TAG HIV Basic Science, Vaccines, and Cure Project Blog

Revitalizing T Cells by Blocking PD-L1

Several years ago scientists discovered a link between T-cell dysfunction and the expression of a receptor named PD-1 on the T-cell surface. The initial discovery related to T cells in mice that had become functionally compromised due to battling a chronic viral infection (LCMV); it turned out that these exhausted T cells expressed very high levels of PD-1. Receptors like PD-1 can essentially be thought of as antennae on the outside of the cell that can interact with, and respond to, specific signaling molecules in the cell’s environment. Depending on the signal, the receptor may sink back inside the cell to convey a message to the command center in the nucleus. This message in turn affects the behavior of the T cell and may lead to greater or lesser expression of the receptor. The PD-1 receptor can interact with at least two molecules (described as ligands): PD-L1 and PD-L2. Because high levels of PD-1 expression were associated with reduced T-cell function, researchers studied the effects of administering an antibody that targets PD-1 and thereby blocks its ability to interact with its ligands. The results of this experiment drew a lot of attention, because the strategy successfully rejuvenated the exhausted T cells and improved their ability to control LCMV replication. Similar laboratory findings were subsequently reported with T cells targeting cancers, leading to the development of anti-PD-1 antibodies as cancer therapies (an approach that has begun to show some success in human trials). PD-1 has also since been found to be highly expressed on exhausted HIV-specific T cells in humans, and a small study in macaques reported that PD-1 blockade reduced SIV viral load.

In addition to blocking PD-1, investigators are looking at the effects of an alternative strategy of targeting the ligand PD-L1. Brent Palmer and colleagues recently reported the first in vivo results obtained with this approach using the humanized mouse model of HIV infection. Encouragingly, the researchers found that blocking PD-L1 led to significant reductions in HIV viral load and preservation of CD4 T-cells counts without apparent adverse effects. Bristol Myers-Squibb supplied the anti-PD-L1 antibody for the study; the company is manufacturing it under the name BMS-936559 primarily for clinical trials in people with cancers.

The AIDS Clinical Trials Group (ACTG) currently has two research protocols in development that plan to investigate an anti-PD1 antibody (MK-3475, made by Merck) and the BMS-936559 anti-PD-L1 antibody in people with HIV infection. The studies will look at both T-cell function and effects on the latent HIV reservoir (due to evidence that latently infected CD4 T cells express high levels of PD-1). Safety will be the primary concern for these trials because PD-1 is also thought to be important in reducing the function of T cells that might otherwise be harmful (e.g., T cells capable of reacting with self antigens and causing autoimmunity).

The Journal of Immunology

January 1, 2013

vol. 190 no. 1 211-219

In Vivo Blockade of the PD-1 Receptor Suppresses HIV-1 Viral Loads and Improves CD4+ T Cell Levels in Humanized Mice 

Brent E. Palmer*, C. Preston Neff†, Jonathan LeCureux†, Angelica Ehler*, Michelle DSouza*, Leila Remling-Mulder†, Alan J. Korman‡, Andrew P. Fontenot* and Ramesh Akkina†

*Division of Allergy and Clinical Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045;

†Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523; and

‡Bristol-Myers Squibb, Biologics Discovery California, Milpitas, CA 95035

ABSTRACT

The programmed death-1 (PD-1) pathway limits the function of virus-specific T cells during chronic infection. We previously showed that blockade of the PD-1 pathway increases HIV-1–associated T cell function in vitro. However, the effect of PD-1 blockade on HIV-1 disease progression in vivo has not been examined. As in humans, HIV-1–infected humanized BALB/c-Rag2−/−γc−/− (Rag-hu) mice express elevated levels of PD-1 on T cells during chronic infection. To examine the effect of PD-1 blockade on disease progression, Rag-hu mice with chronic HIV-1 infection were treated with a blocking mAb directed against programmed cell death-1 ligand-1, the ligand for PD-1. Programmed cell death-1 ligand-1–treated Rag-hu mice exhibited a progressive decrease in the HIV-1 plasma viral load, with a 7-fold decrease by day 7, a 20-fold decrease by day 14, a 178-fold decrease by day 21, and a 269-fold decrease by day 28 postinitiation of treatment. By day 7, the percentage of CD4+ T cells was statistically higher in the treated compared with the untreated group, and this trend was sustained throughout the 28-d treatment period. Moreover, there was a strong inverse correlation between plasma viral load and the percentage of both CD4+ (r = −0.66; p < 0.0001) and CD8+ (r = −0.64; p < 0.0001) T cells in the treated mice but not the untreated mice. This study provides “proof of concept” that humanized mice can be used to examine the effects of immunotherapeutic interventions on HIV-1 infection. Furthermore, to our knowledge, these data demonstrate for the first time that blockade of the PD-1 pathway reduces HIV-1 viral loads.

Australian AIDS Cure Claim Leads to a Maelstrom of Hype and Misinformation

On January 16, a scientist named David Harrich and his institution, the Queensland Institute for Medical Research (QIMR) in Brisbane, Australia, issued a press release invoking the word cure in an effort to publicize a scientific paper containing in vitro (lab dish) study results of uncertain significance at best. The release spawned a maelstrom of misleading media coverage that has continued to swirl for weeks afterward.

Several factors seem to have contributed to the story's gaining traction. Harrich’s work involves a modified version of an HIV protein (Tat) that can inhibit HIV replication; this was presented as a strategy that “turns HIV on itself.” Although this sounds potentially exciting and new (and clearly was appealing to the media), Harrich’s paper explains that, going as far back as the late 1980s, several other HIV proteins have been altered in ways that inhibit viral replication. This type of inhibition involves a well-described phenomenon wherein a modified protein (described as a dominant negative protein) can inhibit the function of the unmodified counterpart. The novel claim Harrich makes for his modified Tat protein, named Nullbasic, is that it appears to be able to inhibit several different steps in the HIV life cycle. This claim has yet to be independently verified but, more importantly, inhibiting HIV replication is not the major challenge in attempting to achieve a cure: as Harrich’s paper also notes, there is an array of proteins than can inhibit HIV. Furthermore, there are proteins that can completely block HIV from entering target cells (a strategy with many advantages compared to those like Harrich’s which attempt to block replication after the virus has entered a cell). The major problem in cure research is delivering these inhibitors to the cells where they are needed, and Harrich’s study does not help address this issue at all.  

In addition to the notion of turning HIV on itself, news stories glommed onto several egregiously irresponsible and unjustified quotes in the press release:

If this research continues down its strong path, and bear in mind there are many hurdles to clear, we’re looking at a cure for AIDS.

The use of the word if and the attempted caveat in the middle of this sentence do not compensate for the wild-eyed claim at the end. Like any other human disease, AIDS cannot be cured in a laboratory dish, and it is impossible to know if you are looking at a cure based on in vitro results. 

You would still be infected with HIV, it’s not a cure for the virus. But the virus would stay latent, it wouldn’t wake up, so it wouldn’t develop into AIDS. With a treatment like this, you would maintain a healthy immune system.

Perhaps unintentionally, this quote sounds like an early misunderstanding of HIV pathogenesis that was debunked by the early 1990s. In the original erroneous model, HIV was thought to be latent during the asymptomatic phase of the infection before somehow awakening to cause AIDS. It was subsequently shown that HIV replicates throughout the course of infection, causing a persistent activation of the immune system that leads to a gradual attrition of immune-system resources, ultimately resulting in AIDS. Many media outlets failed to notice this misstatement, and instead just repeated the claim that Harrich’s protein could prevent the development of AIDS. Harrich's in vitro results do not even show that Nullbasic causes HIV to "stay latent" in infected cells; rather they report a roughly eight- to tenfold reduction in viral replication.

