February 8, 2007
About the Palm Project Interviews
TAG has conducted a series of interviews with leading scientists about the underlying pathogenesis of AIDS to gain insights into emerging lines of research and observations about the current research funding environment.
Douglas Nixon, M.D., Ph.D. is a renowned cellular immunologist who has been working in the HIV/AIDS field since the late 1980s. Nixon’s first published HIV research paper, which came out in Nature in 1988, involved identifying CD8 T cell responses against the virus. At that time, Nixon was working with Andrew McMichael’s immunology group at Oxford in the UK but he subsequently moved to the US, first working at the Aaron Diamond AIDS Research Center before establishing his laboratory at the Gladstone Institute, University of California at San Francisco (UCSF).
Q: What are your research interests at the moment?
We’ve been working with Dr. Esper G. Kallas in a collaborative manner for the past three years; he’s one of the new HIV Vaccine Trials Network sites down in Sao Paolo. That has given us a wonderful opportunity to have an international context on some of the research that we do. The reason we are working with him, apart from the fact that he is an amazing, great scientist and a great guy, is that it gives us the opportunity to study the impact of coinfections on HIV infection in a way that is difficult here.
I’m particularly interested in what happens with MTB coinfection. We have a paper in press in the Journal of Infectious Diseases where we’ve been studying natural killer T cells. These are not natural killer cells. They’re not T cells. But they are a lineage which has lymphoid markers, but a very unique regulatory role. They recognize lipid antigens, presented by the CD1d modules. We found that people with active pulmonary tuberculosis completely lose these cells, they just go. I’m excited about the finding, because there are ways that one could potentially stimulate them. These are early days, but if we find that they are involved in the pathogenesis of the disease, then it gives us another cell type to potentially manipulate in vivo.
We’re also looking at coinfection with GBV, we’re trying to join that controversy, from a cellular immunological perspective. See whether we can contribute to understanding whether or not the GBV effect (in slowing HIV disease progression) is real. And we’re also looking at people who are infected with HTLV-1. That’s also reasonably common down in Brazil and the ability to understand how two exogenous retroviruses interact with each other, I think, is unique.
Do NKT cells have the potential to develop into memory cells?
That’s actually a very good question. They’ve been a neglected cell type, partly because they’re rare in most people, in peripheral blood. They’re common in the liver. And they’re about 4% of the human lymphoid population. In the mouse, they’re 40%. In humans, NKT cells appear to arrive in the thymus, as you would expect, since they have CD3. And they mature. But there’s still debate about their differentiation. They don’t appear to have a memory compartment, although we’re only now using multicolor flow cytometry to subset these NKT cells into different populations. And it is a good question, because the reason that they’re NKT cells is that they have an invariant usage of one of the T cell receptors — V alpha 24 in humans. And there are V alpha 24 T cells which are not NKT cells. But we don’t know whether, for example, if a T cell which has the V alpha 24, which became a memory cell, might, for example, be able to take on characteristics of an NKT cell. So, it’s one of those new areas.
But the reason that they’re so important is that a small number of NKT cells go a very long way, I like to think, because they are such potent cytokine producers. They produce cytokines probably in minutes; they’re much quicker than other cells. And they probably are directing other cells to do things. If you look in mouse models these cells are really important in the NOD mouse diabetic model, for example. And one of the areas I think is really interesting at the moment, and a really dynamic field, is trying to understand regulatory T cell populations, which do not just include the CD25 positive, CD4 positive T cells that we and many, many others are studying, but also these NKT cells. So, there’s this sort of family of regulation.
What we’re interested in doing is to understand how HIV affects that regulation, or causes dysregulation. Because it’s another opportunity to manipulate: if you can manipulate the regulators, you might have a really major effect downstream. Because a lot of us have been working on studying effector T cells, but if you think about it, that’s the last stage that they’ve got to. That’s when the differentiation has occurred, the antigen is being recognized, and the cell is either going to do its job or not. But if you can look upstream, and say, well, maybe I can get more of these effector cells going by turning off the regulation…that, from an in vivo manipulation perspective, is something I’m pretty excited about trying.
Any other major areas of interest?
