TAG HIV Basic Science, Vaccines, and Cure Project Blog

T Cell Vaccines Need Help

A new paper from Genoveffa Franchini's group evaluates the impact of transiently depleting CD4 T cells during the priming phase of a DNA/MVA prime-boost vaccine regimen in macaques. After an SIV challenge, significant differences in viral loads were not seen during the acute phase of infection, but began to emerge over time. These increases in viral loads among the CD4-depleted animals were associated with diminished functionality of HIV-specific CD8 T cells compared to the vaccinated macacques that did not undergo CD4 depletion. The authors conclude with the recommendation that "strategies aimed at eliciting effective T-cell responses to HIV by vaccination must broaden their scope beyond generation of antigen-specific CD8+ T-cells to include optimization of the generation of CD4+ T-cells of the right quality and magnitude."

JVI Accepts, published online ahead of print on 30 July 2008
J. Virol. doi:10.1128/JVI.00893-08

Reduced Protection From SIVmac251 Afforded by Memory CD8+ T-cells Induced by Vaccination in Condition of CD4+ T-cell Deficiency

Monica Vaccari, Joseph Mattapallil, Kaimei Song, Wen-Po Tsai, Anna Hryniewicz, David Venzon, Maurizio Zanetti, Keith A. Reimann, Mario Roederer, and Genoveffa Franchini

Animal Models & Retroviral Vaccines Section, and Biostatistics & Data Management Section, National Cancer Institute, Bethesda, MD 20892; Department of Microbiology & Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy & Infectious Diseases, Bethesda, MD 20892; Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093; Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

Adaptive CD4+ and CD8+ T-cell responses have been associated with control of HIV/simian immunodeficiency virus (SIV) replication. In here, we have designed a study in macaques to assess more directly the role of CD8 SIV-specific responses in control of viral replication. Indian Rhesus Macaques were immunized with a DNA prime-MVA-SIV boost regimen in normal condition or in condition of antibody-induced CD4+ T cell deficiency. Depletion of CD4+ cells was performed in the immunized macaques at the peak of SIV-specific CD4+ T-cell responses following DNA prime. A group of naïve macaques were also treated with the anti-CD4 depleting antibody as control, and an additional group of macaques immunized in normal condition was depleted of CD8+ T-cells prior challenge exposure to SIVmac251. Analysis of the quality and quantity of vaccine induced CD8+ T cells demonstrated that SIV-specific CD8+ T-cells generated in conditions of CD4+ T-cell deficiency expressed low levels of Bcl2 and interleukin-2 (IL-2) and plasma virus level increased over time in these animals. Depletion of CD8+ T-cells prior challenge exposure abrogated vaccine-induced protection as expected. These data support the notion that adaptive CD4+ T-cells are critical for the generation of effective CD8+ T-cell responses to SIV that in turn contribute to protection from AIDS. Importantly, they also suggest that long-term protection from disease will only be afforded by T-cell vaccines for HIV that provide a balanced induction of CD4+ and CD8+ T-cell responses and protect against early depletion of CD4+ T-cells post-infection.

Siglecs Revisited

Back in 2006, a study published in PNAS suggested that chimpanzees may be relatively resistant to AIDS due to proteins called Siglecs (sialic acid-recognizing Ig-super family lectins). Siglecs are involved in downregulating innate immune activation and the PNAS study, authored by Dzung Nguyen and colleagues, showed that chimpanzee T cells express Siglecs while human T cells do not. The study further showed that Siglec expression appeared to make chimpanzee T cells less sensitive to CD3-mediated activation, offering a potential explanation of why the animals rarely develop immune activation (and, ultimately, AIDS) as a result of HIV infection.

Now, a new paper in J. Virology raises a caveat regarding the interpretation of these data. It turns out that the antibody used to stimulate T cells in the PNAS study, dubbed UCHT1, may be intrinsically less able to stimulate chimpanzee T cells compared to other anti-CD3 antibodies. The authors of the new paper, led by Frederic Bibollet-Ruche, show that the activation of human and chimpanzee T cells is far more comparable when a different anti-CD3 antibody (OKT3) is used. These differences are explained by the fact that the two antibodies belong to different isotypes; UCHT1 is an IgG1 antibody but OKT3 is IgG2a.

While chimpanzee T cells still appeared somewhat less efficiently activated even with OKT3, the authors emphasize that the optimal conditions for activating these cells in vitro remains unknown and needs to be resolved in order for future comparisons to be made with any confidence (they note, for example, that the use of anesthesia and restraint prior to sampling could impact the functional profile of the T cells).

JVI Accepts, published online ahead of print on 30 July 2008
J. Virol. doi:10.1128/JVI.01319-08

The quality of chimpanzee T cell activation and SIV/HIV susceptibility achieved via antibody-mediated TCR/CD3 stimulation is a function of the anti-CD3 antibody isotype

Frederic Bibollet-Ruche, Brett A. McKinney, Alexandra Duverger, Frederic H. Wagner, