A Conversation with Doug Richman and Celsa Spina
There are only a handful scientists working on finding a cure for HIV infection. Doug Richman and Celsa Spina, from the University of California–San Diego, are among them. We asked about the scientific and funding barriers they and their colleagues are facing and about the outlook for new and better HIV drugs.
By Bob Huff
Bob: When will we know if curing HIV infection in a person is possible?
Doug: When we succeed. There are two major potential accomplishments in HIV: a vaccine to prevent the disease and an intervention to cure it. One is for the uninfected and one is for the infected. It isn’t clear that either is possible, but the potential benefits of both are so great that it’s absurd to give up without trying.
Lots of people are working on vaccines, but the people who are working on eradicating the latent reservoir of HIV is a pretty small group—there are only about a half dozen investigators’ groups working on eradication. This is partially because some people may not think eradication is an achievable objective; it’s been hard to figure out how to address the problem; and it’s very complicated: we’re not sure what the mechanisms are. And because the reviewers that evaluate NIH grant proposals have been so skeptical, even the few groups that are interested have had a hard time getting funded. With the vaccine there is a lot of successful experience with other viruses, and people know what the two arms of the immune system are. But we don’t even know what the mechanisms of eradication would be. And if we identify the mechanisms then we still have to find small molecules that work. So I think we need a lot of basic science research.
Bob: What would you be screening for right now if you were looking for molecules? Do you have an assay?
Doug: I think Celsa has got the best in vitro model. A lot of the cell line models are very artificial, but she’s got a model using primary human lymphocytes. I think the SIV macaque model reflects latency, but working with macaques is very difficult and expensive and you can’t screen things in macaques; you have to have something you think would work before you start testing it.
I think what a number of us think needs to be done is to set up some sort of a collaboration among the NIH, industry, and some investigators. It begins with discovery. Work on mechanisms is done by different investigators; high-throughput screening of molecules can only be done in the pharmaceutical industry; and developing applications requires a lot more collaboration.
Bob: Can the site where HIV integrates in the host genome be a factor in latency?
Doug: I think the data are pretty convincing that the probability of integration is related to the chromatin structure and activity of transcription of the gene. But those are probabilities. The question is, if it integrates in some other places in much lower frequencies, then do you have to deal with different locations or with different strategies? Are there multiple mechanisms you have to deal with? This is why science is slow and steady and it will take a decade if not longer [to understand this]. There’s not going to be a magic bullet discovered on the first experiment… .
Celsa: We’ve been trying to do things with in vitro models in primary cells. We’d like to look at an individual cell and correlate where the virus integrated with whether or not that virus is replication competent. But at this point we don’t know how to do that.
Doug: We know there’s a lot more integrated DNA than there is replication competent DNA in infected cells. And the questions are: Is it the integration site? Is it whether the provirus is competent or not? There are a lot of details.
Bob: If the integrated DNA can’t make a fully competent virus, can it still make HIV proteins that have toxic effects on their own?
Doug: You know, because a third of our genome is integrated retrovirus, and, the more people look, the more they see that even some of the integrated retrovirus that entered our genome ten million years ago is producing some transcription or translational products—and some of them have consequences. So it is probable that HIV may do that to some extent, too. In fact some of the RNA we’re seeing may be the result of those things being produced, but we’re not confident.
Bob: It seems like the coming of raltegravir really revitalized this field of eradication.
Doug: I have no idea why. That makes no sense to me whatsoever. The thing that turned on a lot of people was the more rapid clearance of RNA. It hasn’t been absolutely proven, but I think, logically—and Bob Siliciano has a paper with modeling—it’s just a function of the mechanism of action. It’s at a step after reverse transcription. So if you have reverse transcripts already, efavirenz is no longer going to be effective until the next round of replication, while raltegravir will, so you clear the RNA faster. But it has no long-term difference in terms of activity; at six months they’re identical. This is mythical thinking rather than scientific thinking, but that happens a lot in the field.
Bob: It was dramatic when we saw it.
Doug: It is a dramatic observation. It’s an incredible drug, but it isn’t going to eradicate, that’s all. In terms of treating people, it’s remarkable.
Bob: Is the fragility of its resistance profile a problem?
