if you purge, say, 95% of the reservoir and then pull the drugs, if the patient does rebound virologically, by the time you detect it they’ve probably re-seeded the entire reservoir and you’re back to square one. To my recollection, the published data on HDAC inhibitors and similar ‘re-activating agents’ has shown only modest results. It’s still a promising area of research, but still very much in the proof-of-concept stage.

    Third, there are bound to be toxicity problems. Getting enough transcriptional activity in CD4 cells to get the virus out, without causing T-cell activation, is a tricky thing. This goes back to point #2: can you nudge someone’s entire memory t-cell compartment hard enough to get the virus to pop out, without inducing a level of global T-cell activation that could be dangerous? Early attempts at purging strategies using mitogens ran into this problem, so the move to HDAC inhibitors was in part due to their milder nature (relative to, say, pumping someone full of anti-CD3/CD28 antibodies, which is a terrible idea).

    I totally agree with Steve that the linked article is a particularly silly mish-mash of poor science reporting and premature hype. I think, at best, we’re in the early stages of translational research, where the goals will be much more modest: can we reduce proviral HIV DNA load? Can we combine purging strategies with vaccination to induce an ‘elite controller’ phenotype (maintenance of high CD4 levels and persistant low level viremia without ARVs)?


  5. Ori Vandewalleon 03 May 2013 at 12:34 pm

    Can someone explain what is meant by an HIV reservoir? I mean, I get that it’s somewhere the virus can hide, but I don’t really know what hiding means in the context of cells and DNA.

  6. Lurking Virologiston 03 May 2013 at 3:21 pm

    “Can someone explain what is meant by an HIV reservoir? I mean, I get that it’s somewhere the virus can hide, but I don’t really know what hiding means in the context of cells and DNA.”

    HIV is a retrovirus, meaning that it’s genome is RNA, which is reverse transcribed into DNA and then inserted into the host cell genome during productive infection. That DNA copy of the viral genome spliced into the host cell genome is called a provirus.

    During normal replication, that proviral genome is transcribed by host cell machinery into RNA that directs the synthesis of viral proteins and new viral RNA genome copies, which assemble into new HIV particles that bud out of the infected cell. This process eventually kills the infected cell (usually within ~ 48 hours).

    Occasionally though, the virus infects a long-lived memory T-cell, the proviral genome gets inserted into the host DNA, but it doesn’t get transcribed. This means no viral proteins, no new viral genomes, and no new viral particles. The HIV provirus is just another 10 kilobases of silent DNA “hidden” amidst the 3 billion bases of the host genome. It can persist this way for years, since memory T-cells are very long lived, and some HIV-susceptible cells undergo a process of self-renewal without classical activation. This means that each new copy of the cell carries the same silent copy of the HIV provirus.

    These silent HIV genomes, lurking in quiescent, long lived T-cells, are referred to as the reservoir. Because there is no viral RNA or protein being expressed, there’s no way for the immune system to detect the provirus and kill the reservoir cell. Occasionally, these long-lived memory T-cells will get reactivated and start to proliferate (upon re-exposure to their specific antigen, for instance). When this occurs the latent HIV provirus becomes active and produces a bunch of new viral particles which re-ignite the infection. Anti-retroviral drugs prevent viral replication, but they don’t kill the reservoir cells, which is why a patient can be on ARV therapy with undetectable viral load for years, but within weeks or months of coming off drugs become viremic again.

    Fully defining the reservoir population is one of the big challenges in HIV research. Until we know definitively which cells are or are not susceptible to this type of long-lived, latent infection, designing strategies to ‘purge’ them of latent provirus will be very challenging. We might hit on the right drug or drug combo empirically, but it’d be a heck of a lot easier if we could replicate the entire reservoir in the lab.

    Does that answer your question?


  7. Ori Vandewalleon 03 May 2013 at 8:46 pm

    Yes. Thank you!

    My only other question would be… is it an “accident” that sometimes HIV doesn’t get transcribed, or is there some mechanism by which it effects this hidden state? I don’t really want to talk about intentions and accidents when discussing evolution and viruses, but the question I’m really asking is, do you all retroviruses sometimes end up in reservoirs, or is there something special about HIV that makes it more likely to sometimes end up in reservoirs?