In case this all sounds like pessimistic naysaying, the good news is that there are several gene therapy approaches that are already in human trials, including approaches that aim to completely protect vulnerable cells from HIV infection (drawing inspiration from the one well-documented case of an individual cured of HIV infection, which involved the transplant of cells lacking the key HIV coreceptor CCR5). These trials are attempting to address the thorny problem of delivering various HIV inhibitors to the most vulnerable cells, and thus are many miles further down the road than Harrich’s research (see TAG's cure research resource page for more information).

Additionally, the hype generated by the QIMR press release does not necessarily mean that Harrich’s development of Nullbasic is of no value; the apparent ability of the protein to block three different steps of the HIV life cycle has the potential to shed new light on how the Tat protein contributes to various aspects of viral replication, which in turn could reveal novel targets for inhibitors. Harrich’s paper is considerably more judicious than the press release in highlighting these prospects, concluding that “the unusual properties conveyed by Nullbasic make it a candidate antiviral agent. At the very least analysis of its mechanism of HIV-1 inhibition could advance discovery of novel antiviral strategies.” In addition to the publication in Human Gene Therapy (which has been made freely accessible by the journal), there appear to be just two prior papers describing Nullbasic, both in the open-access journal PLoS One (one in 2009 and the other in 2012). 

To try and draw some lessons for interpreting media coverage of scientific publications, it is notable that many of the initial news stories only featured quotes from the QIMR press release and included no comments about the study from independent scientists—this is one red flag to look out for. Eventually, outlets did begin to quote other sources, such as Frank Wegmann of Oxford University who raised the critical point that an HIV inhibitor is of no value unless it can be delivered to vulnerable cells. Several subsequent stories also highlighted the lack of animal studies and that, even in the most optimistic scenario, human trials are many years away. Perhaps the most disturbing aspect of this particular debacle is that the irresponsible claims of Harrich and QIMR were hugely successful in generating publicity; we must hope that this success does not tempt other scientists to indulge in misleading "cure" hype in the hopes of attracting research funding.

Hum Gene Ther. 2013 Jan 8. [Epub ahead of print]

A mutant Tat protein provides strong protection from HIV-1 infection in human CD4+ T cells.

Apolloni A, Sivakumaran H, Lin MH, Li D, Kershaw MH, Harrich D.

Source

Queensland Institute of Medical Research, Molecular and Cell Biology, Brisbane, Queensland, Australia

ABSTRACT

Here we show potent inhibition of HIV-1 replication in a human T cell line and primary human CD4+ cells by expressing a single antiviral protein. Nullbasic is a mutant form of the HIV-1 Tat protein that was previously shown to strongly inhibit HIV-1 replication in non-hematopoietic cell lines by targeting three steps of HIV-1 replication: reverse transcription, transport of viral mRNA and transactivation of HIV-1 gene expression. Here we investigated gene delivery of Nullbasic using lentiviral and retroviral vectors. While Nullbasic could be delivered by lentiviral vectors to target cells, transduction efficiencies were sharply reduced primarily due to negative effects on reverse transcription mediated by Nullbasic. However Nullbasic did not inhibit transduction of HEK293T cells by an MLV-based retroviral vector. Therefore, MLV-based VLPs were used to transduce and express Nullbasic-EGFP or EGFP in Jurkat cells, a human leukaemia T cell line, and Nullbasic-ZsGreen1 or ZsGreen1 in primary human CD4+ cells. HIV-1 replication kinetics was similar in parental Jurkat and Jurkat-EGFP cells, but was strongly attenuated in Jurkat-Nullbasic-EGFP cells. Similarly, virus replication in primary CD4+ cells expressing a Nullbasic-ZsGreen1 fusion protein was inhibited by approximately 8 to 10-fold. These experiments demonstrate the potential of Nullbasic, which has unique inhibitory activity, as an antiviral agent against HIV-1 infection.

David Baltimore and Vectored Immunoprophylaxis

In November 2011, the laboratory of Nobel laureate David Baltimore published encouraging results from humanized mouse studies of an approach to HIV prevention they have named vectored immunoprophylaxis (assigned the slightly uncomfortable acronym VIP). The strategy involves the use of adeno-associated virus (AAV) as a vector to deliver genes that make broadly neutralizing antibodies against HIV after delivery into muscle tissue. The ultimate goal is to make an end-run around the well-documented challenges associated with designing a vaccine capable of persuading the human immune system to generate broadly neutralizing antibodies. Instead, AAV would serve as a factory for the production of these antibodies, a task to which it is thought to be well-suited because it can persist for very long periods in the episome of cells. The idea was first developed by Phillip Johnson at the Children’s Hospital of Philadelphia, who is collaborating with the International AIDS Vaccine Initiative (IAVI) to launch phase I human testing of an AAV encoding the broadly neutralizing antibody PG9 (listed as AAV1-PG9 on the IAVI portfolio page). Johnson’s preclinical research in the SIV/macaque model has been covered previously on the blog.

Baltimore’s VIP work is now receiving renewed attention due to the posting of a video by Cara Santa Maria, who runs the appealingly named “Talk Nerdy to Me” science blog on Huffington Post. Inadvertently, the distillation of the research into a short-video-interview format suggests a narrative in which the VIP idea is unprecedented and unique, created by Baltimore and the scientists in his lab. Baltimore’s opening statement, “no one has ever tried this before,” is true in that VIP has yet to be tried in humans, but it risks glossing over the contributions of Johnson and many others who have long been wrestling with the complex issues involved in attempting to develop the technology for clinical testing. In essence, the approach is a gene therapy intended for healthy HIV-negative people, and it is very likely—and entirely appropriate—that plans for human trials will be closely scrutinized by regulators prior to approval. 

Beyond just safety, there are other issues pertaining the use of AAV as a vector that the video does not explore. A study published in Nature Medicine in 2007 demonstrated that humans—unlike mice or monkeys—typically possess AAV-specific CD8 T-cell responses that target the virus for elimination. These CD8 T-cell responses are thought to have contributed to the poor performance (and in some instances, toxicity) of AAV as a gene transfer vehicle in human trials for other conditions, such as hemophilia B. The presence in humans of AAV-specific CD8 T cells may also explain why IAVI-sponsored trials of AAV as a traditional vaccine vector found that it was poorly immunogenic (only around 20% of those receiving the highest dose showed low-level immune responses to the HIV antigens encoded by the AAV-based vaccine—starkly different from the promising-looking immunogenicity seen in macaques).

In their November 2011 Nature paper, David Baltimore and colleagues note that the AAV serotype they have chosen to work with, AAV8, has some differences compared to the more commonly used AAV2. They write:

"Studies in non-human primates have shown that the elicitation of capsid-specific cytotoxic T-lymphocytes is limited to AAV capsids that exhibit heparin-binding activity [26]. Interestingly, serotypes lacking heparin-binding activity, including AAV8, did not induce CTL responses, suggesting that AAV8-based vectors, like the one we have used, may circumvent previously observed immunological barriers to long-term transduction." 

However, they fail to cite the 2007 paper mentioned above, which is explicit that: “alternative serotypes currently being considered for clinical applications (for example, AAV-1, AAV-8) are processed in a manner appropriate for presentation of the same epitope(s), at least by human cells, resulting in expansion of functional CD8+ T cells that are indistinguishable from those elicited by AAV-2 capsid.”  

So far it appears that the only clue as to how this might play out in humans comes from a study of a hybrid AAV vector comprising the backbone of AAV2 with an AAV8 capsid, used to deliver the gene for factor IX. In a small clinical trial for the treatment of hemophilia B in which the vector was given via peripheral vein (to target the liver), encouraging evidence of therapeutic efficacy was observed, which was not the case in a prior trial involving a vector consisting entirely of AAV2. But most participants did show some evidence of T cell responses against the AAV8 capsid, indicating that the hope that this serotype would be completely invisible to CD8 T cells has not borne out. 

