Day 93: Integrins again show importance in HIV infection

A new story came out from Fauci’s lab at NIAID indicating that the HIV spike component gp120 can bind the integrin alpha4 beta7 (a4b7). The gp120 protein is responsible for HIV binding to CD4; it is also known that it can bind some other molecules, most notably galactoceramide. The physiologic ramifications of gp120 binding to proteins other than CD4 is not really known, although I think most feel that it is not a major contributor to HIV disease. 

The a4b7 story seems to have a little more importance, though. Integrins have been known to be important for HIV attachment, as they are found on the virus and studies have shown that if you block the integrin interactions (particularly the ICAM-1/LFA-1 interaction), you decrease HIV attachment. Fauci’s group, led by James Arthos, found the interaction while investigating CD4 T cell depletion in the gut associated lymphoid tissue (GALT). Early in HIV infection, CD4 cells undergo a massive depletion in the gut—the site of approximately 2/3 of CD4 cells in the body. It’s believed that this massive insult is important to establishing chronic infection and disease. One of the hypotheses for the massive infection and depletion in the gut is due to the high number of CD4+ CCR5+ T cells in the gut. However, the mechanisms for this depletion are not yet worked out—hence the new paper in Nature Immunology from this group. 

They started with natural killer (NK) cells, which do not express CD4 (although I believe NK T cells do), yet have disrupted activity by gp120. The researchers found that gp120 binds the NK cells, but only in the presence of calcium. Using binding studies with cell lysate and mass spectrometry, the authors found that HIV binds the integrin a4b7. Furthermore, they found that this binding activates the integrin (as measured by phosphorylation of p38 mitogen-activated kinase). These findings also hold for T cells. The authors note that T cells in the periphery have low levels of active a4b7, but that T cells in the gut have high levels of the activated integrin. This integrin is actually important in signaling T cells to migrate to and stay in the gut. Therefore, the authors used PBMCs (not from the gut), stimulating them with retinoic acid to achieve a “gut-like” phenotype. Now, it is difficult to differentiate whether the gp120 is binding to CD4 or to a4b7, so the authors conducted their binding studies in the presence of a monoclonal antibody that blocks the CD4-gp120 interaction. They noted gp120 binding to T cells in the presence of the antibody. This binding was not evident in the absence of calcium, suggesting that the binding was mediated by a molecule other than CD4. The binding was also abrogated when they added the a4b7-ligand MadCAM (sounds like the name of a heavy metal band, right?). The authors also blocked the interaction using three other antibodies that interact with a4b7. They observed similar results for CD8 cells. So, the binding studies seem pretty solid to me. 

The next order of business was to find the a4b7-gp120 binding sites. Since gp120 binding activates the integrin, it makes sense that gp120 might bind the same region as the natural ligands. A hexapeptide mimicking the MadCAM binding site inhibited gp120-a4b7 binding in a dose-dependent manner. The gp120 molecule has a region similar to the MadCAM binding site. One amino acid in this region is conserved in more than 98% of the gp120 sequences in the Los Alamos database; it’s in the V2 loop of gp120. Using site-directed mutagenesis and binding studies with surface plasmon resonance, the authors confirm that the binding site is in the HIV V2 loop. These gp120 mutants could still bind CD4, but had little CD4 independent binding. 

Apparently, not all gp120 molecules bind a4b7 with the same efficiency. The “V” in the “V2” loop stands for “variable”, which would explain differences in binding ability between gp120 molecules. Previous studies with the chimeric SHIV (a mix of HIV and SIV) produced two viral variants with differential ability to infect the GALT. One strain is CXCR4 oriented and the other is CCR5 oriented (see an earlier post for an explanation of this if you need it). As noted above CCR5+ CD4+ T cells are more highly expressed in the GALT than in the periphery. The authors tested the ability of gp120 from these viruses to attach to T cells with the gut phenotype. They found that in the presence of CD4-blocking antibody, the gp120 from virus that preferentially infects GALT has residual binding, while the other variant does not. They also discovered that the difference in biding is due to the differences in the V2 loop binding site, suggesting that the background binding in the absence of CD4 is a4b7 mediated and that the variant which infects GALT better has better CD4-independent binding. 

Finally, the authors wondered whether this binding has any functional significance. LFA-1 activation is linked to the a4 molecule. LFA-1 also happens to be a really important player in the immune response, forming part of the immunologic synapse (the pSMAC—peripheral supramolecular activation complex). Everyone knows that HIV needs activated T cells to replicate. As you might expect, gp120 that has the ability to bind a4b7 and this activates LFA-1, facilitating the clustering of LFA-1 and CD4. So, this could help the virus enter the cell. Of course, these sorts of things are also dependent on the stoichiometry of an interaction, so there is no telling whether this occurs under physiologic conditions. Bombarding a cell with recombinant gp120 is vastly different than having variable viral levels. So, you have to make that caveat. 

However, the group conducted some in vitro studies showing that the gp120-a4b7 binding is important for HIV replication. PBMCs cultured in retinoic acid had decreased viral replication when exposed to viral variants with mutated V2-loop binding sites; although this is not necessarily due to decreased a4b7 binding (it’s only suggestive). 

The authors make three arguments that this interaction is important:

·        “The highest frequencies of HIV-1 infection occur in the memory CD4+ T cell compartment in the gut, in which, unlike in almost all other tissue compartments, memory CD4+ T cells express activated a4b7.”

·        “Second, this interaction is well conserved. We have shown that gp120 proteins derived from HIV-1 subtypes A, B, C and D, as well a simian immunodeficiency virus (SIVsmm) gp120, bound to a4b7.”

·        “Finally, we have shown that gp120 activated LFA-1 in an a4b7-dependent way. The capacity of LFA-1 to increase the efficiency of HIV-1 infection is well established.” 

Is this an important observation? Well, it’s certainly an important basic science observation; the physiological relevance remains to be determined. If a4b7 is important in the establishment of infection, then this might offer a way to either prevent initial infection or lessen the impact of initial HIV pathogenesis in the GALT. At best, this could potentially prolong HIV disease progression. That’s still a long way off, though, so it will be interesting to see where this goes. It appears that there are a4b7-blocking agents in development, so studies in animal models may help clarify some of these questions. 

I would also like to point put that there are 21 authors on this paper. For those of you that haven’t worked in laboratory science, it often (but not always) takes this many people to produce a high-quality paper. It’s one of the reasons why PhD studies now take closer to 6 or 7 years, and not the traditional 4 years, and that post-doctoral fellowships have been extended by 2-3 years. It makes me think that the traditional endpoint of PhD candidacy should have less emphasis on publication, because—speaking from experience—it is very difficult to compete with large groups working on similar projects. But that’s another story.

M. Linde

Day 47: Thoughs on “Will there ever be an HIV vaccine?”

Robert Steinbrook presents an interesting commentary on the prospect of an HIV vaccine in this week’s New England Journal of Medicine. The article focuses on the Merck vaccine failure and what it means for the future of HIV vaccines. The most sobering part of the article comes not from Dr. Steinbrook, though, but Anthony Fauci, who says “To be brutally honest with ourselves, we have to leave open the possibility . . . that we might not ever get a vaccine for HIV. People are afraid to say that because they think it would then indicate that maybe we are giving up. We are not giving up. We are going to push this agenda as aggressively and energetically as we always have. But there is a possibility—a clear finite possibility—that that’s the case.”

In my interactions with HIV basic scientists and immunologists, I get the impression that most researchers are not too favorable on the prospect of a workable vaccine anytime in the near future. While I hate to be pessimistic and I think all options must be considered, I tend to agree. There are only two approaches to a preventative vaccine that I think are really worth merit and, unfortunately, most of the vaccine candidates are not looking at these options (more below). Currently, most vaccine candidates are relatively traditional, focusing on generating an immune response against viral proteins. HIV reverse transcriptase is so error prone, though, that I think the virus will be able to squeak out of any response targeted against the viral proteins. Everyone knows this and yet all of the vaccines I see still target the viral proteins. Other methods have looked at creating antibodies that target the CD4-gp120 complex—when conserved aspects of the viral spike are no longer shielded by sugars and are exposed. While I think that these antibodies might block infection, I wonder about the concentrations needed to provide protection. These epitopes are exposed for extremely brief periods of time, meaning that you need an antibody with a very fast on-rate at very high concentrations. It doesn’t seem reasonable to me. Then again, as I like to frequently point out, I am often wrong.

One of the roads that I do find promising that some are looking at is the composition of the virus at infection. When HIV infection is established, there are certain aspects of the virus that are conserved. Once infection is established, the virus quickly mutates and evolves to be better suited to the environment. Thus, the viral particles that establish infection are different from the majority of viral particles during infection. It may be that there are certain characteristics of HIV that are important for establishing infection that can be targeted by a vaccine. If we can tease out the aspects of the virus that are important for the initial establishment of infection, we could design vaccines against these features. It’s a tricky prospect, though, because you have to get viral samples very soon after initial infection. I know that at least a couple of groups are working on this, including Julie Overbaugh at the University of Washington.

The other road that I think is at least worth considering is looking at host factors on the virus. I have mentioned this a couple of times in the blog, but HIV is highly enriched in host proteins in the envelope including MHC molecules. Unlike viral proteins, host proteins won’t mutate and evade a vaccine. Plus, MHC molecules are some of the most immunogenic molecules out there. An allovaccine would be easy to create and might have activity against HIV and other retroviruses. There are, of course, serious considerations with this type of vaccine, though, not the least of which is its effect on fertility. It’s still worth looking at, although I fear that almost no one is considering this option.

 

M. Linde

Day 46: The high prevalence of HIV among black MSM

There was an interesting brief report in the journal AIDS recently looking at HIV rates, risk factors, and ethnicity. Using a survey of men who have sex with men (MSM) at a San Francisco clinic, Berry and colleagues found that black men were more likely to have partners of the same race and partners who were at least ten years older than themselves compared with white, Latino, or Asian/pacific islander respondents. The authors undertook the survey to help address why HIV prevalence is higher among the black MSM compared with white MSM, despite lower risk behavior patterns among black MSM. Based on the findings, the authors suggest that older black MSM are passing HIV to younger black partners, potentially explaining the noted prevalence patterns.

This seems the simplest explanation and certainly seems reasonable, but I can’t help but wonder if some other factors are at play. This is just a though, but there have been studies showing that MHC divergence between serodiscordant partners seems to be protective for transmission. One possible explanation for this finding is that alloimmunity may provide a protective response against incoming virus—which is loaded with MHC molecules. Alloimmunity is very strong—a normal reactive antigen may stimulate 1% of T cells, while an allo-antigen can stimulate 5% of T cells. So, if black MSM are having sex with other black men, the level of MHC discordance may be lower than white MSM. This all depends on the amount of MHC divergence within the black community. The other factor that may be involved is the age difference. The authors don’t report the ages within the cohort. Now, a ten year discrepancy between partner ages could be a surrogate for younger age. Younger age coupled with fewer risk behaviors (fewer partners) might mean that many black MSM have not developed alloreactivity to divergent MHCs. Other ethnicities, which have a smaller age discrepancy, may be a surrogate for an older population—one which has a more developed alloimmune response as a result of repeat exposures. It is a bunch of hand waving and there are a bunch of “ifs” involved, but I couldn’t help but think this might be involved.

It reminds me of a friend I had who had a really unique ethnic background—he was pretty much part everything. He had several partners who were positive, yet he was never infected. I always wondered whether he had some really strange MHC combination and had strong alloresponses against any virus he came in contact with. Anyway, I just thought I would throw that out there.

Day 34: HIV infectivity in semen

In a rather unexpected paper, Frank Kirchoff’s group and others (about 20 authors or so) show that amyloid fibers in semen enhance the infectivity of HIV. According to the Cell paper, HIV piggybacks on the fibers. Now, the issue of HIV attachment to spermatozoa has always been a controversial one. You see data for and against, much of it terrible. There are a couple of papers out there that claim that HIV actually enters (and possible infects) spermatozoa. I’ve seen papers with electron micrographs of spermatozoa with enveloped cytoplasmic particles that the authors claim are virions. Never mind that this seems virtually impossible—I might buy it if the particles were in a vesicle or there was just a viral core, but I wish they would explain how the virus manages to pass the cell membrane and retain its envelope. There are also data with pull-downs of spermatozoa/virus that show by RT-PCR that no virus attaches to the spermatozoa. The only problem is that the process used to pull-down the spermatozoa in these papers is the same process used to “wash” HIV from sperm, so the authors never actually show that the pull-down process doesn’t shear or detach HIV from the spermatozoa surface. My own (unpublished) data indicate that HIV does attach to spermatozoa, in a ratio of approximately 12 virions per cell.

 

How attachment is mediated is also controversial. Some people claim that spermatozoa carry CD4 (which I do not believe); while others claim it is mediated by gp120 affinity for glycosphingolipids. I am not certain whether this is the whole story. Semen contains a lot of what are called “prostasomes”. Prostasomes are exosomes made by the prostate. If you look at the prostasome protein composition and compare it to HIV composition, they look very, very similar. Prostasome, electron micrographs look almost identical to immature HIV particles. It’s known that prostasomes are important for spermatozoa viability, although it is not entirely clear how. If I remember correctly, prostasomes attach to spermatozoa and some believe that they may dampen an immune response targeted against the sperm (sexual reproduction is an evolutionary war waged by the immune system, but that is another story). So, it stands to reason that HIV may use the same methods as prostasomes to attach to spermatozoa.

 

Why is this important? I believe the key to creating a viable preventative vaccine is by preventing the key steps that aid in the establishment of infection (not a shocking statement—kind of like saying the key to driving is starting the car). As my old advisor was fond of saying, once the puck gets past the goalie, the game is over (only true in overtime). Preventative vaccines right now focus on priming the adaptive immune response so it will occur before the viral replication gets out of control. I think a better response is to target conserved aspects of the virus that allow it to infect those first few cells. So, what happens to the billions spermatozoa that don’t fertilize an egg? I imagine some of them are taken up and cleared by macrophages (I am not sure, but it seems reasonable). Any virions attached to these sperm would love to be exposed to macrophages.

 

This brings us back to the Cell paper by Munch and colleagues. They show that prostatic acid phosphatase (PAP) fragments forms amyloid fibers capture HIV and present virus to target cells. They call these fibers SEVI, for semen-derived enhancer of viral infectivity. They suggest that the by piggybacking on the SEVI fibers, the virus is presented to target cells that are normally protected by the mucosal barrier. The fibers increased infectivity by at least 1000-fold. This is important, because it has been observed that sexual transmission of HIV is actually not that efficient—although it is obviously efficient enough to result in a massive epidemic. If you could target these fibers in some capacity (like a microbicide) and decrease the sexual transmissibility by 1000-fold, that would be a very good thing.

 

One aspect of the findings that the group does not discuss, which I would like to see, is the effect of these fibers on the immune cell activation. It is hypothesized that the adaptive immune system is primed by “danger signals”. Do these amyloid fibers activate immune cells? Do macrophage toll-like receptors recognize them? It could be that one of the reasons HIV attached to these fibers is more infectious is because these virions are presented to cells in that are in a state of initial activation, which would be the perfect target. This might also be true for dendritic cells, which may travel to the lymph nodes following interaction with SEVI fibers. If that is the case, than a small molecule which blocks this activation could also be a reasonable microbicide. That’s all conjecture, though.

 

M. Linde

Day 31: Another player for infection in trans?

You would think that after 25+ years of research, we would have some sort of handle on how HIV infection is actually established. But as far as I can tell, there is still a considerable amount of debate on the subject. Quick, which is more infectious—cell-associated virus or free virus? Which is more important in establishing infection—genital tract infection or spread in the lymph nodes?

 

One of the widely regarded hypotheses is that HIV “hitchhikes” its way to the lymph nodes, where it gains easy access to CD4 cells. It has been shown that viral particles can attach to dendritic cells (and possibly infect, but that’s another story), which make their way to the lymph nodes when activated. Dendritic cells are professional antigen presenting cells, meaning that they do a lot of T-cell activation. They are designed to interact and stimulate CD4 cells. So, you can easily see how a virus attached to or hiding in a dendritic cell would be able to successfully infect an activated CD4 cell. The DCs pick up the virus, the DCs travel to the lymph nodes, stimulate some CD4 cells and, at the same time, HIV infects these cells.

 

The main protein on DCs that has been identified in this trans-infection is DC-SIGN, an adhesion molecule. A new paper in PNAS has also identified another player, syndecan-3. Most of the figures in the paper are supportive that syndecan-3 is a player, but they are not conclusive. However, the authors use siRNA to knockdown syndecan-3 and show that this results in less HIV attachment, which is fairly strong evidence. The authors showed that syndecan-3 knockdown did not affect DC-SIGN expression by flow cytometry, but it did not say in the paper whether this was surface expression or intracellular expression. They also did not show whether DC-SIGN trafficking was altered by syndecan-3 knockdown. Obviously, if syndecan-3 knockdown prevents DC-SIGN from reaching the cell surface or changes the molecule’s conformation, then knockdown of syndecan-3 would affect binding mediated through DC-SIGN. It would have been nice if they had incubated virus (both wild-type and virus without gp120) with DC lysate, pelleted the virus, and then done a western blot for syndecan-3. Still, the paper shows that syndecan-3 knockdown affects both HIV binding and also transmission of the virus to T cells, so it has to be doing something.

If syndecan-3 and DC-SIGN are important players for infection in trans, then small molecules that target these interactions may be good candidates for microbicides.

M. Linde

Day 23: My favorite subject

I wrote about HIV for a number of years and thought I had a decent understanding of the virus. Then I joined Dr. James Hildreth’s lab and my perception of the virus changed radically. James and Dr. Steve Gould received a bit of press in the field for their “Trojan Exosome Hypothesis” a few years back. I am not going to get into the academia/political aspect of the paper, but I will say that prior to reading the paper I thought that the only important proteins in HIV were the virally-encoded proteins. I had no idea that the bulk of the viral envelope was made up of host proteins. With the idea that a virus doesn’t carry anything it doesn’t need, I started studying host protein incorporation. With all I have written and studied about HIV, this is still my favorite HIV topic. I think it’s under appreciated and under studied. There are all of these host molecules on the viral envelope and, from my experience, most people just disregard them. Essentially, HIV is a free-floating immunological synapse.

 

However, there has been an increasing interest in why these are the proteins incorporated into the viral envelope. Within the past year or so there have been a handful of papers showing that HIV preferentially buds from tetraspanin-enriched membranes. Well, there’s a new paper that came out in the Journal of Virology that shows this to be true for another retrovirus, Moloney murine leukemia virus (MoMLV). Segura and colleagues used proteomics to identify proteins incorporated into MoMLV virions. The list was the usual suspects; they look exactly like an exosome. You have tetraspanins (CD9, CD63, CD81), tetraspanin-associated proteins (CD9P-1, beta-1 integrin), rab proteins, MFG-E8, lamps, and cytoskeletal proteins. If you compare the proteins found in this paper with those found in HIV (Chertova J Virol 2005, I think), you get almost a complete overlap.

 

What I find most intriguing about these proteins is that they look exactly like a tetraspanin enriched membrane domain (TEMs). Nobody has figured out what tetraspanins do, although they are highly conserved and found in every cell in the body (as far as I can tell). So, do tetraspanins have some importance in HIV? The jury is still out, but I find it highly unlikely that retroviruses selectively incorporate them for no specific purpose. Hopefully someone will figure this out. I tried my hand at it, but that story is best told over a few beers.

 

M. Linde

Day17: Yet another hypothesis for chronic immune activation

One major field of study in HIV is the difference in pathogenicity between SIV and HIV, since many species of monkeys which acquire SIV do not develop immunodeficiency. One of the observed differences is that monkeys which do not develop immunodeficiency do not show chronic immune activation upon SIV infection, while chronic immune activation is one of the hallmarks of HIV infection. Recently, Rawson and colleagues report in Nature Medicine that the chronic immune activation observed in HIV infection may be related to antigen processing during cell death.

 

Apotosis (pronounced apo-toe-sis) is the process of programmed cell death. When a cell suffers certain types of insults or is signaled in certain specific manners, the cell starts a chain reaction that leads to an orderly death of the cell. The cellular DNA is cleaved, the membrane “blebs” (breaks into smaller particles, similar to budding) and changes composition, and the cell is taken in by antigen presenting cells (APCs) for orderly disposal. This process is important during development and is also a pivotal process in the proper maintenance of the immune system. One key class of proteins in this process is the caspases. These proteins are the initial effectors of the chain reaction leading to apoptosis. They are proteases, similar to HIV protease in function, but they have different specificities.

 

According to the recent Nature Medicine paper, active apoptosis leads to an alteration of normal antigen processing. The authors took non-apoptotic and apoptotoc cells and used proteomics to determine differences in protein abundance for the two conditions. Using mass spectrometry, the authors observed that several of the proteins that had reduced abundance during apoptosis are proteins known to be targets in autoimmunity. The authors then tested the immunogenicity of the identified peptides for HIV-positive and HIV-negative subjects. Effector CD8 cells for the HIV-positive subjects showed greater responses to the peptide pool than HIV-negative subjects. After several rounds of in vitro stimulation, CD8 cells from HIV-negative subjects also reacted to the peptide pool, suggesting that CD8 cells specific for these epitopes are present in uninfected subjects, but are ignorant of their target.