We have a major research interest in work we have not yet published, but we are presenting as one poster and one oral presentation at the Retrovirus conference. This is work in collaboration with the Canadian group of Mario Ostrowski, and, in particular, graduate student Brad Jones in his group, working with Keith Garrison in my group. Brad is giving an oral presentation and Keith is giving a poster presentation. And this is our work on endogenous retroviruses. I think it’s the most exciting thing that we’re doing at the moment, because it’s completely novel and, I think, has some important implications.
What we have found is that HIV does not infect a cell in a retroviral vacuum. We all have endogenous retroviruses as part of our genome; about 8% of our DNA is endogenous retroviruses. Sort of remarkable. These are thought to represent ancestral viral fossils, if you like. The past waves of nasty, infectious diseases. It’s like recapitulating, probably, what happened with HIV in a chimp population. I can imagine that if you go back through these primate lineages, that you can see this evidence in the genome for these retroviral sequences which have integrated, and in most cases, lost the ability to have any transcription or translation occurring.
But there are a few members of these families which are probably intact enough that you can get some translation, or transcription and translation, going, in the rather unique developmental circumstances where these endogenous retroviruses have actually been co-opted by the host to do good. And one example is in pregnancy, where the HERV — human endogenous retrovirus HERV-W sequence, actually — is lending its envelope to the human body as part of this syncytiotrophoblast that leads to the formation of the placenta. So, humans would not have pregnancy in the way that we know it, unless there was expression of this endogenous retrovirus. But normally, they’re not expressed.
I got interested in this when I was back in New York at Aaron Diamond, when I was interested in thinking about endogenous retroviruses in the context of HIV. We did a side project, looking at endogenous retrovirus immunity in people with a past history of seminoma, because these endogenous retroviruses can be expressed in cancer patients with breast cancer, ovarian cancer, or testicular cancer — germ cell drivers. And so, actually, it was January last year, we finally published our paper looking at T cell responses. So, we could see T cell responses at low levels. But this had got us thinking about, well, what happens with HIV infection? And it’s what happens in HIV infection that is absolutely remarkable.
The first thing that we have found is, in cells which are infected with HIV, there is an incredible amount of transcription of endogenous retroviral sequences. So, in an HIV-infected cell, the endogenous retrovirus sequences go wild. And we think that’s probably due to a number of mechanisms. The HIV Vif protein has this ability to turn off the natural APOBEC components, which are probably sitting in a cell, turning these endogenous retroviruses off — that’s probably their job. They were there well before HIV came into this. So, we think what is happening is that whatever mechanisms that are keeping endogenous retrovirus sequences untranscribed are released, and you get transcription and translation of endogenous retroviruses.
From a virological perspective, that takes us down one route. But, as immunologists, we were thinking, what would that do? Since we’ve found translated HERV products that could potentially stimulate an immune response. And in primary HIV-infected people, we see a very strong endogenous retrovirus-specific immune response, and we’ve gone on to show that that immune response is actually closely related to control of HIV viremia. There’s been this controversy about can you tell whether HIV-specific immunity is related to control of viremia. At the moment, we have found that people’s viremic level appears to be related to the amount of endogenous retrovirus immunity that they’re stimulating. So, that’s where we’ve got to. We’re doing tons of experiments in this area.
From a vaccine perspective, we think that this could, potentially, open up a completely new avenue to vaccination. And the rationale is this: if you could stimulate HERV-specific immunity, then those HERV-specific T cells would be able to help in the elimination of HIV by two mechanisms. The first mechanism is that the HERV-specific T cell is only going to recognize an HIV-infected cell, because it’s only HIV-infected cells expressing the HERV antigens. The second thing is, we found that there was cross-reactivity between some of the HERV epitopes recognized and some of the HIV epitopes. So, HERV-specific T cells may be able to recognize HIV-presented peptides, in a cross-reactive manner. And so, there are two potential ways of eliminating an HIV-infected cell.
The third thing, which makes me most excited, is that HERVs are invariant. The sequence doesn’t change. So, it doesn’t matter which HIV has infected the cell — it bypasses all the potential problems associated with variation in HIV.
Of course, that’s our great wishful thinking. We are at an early stage. And we are enthusiastically pursuing research in this, both from a pathogenesis perspective, but also from a vaccine perspective. Clearly, though, a caveat is the many unknowns. And one of the things that people say is, well, might you be stimulating an autoimmune response? And I say, yes, but that’s what you want. If you can get an autoimmune response to get rid of your HIV-infected cells, I think that’s going to be perfectly acceptable. Because, if you think about autoimmunity, it’s really a threshold thing. We’ve got autoimmune phenomenon going on, and on a daily basis, within us. It’s just that it’s suppressed in the majority. And then, occasionally, it breaks through. I think that if we can target an endogenous protein that is only expressing HIV-infected cells, then you’re going to get rid of the HIV-infected cells, and that would be great. So, that’s another thing that we’re doing.
Have you conducted research in highly exposed seronegative cohorts?
We have. Another area of interest is, we’re looking at NK cells in the exposed seronegatives. There have been a couple of papers, most recently in the Journal of Immunology from a Belgian group, suggesting that there are certain NK cell subpopulations that may be present in exposed seronegatives that are not in control groups. So we are also working with NK cells, and we’re very fortunate, in that Lewis Lanier at UCSF, who is one of the world experts on NK cells, likes collaborating with us, and we like collaborating with him. And so we are trying to better understand the role of natural killer cells, and what they may be doing in both helping prevent infection, and also, in the very early stage of infections.
But natural killer cells — the innate immune response — people sort of think only in terms of vaccines. So, people think, oh, well, the innate immune response kicks in first, and then you have your adaptive response. But, in the presence of a chronic infectious disease like HIV, it’s continuing to replicate in the context of innate immunity. So, it makes a lot of sense to follow up on Mary Carrington’s suggestions from the genetics, that there are certain NK cell-related parameters that may be associated with better viral control. And so we’re trying to do that here, too.
Do you think that’s been overlooked a little?
Well, there was a lot of activity in the 1980s in research on natural killer cells. And then that went quiet. What’s happened in the ’90s is that people working both in the mouse and in the humans developed new reagents — new antibodies — to help better identify different subpopulations of natural killer cells. This is an area that Tony Fauci is pretty good in. He’s got a great group working on natural killer cells. They have been helping push this research. But there really aren’t all that many people working in this area, compared to the T cell area. And I really do think it’s important.
One thing that we found, that we’re getting ready for publication, is that the bulk of the interferon gamma that’s produced in response to HIV peptides, in our in vitro assays, comes from natural killer cells. And what is happening is that the peptides are presented to T cells, they’re stimulated, and they produce cytokines that cause the natural killer cells to release gamma interferon. So, when a cellular immunologist has been thinking that in our PBMC population, all the HIV-specific interferon gamma that we measure is coming from T cells, it’s not. Half or more is coming from natural killer cells. So, I think natural killer cells are very important, and also, potentially manipulable in vivo.
I’m not just interested in understanding the mechanisms, which is important and we need to do that. But I’m interested in thinking, well, is this going to be of any use in helping infected people or in the vaccine? So I would like to see more emphasis on natural killer cells.
But one thing that’s amusing at the moment is, the people who work on APOBEC, an intrinsic, intracellular defense, are now becoming, if you like, surrogate immunologists. Because they have discovered that the cell itself is defending itself all the time, against, if you like, molecular biological attack. I sort of look upon it like that that, in the sense that, once the cell is infected, then a number of different parts of the cellular machinery are kicked into gear to try and kick those viruses out. So, it’s sort of different from the cellular perspective. But they are now talking about the innate immunity of the cell. And when we talk about innate immunity, we’re talking about natural killer cells, or natural killer T cells, or regulatory T cells.
I would like to look upon it as a new opportunity for a mix of two different cultures because, normally, virologists and immunologists don’t talk all that much to each other. And that’s actually one of the problems, I think, in HIV research: we don’t have enough virology-immunology crosstalk. But maybe the cellular innate and the intrinsic innate people will be the first to merge. And it will be interesting to see what happens in the next few years on that.
Is that something that has changed over time? Has there been any improvement in immunology-virology collaboration, or is it still an issue?
I would say it’s still a bit of an issue. I think, for example, if you just look at the major conferences, the Retrovirus is considered to be a virology/clinical conference, with not so much immunology. And the Keystone conference is considered to be more of an immunology congress, with some virology, and less clinical. So, there really are areas where people don’t overlap.
One area I’m real interested in is the intersection of immune responses to drug-resistant mutant virus. But the drug-resistant virology field is a very close knit group who all know each other, and think of things in terms of sequence, and have not really embraced an outside lateral thought about, well, maybe you can pressure the virus in drug-resistant mutant areas with the immune response. And so this is the sort of thing where we do get some good leadership from the NIH, from some of the really good program officers in the Division of AIDS who I’m impressed with. But this is an area where, maybe, they could take more of a proactive role in having the workshops or by saying, well, let’s bring the intrinsic and innate immunologists together. Let’s bring the drug-resistant virologists and immunologists together. Because I think that’s where the next big step is going to come, by mixing these people up. I think there’s a role for some continued leadership, and I would like to see the Division of AIDS spearhead that, because they’re a neutral territory.
In terms of pathogenesis, do you have particular ideas about where things are with pathogenesis, or where they should be going? There’s been a lot of attention on the gut recently, and immune activation, is that part of the territory you cover?
Yes. But, I think when you think about pathogenesis, that all of us are thinking in a global context, so that we have to be looking at activation. We have to be looking at the gut. But you can’t study it all. And so, my angle has been to try and understand the impact of coinfections on activation and the gut. And then, also, to look within us, at the viruses within us, these endogenous retroviruses. So, I pay attention to the whole immunopathogenesis picture. But I think it is important to focus in on some areas. And then, one reads, and talks, and collaborates, and communicates with your colleagues, to try and get the bigger picture. But I think the study of the gut is important. And I think there’s clear evidence, for a long time, that immune activation is associated with a more rapid decline in CD4 cells. And it’s important to understand why, and to understand whether there can be selective suppression of some of that activation. Immune activation is a broad hat, and you don’t want to turn some things off.
I think this is where the future of therapeutic immunology is going, in terms of being much more targeted about turning things on and off. And one of the advantages of UCSF is that we have people like Jeff Bluestone around, who, with the immune tolerance network, is helping deliver things. Then I also read the cancer immunology field because they’ve been doing a lot of immunotherapy work. As we get better tools, I think that immunotherapy will become more targeted, and therefore, potentially, more used.
There’s still this immunology and clinician divide, in that clinicians understand viral load measurement, and low is better, and I agree with that. But there’s a lot more to it than that. And I think, as with pharmaceutical companies going the route of individualization of treatments, based on genomics, that you can imagine, in some utopian world where there was tons of money, to be able to take an HIV-infected person, and look at their genetics and their viruses, and look at their immune system, and then come up with an algorithm to help that person do best. If someone’s HLA B*57, they’re probably going to have a low viral load, but you still want to be able to work with that patient, to maximize their chances. Someone who’s got a rapid progressing HLA allele, you may want to talk to them individually, and start treatment. And that’s just, you know, based on HLA, let alone KIR type, other genetics, virus immune response. I’m not sure we’ll ever get there, but it’s a nice idea.
Is there anybody working on using immunological analyses in this way? HLA typing is quite expensive, isn’t it?
Well, it’s, it is quite expensive. It’s not a simple test. But I haven’t really talked with Steve. One of the wonderful things about working here is the presence of Steve and Rick and other clinicians. But I’m not sure what he would say if I said to him, well, let’s start treating patients based on their immunity! Well, it’s the sort of thing Steve would do, because he’s at the forefront of everything clinical. But it would need to be well thought out.
Switching gears to vaccines, do you think the T cell-based vaccines that are now entering efficacy trials might have some effect?
Well, it depends what you mean by “might have some effect”. I am optimistic that they will stimulate T cell immunity in humans. And the question is, is it going to be of sufficient magnitude, and are those going to be T cells with the right multi-potent ability to release cytokines and kill. The multi-killers, I call them. I’m not a part of those trials, so I have not seen the data. That’s going to be something I’m going to be very interested in. The caveat is that we have been disappointed in some of the translatability from primate models to humans, in that what appears to have been immunogenic in a primate has not necessarily translated into immunogenicity in humans. And I think that there are some clever people working around that. I’m hopeful that the efforts that are going into learning how to better deliver DNA and to modify the adenovirus or other vectors are going to pay off, and we will be able to stimulate a T cell component of the vaccine. But it still is leaving the neutralizing antibody component, which is as important if not more important. And I think that the variation in HIV is going to be its problem. But I think we’ll get the T cell vaccine.