Thankfully though, that is not the end of the story. A study published just a couple of days ago in the journal Blood suggests that additional modifications to AAV can significantly reduce CD8 T cell recognition. And last year in the same journal, researchers reported that the AAV2 vector used to deliver the gene for factor IX in the first hemophilia B clinical trial could still be detected in muscle tissue ten years after administration. Although the level of factor IX production achieved in this trial was too low to be therapeutic, the authors conclude: “these data do establish that AAV2-mediated gene transfer to human skeletal muscle can persist for up to a decade. The use of alternate serotypes and/or delivery techniques that can perfuse muscle more extensively may improve therapeutic efficacy for this approach." This conclusion also offers hope for VIP because, as David Baltimore stresses in the video interview, his lab’s humanized mice experiments suggest that protection against HIV infection might be achievable with relatively low levels of broadly neutralizing antibodies.

Dendritic Cell-Based Therapeutic HIV Vaccine Transiently Modulates Viral Load

A study published in the January 2 issue of Science Translational Medicine reports that a dendritic cell (DC)-based therapeutic HIV vaccine was able to significantly lower viral load after an antiretroviral therapy (ART) interruption, albeit only transiently. The publication drew considerable press coverage, most of it reasonably accurate although some headline writers got carried away (while potentially representing a step forward for therapeutic HIV vaccine research, the results are not a “huge breakthrough” as one headline stated).

A number of prior trials have offered hints that therapeutic vaccination can mildly improve immune control of HIV replication, but they have tended to be small and uncontrolled (lacking a placebo comparator). A randomized, placebo-controlled trial of the Merck Ad5-based HIV vaccine conducted by the ACTG did find a trend toward lower viral load during a treatment interruption, but the result did not quite reach statistical significance. The major strengths of this new study, led by Felipe García from the University of Barcelona, are that it was randomized and placebo-controlled, and that the viral-load difference between vaccine- and placebo recipients was statistically significant at the 24-week timepoint after ART interruption (−0.80 vs. −0.19 logs, P = 0.01). However, after 48 weeks of follow-up, the difference was no longer significant (P = 0.66).

The researchers also report the following number of participants who displayed viral-load decreases of greater than 1 log (a reduction of 90 percent or more compared to baseline) in the vaccine versus placebo groups at different timepoints during follow-up:

• Week 12: 12/22 (55%) versus 1/11 (9%)
• Week 24: 7/20 (35%) versus 0/10 (0%)
• Week 48: 3/17 (18%) versus 1/6 (17%)

These differences were statistically significant in favor of the vaccine group at weeks 12 and 24, but not at week 48. There were no significant differences in CD4 T-cell counts between the two groups at any time over the 48-week period. Analyses of HIV-specific T-cell responses (using an ELISPOT assay measuring interferon-gamma production in response to HIV Gag, Nef, and Env gp41 peptides) revealed a statistical trend toward an inverse association with viral load in the vaccine group (P = 0.08), while in the placebo group there was a significant positive association with viral load. This result suggests that HIV-specific T-cell responses in vaccine recipients were at least partly effective, whereas in placebo recipients the detected HIV-specific T cells were flailing away ineffectively.

The researchers manufactured the vaccine by harvesting monocyte-derived DCs from study participants and exposing them to heat-inactivated HIV isolated from the same individuals. The placebo consisted of DCs unexposed to HIV. A relatively high dose of ~10 million DCs was administered three times, at two-week intervals (either before or immediately after ART interruption). In discussing the results, the researchers point out that several DC-based vaccines have previously shown hints of promise, with the use of HIV or HIV antigens from individual study participants (autologous HIV) appearing to be important for achieving significant viral-load effects. They acknowledge that the degree of virological control achieved in their study is far from the optimal goal of achieving a functional cure, which is defined as a long-lasting reduction in viral load to undetectable levels after ART interruption. Despite this caveat, they conclude: “This is a proof of concept justifying further investigation of new candidates and/or new optimized strategies of vaccination with the final objective of obtaining a functional cure as an alternative to ART for life.”