 

The authors further confirmed the existence of self-reactive CD8 cells in HIV-positive subjects by tagging these cells with pentamers and analyzing the frequency using flow cytometry. In HIV-negative subjects, these reactive cells numbered less then 0.02% of CD8 cells. The number of positive CD8 cells for HIV-positive subjects was much higher. The number of self-reactive CD8 cells in HIV-positive subjects directly correlated with the percentage of apoptotic CD4 cells. The strength of self-reactive response inversely correlated with the number of live non-apoptotic CD4 cells in each HIV-positive subject.

 

The data also show that APCs presented with lysed apoptotic cells are better at stimulating CD8 responses against the self-reactive peptides than APCs presented with lysed non-apoptotic cells. When the apoptotic cells were cultured with caspase inhibitors, APC activation of CD8 effectors was decreased.  I am not entirely sure how they managed to generate apoptotic cells in the presence of a caspase inhibitor (particularly caspase 8 when they used a fas-method of apoptosis induction) and the methods do not clearly define this. Or maybe I am too dense to understand what they actually did here, but it seems problematic to me.

 

The study suggests that the autoreactive CD8 cells may contribute to CD4 loss during HIV infection. In the context of chronic immune activation, these CD8 cells, which would normally not be activated, undergo clonal expansion and are primed by cross-presenting APCs. This cross-presentation was blocked by caspase inhibitors, suggesting that the peptide fragments necessary for this self-reactivity are dependent upon caspases and may be directly cleaved by the caspases. It is easy to imagine a feedback cycle where HIV-associated apoptosis results in the priming of self-reactive CD8 cells, which in turn cause more apoptosis and a resulting chronic immune activation. As usual, more research will need to be done to determine if this hypothesis is correct, but if it is it may be possible to break the cycle of chronic immune activation in HIV-infected individuals and, hopefully, decrease HIV pathogenesis.

Day 3: The first good therapeutic vaccine idea in a long time

There was an interesting paper that came out of Doug Nixon’s lab at UCSF. The paper, reported in PLoS Pathogens (open access), looks at the relationship between HIV and human endogenous retroviruses (HERVs). HERVs are retroviruses that are already in your genome. Presumably, they entered into the human genome in ancient times and now are stably integrated. They are held in check by host proteins that presumably evolved in response to these retroviruses.

 

As HIV is a retrovirus, some of these proteins can also hold HIV in check. It would be nice if they did (I would happily be out of a job), but HIV has found a way to negate the action of these proteins. Further, some HIV proteins that help HIV replicate also help HERVs replicate. So HIV also activates the dormant HERVs in the cells it infects. Lots of work in this field has been done by Brad Jones (who is second author on the paper), a grad student at University of Toronto who seems poised to be a real player in HIV research. Let’s hope he stays in the field.

 

Now, when the immune system is presented with cells producing proteins that are abnormal, it generates a response. This usually results in suppression of whatever it is that causes the abnormal proteins. HIV, however, mutates rapidly and can escape from the immune system. HERVs are encoded in the genome, though, so they don’t mutate like HIV. Therefore, the immune system can generate a response against HERVs and kill the cells that express them. As these would also be HIV infected cells, this would likely be a good thing.

 

First, Garrison and colleagues show that HIV-positive subjects have significantly greater HERV expression than HIV-negative subjects. They also found that the HIV-positive subjects generated an immune response to HERV-specific sequences, while the HIV-negative subjects did not. These responses looked normal for what one would expect in a controlled response against an infection. One of the patients who showed good response against HERV sequences was also able to control HIV infection without the use of antiviral therapy and, overall, patients who showed good response to HERV sequences also had lower amounts of virus in the blood. It’s easy to visualize how HERV responses might also help control HIV spread in the body.

 

So, the authors suggest that maybe by vaccinating infected patients against HERV sequences could help HIV-positive patients control their infection without anti-HIV therapy. It would be cheap and easy—more than I can say for most therapeutic vaccine ideas out there. Seems like a good idea, don’t it? I hope it pans out.

 

M. Linde