Do you think they might have some effect on the post-infection viral load?
I do. I think it’s a pretty exciting time — well, it’s been going on for a while — in terms of understanding correlates of protective immunity. So, Bruce Walker and Steve Deeks’s work, I think, is really going to help look at elite controllers in the terms of what are they producing. And that has to be coupled with studies of looking at people who don’t control — you have to look at the spectrum, so you know what’s not working, as well as what is.
I’m curious as to whether we need to better understand the subsets of lymphocytes, in terms of what may be potent in viral control. Because we still have Jay Levy’s CAF (CD8 antiviral factor) sitting around uncharacterized. We have the realization that natural killer cells can themselves produce very potent antiviral cytokines. When we subset CD8 or CD4 cells, we can show that certain populations produce more cytokines or kill more than others. So, we’re working our way towards a better understanding of what cells we actually need to stimulate, and whether these vaccines stimulate all of them, or maybe they’re stimulating some subsets but stimulating a suppressive population at the same time.
What I would like to see in the next two to three years is a better understanding of the cells that are actually producing the best antiviral activity. Someone like Otto Yang is ideally poised to understand which cell types in his viral suppression assay. And then, when he’s worked out which cell is the one that’s suppressing virus the most, to be looking at these vaccine strategies to see whether they’ve expanded that population. And, as someone who works on the regulatory T cells, I’m well aware that with any vaccine, you could be stimulating cells that regulate these other cells. And so, maybe you have to work out how to specifically just stimulate those cells that are the most potent. I think that’s an area that’s also worth putting money into at the moment.
So, there are still some basic questions, you think, about what needs to be switched off, as well as what needs to be switched on?
That’s right. But I think that should go in parallel, obviously, with the trials.
Recently, there’s been a shift to a sort of big science approach on the vaccine front. Do you think that some of these basic questions may get forgotten in that process?
Well, I think the basic questions are really important. I’m not involved in those big vaccine groups. What I would like to see, of course, is additional money, so that we both have the big vaccine groups, plus additional resources for the investigator-initiated basic research. I think we need more money, more funding.
Has the flat funding of NIH had an impact on your work?
Yes, it has. Although, I must say, the people in the Division of AIDS have been extremely supportive and they are working under difficult circumstances. But when grants are at a 10% or an 8% funding, it means that, as an individual, you’re spending, really, most of your time writing grants, and worrying about getting grants, and realizing that some of your colleagues are not getting grants and are moving out of the field, and you wonder about your own grants, and hope for the best.
The hardest thing to see is the demoralization for the younger scientists, who are choosing not to go into HIV research, or to do other things, because the funding is so difficult. And that’s a bigger political question, in relation to science education in America and prioritization for funding and career structures for scientists. How to encourage people, while maintaining quality?
When I started, the payline was 22%. And I think, for some people, when they started it was 30%. Nowadays, we’re at the stage where good grants — very good grants — are not getting funded. Before, you felt that the process was such that grants would be improved, so the good study would get funded. Now, good studies are not getting funded. And HIV continues to be a huge problem.
So, I think it’s something which people in the lab really notice. And I feel it’s difficult to explain to the younger people how it’s going to get better. And that’s demoralizing for me. Because I think global infectious diseases — not just HIV but the others — this is something that we can really contribute to. We can make vaccines. We just have to put the resources into the right area. So, I think we need more funding.
Are there recommendations that you can think of in terms of trying to support the young investigators?
Well, I believe that UCSF and other institutions are beginning to think about trying to use some of their internal resources to create bridge funding, to get people over this particularly difficult period. You can imagine a situation where a young investigator puts in a grant, and it gets a great score, but is not funded. Now, what do you do with that, as an institution? You’ve got a potential winner — someone who is going to do it. But because of the unique circumstances in 2007, funding isn’t there. But that’s a smart person. That’s a person who has been judged by the peers to be good, but they didn’t get funded. And so, that sort of person, I would say, from a university perspective, is someone worth giving a $50,000, $100,000 bridge. Cover them over to their next grant resubmission, to answer their critics and to give them some encouragement.