The publication of this study occurs at a time of renewed interest in therapeutic HIV vaccines in the context of cure research, prompted by a study suggesting that HIV-specific immunity needs to be enhanced in order to help eradicate HIV reservoirs. Furthermore, there is some evidence that a proportion—perhaps even the majority—of the latent HIV reservoir resides in HIV-specific CD4 T cells, leading to the hypothesis that therapeutic HIV vaccines could also help activate these CD4 T cells and thus awaken the virus they contain, making it visible to the immune system. Studies are now being planned that will further investigate these issues. 

Sci Transl Med 2 January 2013: Vol. 5, Issue 166, p. 166ra2 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3004682

RESEARCH ARTICLE

A Dendritic Cell–Based Vaccine Elicits T Cell Responses Associated with Control of HIV-1 Replication

Felipe García1,*,†, Nuria Climent1,*, Alberto C. Guardo1, Cristina Gil1, Agathe León1, Brigitte Autran2, Jeffrey D. Lifson3, Javier Martínez-Picado4,5, Judit Dalmau4, Bonaventura Clotet4, Josep M. Gatell1, Montserrat Plana1,*, Teresa Gallart1,*, For the DCV2/MANON07-ORVACS Study Group

1Hospital Clinic-IDIBAPS, HIVACAT, University of Barcelona, 08036 Barcelona, Spain. 2INSERM UMR-S-945, Université Paris-VI Pierre-et-Marie-Curie, Hôpital Pitié-Salpêtrière, 75013 Paris, France. 3AIDS and Cancer Virus Program, SAIC-Frederick Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. 4AIDS Research Institute IrsiCaixa, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, 08916 Badalona, Spain. 5Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain.

*These authors contributed equally to this work.

ABSTRACT

Combination antiretroviral therapy (cART) greatly improves survival and quality of life of HIV-1–infected patients; however, cART must be continued indefinitely to prevent viral rebound and associated disease progression. Inducing HIV-1–specific immune responses with a therapeutic immunization has been proposed to control viral replication after discontinuation of cART as an alternative to “cART for life.” We report safety, tolerability, and immunogenicity results associated with a control of viral replication for a therapeutic vaccine using autologous monocyte-derived dendritic cells (MD-DCs) pulsed with autologous heat-inactivated whole HIV. Patients on cART with CD4+ >450 cells/mm3 were randomized to receive three immunizations with MD-DCs or with nonpulsed MD-DCs. Vaccination was feasible, safe, and well tolerated and shifted the virus/host balance. At weeks 12 and 24 after cART interruption, a decrease of plasma viral load setpoint ≥1 log was observed in 12 of 22 (55%) versus 1 of 11 (9%) and in 7 of 20 (35%) versus 0 of 10 (0%) patients in the DC–HIV-1 and DC-control groups, respectively. This significant decrease in plasma viral load observed in immunized recipients was associated with a consistent increase in HIV-1–specific T cell responses. These data suggest that HIV-1–specific immune responses elicited by therapeutic DC vaccines could significantly change plasma viral load setpoint after cART interruption in chronic HIV-1–infected patients treated in early stages. This proof of concept supports further investigation of new candidates and/or new optimized strategies of vaccination with the final objective of obtaining a functional cure as an alternative to cART for life.

Lymph Node Fibrosis, CD4 T Cells, and Immune Reconstitution

One of the less well-publicized consequences of the persistent immune activation caused by HIV infection is a type of scarring damage to lymph tissues described as fibrosis. Some early studies of lymph nodes from HIV-infected individuals reported evidence of this problem, but it wasn’t until the publication of a study by the research group of Ashley Haase in 2002 that a connection was made between the extent of fibrosis (as measured by deposition of collagen) and maintenance of CD4 T-cell numbers. Haase and colleagues showed that there was an inverse correlation between lymph node fibrosis and the number of CD4 T cells measurable in the same node. Importantly, they also found that the degree of fibrosis was significantly associated with the magnitude of CD4 T-cell increases after initiation of antiretroviral therapy, with greater fibrosis linked to poorer CD4 T-cell recovery.