Doug: I don’t get the fragility thing. Two of the most fragile drugs we have are the NNRTIs and 3TC or FTC, and they’re both components of one of the best regimens we have. But if they are potent, and people take their drugs, there will be no fragility. Those drugs have a low genetic barrier, so if people don’t take their drugs properly, and you get replication in the presence of suboptimal concentrations of drug, you get failure with resistance. The number of people who failed with resistance to raltegravir in the study of initiating treatment is very small. Even in the salvage study it was people who had nothing to add to it. That shows what a great drug it is.
Bob: In a clinical trial, why does it take many weeks or months to get, say, 90% of the trial population below 50 copies? What is going on during that period? Is replication continuing?
Doug: I think all new infections are blocked. But you’ve got a lot of cells that are already infected; that are producing virus; that don’t get killed off right away. So the activated T lymphocyte has a half-life of a day or day and a half, but macrophages and nonactivated T cells that are infected are going to get activated and produce virus; the macrophages are constantly producing virus until they die off. But I don’t think you’re getting new infections because we really don’t see much evolution once you start therapy.
Bob: Do you think we will see another generation of ARVs?
Doug: The number of people looking has diminished. And the need is, to some extent, less now that it has ever been; we have more at our disposal that works than we ever had. Could we do even better? Yes. Are there people for whom the drugs are not enough? Sure. But the impetus to find more drugs is diminished in the pharmaceutical industry. The number of companies actively looking is about half of what it was five or ten years ago. But there are some really good companies that are trying to find new drugs.
I think the NNRTI from Idenix looks promising. But I don’t see anything else in clinical trials that I’m aware of that is that exciting.
Bob: Do you think you could get more bang for your buck by developing new formulations like a patch or a depot for people who have trouble taking pills consistently?
Doug: There aren’t many of those people.
Bob: Even in a clinical trial there’s that last 10% who fail.
Doug: There’s 10% failure, but it’s usually 7 or 8% who are lost to follow up or withdraw from the study. You can’t treat those people. In most studies during the last five years, at most 1–2% have drug resistance. A person who fails with drug resistance is a nonadherer. That’s a pretty small failure rate. Getting nine out of ten to comply is good. There are enough people with emotional or substance abuse problems for whom antiretrovirals are not the most important issues; those are the limitations in our clinic.
Bob: How do you see HIV treatment guidelines evolving in the United States?
Doug: The guidelines are changing. The data that’s accumulating about the earlier initiation of treatment having an impact on non-AIDS-related morbidity and mortality have convinced the leaders about starting earlier. The question is whether you treat everybody or start at 500 instead of 350; it’s gone up to that level. The practical issue is that since nobody’s been able to implement the CDC guidelines [on testing and referral to care], we’re still identifying new patients with low CD4 counts, so it’s not a realistic argument for me.
Celsa: What about the developing countries?
Doug: That’s a disaster. We’re treating three million people with regimens we wouldn’t give our own patients. People are getting neuropathy; getting lipodystrophy; lactic acidosis; all the problems you get with thymidine analogs. Resistance is accumulating. We’ve got great drugs for the United States. If you’re going to make a big difference, you take the drugs that are really good and figure out how to get them to the people who need them.
Bob: Under the current conditions for science funding, what is the outlook for a young investigator?
Doug: We have already lost a significant portion of a generation in this country. The young people who are still here, for example, amaze me. I’m not sure that I would have persisted in the face of the obstacles that they have dealt with. It was easier for me as an assistant professor to get a grant, but I don’t think I would have had the strength to do it otherwise. And we have all lost a lot of time. I have never been as unproductive as in the last several years . . . because I’ve been writing grants instead of doing science. A combination of the increased grant writing plus the incredible amount of paperwork that’s being generated by bureaucracies that have never existed before has really inhibited creativity. We’re losing a generation . . . and some of us need to be replaced. When I go to Europe or Australia or India or China, I can see where the future is. Hopefully there will be a change.
Celsa: But it will take a while to recover. The great thing about science in the U.S. was that it allowed off-the-wall thinking. In other countries where they didn’t have the resources, you didn’t have that creative thinking.
Doug: That’s what’s happened here, so that latency research has basically been stymied.
Celsa: Anything that is too innovative or too risky is not being funded.