Now, of course, that money has to come from somewhere. And so, maybe the university should be specifically going out to donors and saying, look, in this time we need bridge funding. It’s sort of a political issue, but I think that bridge funding would be helpful. But if that bridge funding is used in that way, then maybe it’s the pilot studies for established investigators which go. Or something else has to give, somewhere. But I would like to see university sponsored bridge funding for investigators who submitted a really good grant which wasn’t funded but was close. And I think that’s the only practical immediate thing that could happen that would help lift morale, and also buy people time. And if we can get to 15, 16, 18% funding level, then the young investigators will start to get their grants again. Because — while I think it’s true that you give young investigators a break, on review — if you’re going to fund five grants out of 80, and you have ten senior people who are well established, who all have great grants, all of which you could fund, and then, some young investigators who are clearly very promising but don’t have the publication record or the track history, what’s the study section going to do?
Are there any other frustrations and obstacles, access to reagents or things that sort, which interfere with the kind of research that you want to do?
For my own research, no. We’ve had a really good relationship with the NIH AIDS Reagent Program. And I would want to give that a big plug. They’ve been receptive, responsive, helpful, innovative, really good.
Any other issues that you would like to highlight? Anything else that we could be doing, to help facilitate your work and that of young investigators?
Well, the funding is one. I would say, maybe, co-working with the Division of AIDS, to help identify these areas of collaboration that would bring people together, like the intrinsic and innate immunologists, like the drug resistant virologists and immunologists, like bring a group of clinicians together and say, let’s have a — what did they do at the CDC recently, when they had the flu? — some sort of mock trial. The idea is to not have a war game, but say, bring clinicians and immunologists, and say to them, OK, we want you to use the immune system to direct your clinical decision makings in this game. And then, you have patients who, you know, you have dummy patients. You’ve got dummy results. And you say, well, what happened? That sort of think tank. A practical think tank, with an end result, I think, would be very helpful for the advocacy groups to work on.
Glossary & Bibliography
Natural Killer T cells (NKTs): An unsual subset of lymphocytes with properties of both T cells and natural killer cells. http://en.wikipedia.org/wiki/Natural_Killer_T_cell
CD1d Receptor: A receptor expressed by NKT cells. http://en.wikipedia.org/wiki/CD1d_receptor
T cell Receptors (TCRs): TCRs are docking bay-type structures on the T cell surface via which the T cell engages and recognizes pathogens (specifically, small slices of pathogen-derived proteins called epitopes). There are many slightly different shaped TCRs that a T cell can have, so scientists group different TCRs into families. V alpha 24 is the name given to a specific T cell receptor that is found both on normal T cells and the less common subset of natural killer cell/T cell hybrids called natural killer T cells (NKTs, see above). NKT cells possess both the CD1d receptor and the V alpha 24 T cell receptor.
GBV: GB virus C, a virus first identified in 1995 that is genetically related to the hepatitis C virus but does not cause disease. Studies have suggested that infection with GBV may slow HIV disease progression.
CD3: A molecule expressed on all T cells, also called a pan-T cell marker.
Regulatory T cells: T cells that suppress rather than enhance immune responses.
CD25: Receptor for the cytokine interleukin-2, expressed by activated T cells and also used as a marker to identify “regulatory” T cells capable of suppressing immune responses.
HERV: human endogenous retrovirus. HERVs are remnants of ancient retroviruses that infected human germ line cells at some point in history and are now permanent parts of the human genome. HERVs cannot replicate or form infectious viruses.
HTLV-1: human T-cell lymphotropic virus type 1, a retrovirus first discovered in Japan in 1977. http://en.wikipedia.org/wiki/Human_T-lymphotropic_virus
APOBEC: A family of human cellular proteins, some of which have strong antiviral effects. The HIV gene vif is thought to have evolved to suppress APOBEC activity, in order to facilitate HIV replication.
HLA: Human leukocyte antigen system, see HLA genes & immunity article for a brief description: http://www.aegis.com/pubs/iavi/2001/IAVI2001-0707.html
KIR: Killer Immunoglobulin Receptors. Expressed by NK cells, these receptors interact with HLA molecules and facilitate killing of potentially pathogen-infected cells by NK cells. Genes for specific KIRs have been associated with slower progression of HIV infection, suggesting an important role for NK cells in the immune response to HIV.