In the subsequent years, Haase’s group has delved further into the mechanisms underlying these findings. In 2011, they reported that fibrosis disrupts the fibroblastic reticular cell (FRC) network, which forms pathways along which T cells travel on their journey through lymph tissue. The FRC network provides fuel for maintaining T-cell health in the form of the cytokine IL-7, and fibrotic damage to FRCs was found to inhibit the ability of T cells to access IL-7, leading to cell death. The study also identified the cytokine lymphotoxin-β as critical for maintaining FRCs, and suggested that loss of CD4 T cells was linked to a decline in lymphotoxin-β production, further exacerbating the problem created by the fibrosis.

In an important paper published last summer that I neglected to write about at the time, the researchers confirm that CD4 T cells are the major source of lymphotoxin-β, thus demonstrating that fibrosis creates a vicious cycle by depleting factors needed for CD4 T-cell survival, leading to CD4 T-cell loss, which in turn removes a critical source of factors needed to maintain the FRC network that provides sustenance to CD4 T cells. The study offers evidence that this problem is relevant to not just HIV infection but also CD4 depletion after chemotherapy and irradiation in individuals with cancer. 

In an accompanying editorial, Steve Deeks from UCSF notes that the research suggests possible interventions that could be evaluated in the context of HIV-induced persistent immune activation and CD4 T-cell depletion: “These experimental interventions include drugs that remove pro-inflammatory pathogens and microbial products (eg, valganciclovir for CMV, rifaximin for gut microbes, sevelamer for lipopolysaccharide), drugs that directly prevent fibrosis (eg, angiotensin II receptor antagonists* and ACE inhibitors), and drugs that have more broad effects in reducing inflammation (eg, statins, nonsteroidal antinflammatory drugs, methotrexate, and mesalamine).” Deeks also points out that the best way of avoiding fibrotic damage to the lymph nodes is to suppress HIV replication as soon as possible after infection.

A more recent study, published in the Journal of Infectious Diseases this past October, offers further support for the conclusions of Haase et al. Researchers led by Brian Tabb from the laboratory of Jacob Estes at NCI–Frederick report that blocking the inflammatory cytokine TNF alpha in early SIV infection reduced lymphoid-tissue fibrosis and was associated with better preservation of CD4 T-cell numbers in macaques (without affecting SIV viral load). The authors conclude: “This initial study highlights the importance of early inflammatory responses to lentiviral infections and underscores the need for additional studies to ascertain the potential clinical benefits of adjunctive therapies to attenuate these responses and to improve patient outcomes.”

*TAG’s new HIV project director, Tim Horn, has recently led an effort to support AIDS Clinical Trial Group investigators seeking to obtain the angiotensin II receptor antagonist telmisartan (trade name: Micardis) from the manufacturer, Boehringer Ingelheim, for a study in people with HIV. Unfortunately, the company remains unwilling to provide drug for the planned trial, citing regulatory concerns. This situation highlights issues that will likely arise again in the future as investigators attempt to conduct exploratory studies of these types of potential adjunctive treatments in HIV infection: many of the candidate interventions are already indicated for other uses and are off-patent or toward the end of their patent life; additionally, the research is at such an early stage that it is probing questions of disease pathogenesis rather than carving a clear path toward an FDA-approved HIV indication. Activists are continuing to discuss possible approaches to addressing these issues in order to ensure that needed research can proceed.

Blood August 30, 2012 vol. 120 no. 9 1753-1754

HIV infection, lymphoid fibrosis, and disease

Steven G. Deeks

In this issue of Blood, Zeng and colleagues demonstrate in SIV-infected macaques and HIV-infected humans that CD4+ T cells actively maintain the fibroblastic reticular cell network in lymphoid tissues and that this network in turn is needed to maintain normal T-cell homeostasis and function.