  8. Jared Olsenon 03 May 2013 at 10:13 pm

    Excellent question Ori, and great answer LV! I too was wondering about that.

  9. locutusbrgon 04 May 2013 at 9:27 am

    I have known the gross biochemical details for years. That is the most succinct complete explanation I have ever seen.

    I am going to use it if it OK with you?

  10. sonicon 04 May 2013 at 12:37 pm

    Lurking Virologist-
    A relative of mine got HIV years ago.
    Your description of the reservoir problem is amazing.
    I think I finally understand something that has been bugging me for sometime.

  11. psychsurvivoron 04 May 2013 at 2:20 pm

    OK, I am the first to admit that this is completely off topic, I just put it here because there is no recent entry on the matter.

    It seems that the US government is adopting “officially” talking points that had been criticized here as “anti psychiatry nonsense”

    “The strength of each of the editions of DSM has been “reliability” – each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure. In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever. Indeed, symptom-based diagnosis, once common in other areas of medicine, has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best choice of treatment.”

    “It became immediately clear that we cannot design a system based on biomarkers or cognitive performance because we lack the data. In this sense, RDoC is a framework for collecting the data needed for a new nosology. But it is critical to realize that we cannot succeed if we use DSM categories as the “gold standard.”2 The diagnostic system has to be based on the emerging research data, not on the current symptom-based categories. Imagine deciding that EKGs were not useful because many patients with chest pain did not have EKG changes. That is what we have been doing for decades when we reject a biomarker because it does not detect a DSM category. We need to begin collecting the genetic, imaging, physiologic, and cognitive data to see how all the data – not just the symptoms – cluster and how these clusters relate to treatment response.

    That is why NIMH will be re-orienting its research away from DSM categories. Going forward, we will be supporting research projects that look across current categories – or sub-divide current categories – to begin to develop a better system”

    Now, as a psychiatric survivor, I fear that this is just the n-th time that psychiatry admits it has been wrong and it is ready to move to its next pseudo-scientific proposition but, at least in the short term, it gives me great pleasure to read the US government say, “yeah, the DSM is basically a scam” (with all nuances, etc).

  12. Lurking Virologiston 06 May 2013 at 2:37 pm

    Go for it Locutus, glad I could be helpful.

    Ori wrote:

    “My only other question would be… is it an “accident” that sometimes HIV doesn’t get transcribed, or is there some mechanism by which it effects this hidden state? I don’t really want to talk about intentions and accidents when discussing evolution and viruses, but the question I’m really asking is, do you all retroviruses sometimes end up in reservoirs, or is there something special about HIV that makes it more likely to sometimes end up in reservoirs?”

    In order for HIV to successfully replicate, it needs a number of different host cell transcription factors, which bind to the LTR (long-terminal repeat) region of the HIV genome and drive expression of HIV early genes. Once HIV is able to start expressing its genes, several of which regulate subsequent steps of viral gene expression (export and splicing) and subvert host cell defense mechanisms, the virus is good to go for lytic replication.

    However, the viral capsid is carrying (more or less) just what HIV needs to perform reverse transcription and then integrate that new proviral DNA into the host genome. This process, from entry to integration, can take many hours. One of the more popular current models for latency is that a viral particle infects an activated T-cell as it’s downshifting to a quiescent, memory phenotype, thus the provirus finds itself in a ‘resting’ cell by the time it finally completes integration, and is consequently “silenced,” with no means of expressing it’s early genes until the T-cell becomes re-activated.

    Evolutionarily, this is clearly working to the virus’s advantage. Even in patients who achieve elite controller status, latency allows the virus to persist in a form that is undetectable by their CD8 (‘killer’) T-cells, and maintain a bit of residual viremia. I can’t speak with expertise about other retroviruses, but given the number of endogenous retroviral elements in our own genome, it’s pretty clear that these wee beasties have been very successful.

    Side note: pretty much every primate we’ve looked at has it’s own species-specific HIV-like lentivirus, which we call Simian Immunodeficiency Viruses (SIVs), and all of those that we’ve studied produce the same type of lifelong infection. Interestingly, SIVs that have been with a particular host for a long period of time (such as African Green Monkeys and Sooty Mangabeys) seem to have adapted or attenuated in such a way that they achieve high levels of viremia without causing CD4 decline or any other symptom of overt disease.


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