Multicolor Flow Cytometry: A flow cytometer is a machine that allows labeling and analysis of cells (cyto is Greek for cell). More sophisticated flow cytometers can label multiple different markers on cells with different colors, allowing highly specific sorting of different cell populations.
CAF: CD8 antiviral factor. This is a yet-to-be-identified substance with strong anti-HIV effects, produced by CD8 T cells.
Natural Killer (NK) Cells: Lymphocytes that respond non-specifically to pathogens. NK cells are part of the innate immune system. http://www.immunecentral.com/immune-system/iss9.cfm
NIH: National Institutes of Health, www.nih.gov
>NIAID: National Institute of Allergy & Infectious Diseases, www3.niaid.nih.gov
DIADS: Division of AIDS, www3.niaid.nih.gov/about/organization/daids/
NIH AIDS Research & Reference Reagent Program: Provides important materials (such as virus isolates and peptides that allow analysis of immune responses) to researchers working on HIV infection and AIDS. https://www.aidsreagent.org/Index.cfm
- Ballan WM, Vu BA, Long BR, Loo CP, Michaelsson J, Barbour JD, Lanier LL, Wiznia AA, Abadi J, Fennelly GJ, Rosenberg MG, Nixon DF.
Natural Killer Cells in Perinatally HIV-1-Infected Children Exhibit Less Degranulation Compared to HIV-1-Exposed Uninfected Children and Their Expression of KIR2DL3, NKG2C, and NKp46 Correlates with Disease Severity.
J Immunol. 2007 Sep 1;179(5):3362-70.
- Karlsson AC, Chapman JM, Heiken BD, Hoh R, Kallas EG, Martin JN, Hecht FM, Deeks SG, Nixon DF.
Antiretroviral drug therapy alters the profile of human immunodeficiency virus type 1-specific T-cell responses and shifts the immunodominant cytotoxic T-lymphocyte response from gag to pol.
J Virol. 2007 Oct;81(20):11543-8. Epub 2007 Aug 1.
- Willberg CB, Pillai SK, Sharp ER, Rosenberg MG, Agudelo JD, Barbour JD, Nixon DF.
Rational peptide selection to detect human immunodeficiency virus type 1-specific T-cell responses under resource-limited conditions.
Clin Vaccine Immunol. 2007 Jun;14(6):785-8. Epub 2007 Apr 4.
- Snyder-Cappione JE, Nixon DF, Loo CP, Chapman JM, Meiklejohn DA, Melo FF, Costa PR, Sandberg JK, Rodrigues DS, Kallas EG.
Individuals with pulmonary tuberculosis have lower levels of circulating CD1d-restricted NKT cells.
J Infect Dis. 2007 May 1;195(9):1361-4. Epub 2007 Mar 20.
- Northfield JW, Loo CP, Barbour JD, Spotts G, Hecht FM, Klenerman P, Nixon DF, Michaelsson J.
Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T(EMRA) cells in early infection are linked to control of HIV-1 viremia and predict the subsequent viral load set point.
J Virol. 2007 Jun;81(11):5759-65. Epub 2007 Mar 21.
- Karlsson AC, Iversen AK, Chapman JM, de Oliviera T, Spotts G, McMichael AJ, Davenport MP, Hecht FM, Nixon DF.
Sequential broadening of CTL responses in early HIV-1 infection is associated with viral escape.
PLoS ONE. 2007 Feb 21;2(2):e225.
- Carr WH, Rosen DB, Arase H, Nixon DF, Michaelsson J, Lanier LL.
Cutting Edge: KIR3DS1, a gene implicated in resistance to progression to AIDS, encodes a DAP12-associated receptor expressed on NK cells that triggers NK cell activation.
J Immunol. 2007 Jan 15;178(2):647-51.
- Legrand FA, Nixon DF, Loo CP, Ono E, Chapman JM, Miyamoto M, Diaz RS, Santos AM, Succi RC, Abadi J, Rosenberg MG, de Moraes-Pinto MI, Kallas EG.
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