Blood August 30, 2012 vol. 120 no. 9 1856–1867

Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution

Ming Zeng1, Mirko Paiardini2, Jessica C. Engram3, Greg J. Beilman4, Jeffrey G. Chipman4, Timothy W. Schacker5, Guido Silvestri2, and Ashley T. Haase1 

1Department of Microbiology, Medical School, University of Minnesota, Minneapolis, MN;

2Yerkes National Primate Research Center and Emory University, Atlanta, GA;

3University of Pennsylvania School of Medicine, Philadelphia, PA;

4Department of Surgery, University of Minnesota, Minneapolis, MN; and

5Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN 

ABSTRACT

Loss of the fibroblastic reticular cell (FRC) network in lymphoid tissues during HIV-1 infection has been shown to impair the survival of naive T cells and limit immune reconstitution after antiretroviral therapy. What causes this FRC loss is unknown. Because FRC loss correlates with loss of both naive CD4 and CD8 T-cell subsets and decreased lymphotoxin-β, a key factor for maintenance of FRC network, we hypothesized that loss of naive T cells is responsible for loss of the FRC network. To test this hypothesis, we assessed the consequences of antibody-mediated depletion of CD4 and CD8 T cells in rhesus macaques and sooty mangabeys. We found that only CD4 T-cell depletion resulted in FRC loss in both species and that this loss was caused by decreased lymphotoxin-β mainly produced by the CD4 T cells. We further found the same dependence of the FRC network on CD4 T cells in HIV-1–infected patients before and after antiretroviral therapy and in other immunodeficiency conditions, such as CD4 depletion in cancer patients induced by chemotherapy and irradiation. CD4 T cells thus play a central role in the maintenance of lymphoid tissue structure necessary for their own homeostasis and reconstitution. 

J Infect Dis. (2012)

doi: 10.1093/infdis/jis643

First published online: October 19, 2012

Reduced Inflammation and Lymphoid Tissue Immunopathology in Rhesus Macaques Receiving Anti-TNF Treatment During Primary SIV Infection

Brian Tabb1,7, David R. Morcock1, Charles M. Trubey1, Octavio A. Quiñones2, Xing Pei Hao3, Jeremy Smedley4, Rhonda Macallister4, Michael Piatak Jr1, Levelle D. Harris5, Mirko Paiardini6, Guido Silvestri6, Jason M. Brenchley5, W. Gregory Alvord2, Jeffrey D. Lifson1 and Jacob D. Estes1 

1AIDS and Cancer Virus Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD

2Statistical Consulting, Data Management Services, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD

3Pathology and Histotechnology Laboratory, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD

4Laboratory Animal Science Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD

5Immunopathogenesis Unit, Lab of Molecular Microbiology, NIAID, NIH, Bethesda, MD

6Yerkes National Primate Research Center, Emory University, Atlanta, Georgia

7Present address: XYZ, Memphis, TN 

Abstract 

Background. HIV/SIV infections induce robust, generalized inflammatory responses that begin during acute infection and lead to pathological systemic immune activation, fibrotic damage of lymphoid tissues (LTs) and CD4+ T cell loss, pathogenic processes that contribute to disease progression.

Methods. To better understand the contribution of TNF, a key regulator of acute inflammation, to lentiviral pathogenesis, rhesus macaques (RMs) newly infected with SIVmac239 were treated for 12 weeks in a pilot study with adalimumab (Humira), a human anti-TNF mAb.

Results. Adalimumab did not affect plasma SIV RNA levels or measures of T-cell immune activation (CD38 or Ki67) in peripheral blood or lymph node T cells. However, compared to untreated RMs, adalimumab-treated RMs showed attenuated expression of pro-inflammatory genes, decreased infiltration of polymorphonuclear cells into the T cell zone (TZ) of LTs and weaker anti-inflammatory regulatory responses to SIV infection (i.e. fewer presumed alternatively activated (CD163+) macrophages, IL-10+ and TGFβ+ cells), along with reduced LT fibrosis and better preservation of CD4+ T cells.

Conclusions. While HIV/SIV replication drives pathogenesis, these data emphasize the contribution of the inflammatory response to lentiviral infection to overall pathogenesis, and suggest that early modulation of the inflammatory response may help attenuate disease progression.

J Infect Dis. first published online October 24, 2012

doi:10.1093/infdis/jis648

EDITORIAL:

Cooling off the Host Immune Response to Acute SIV Infection—Is Less More?

Nelson L. Michael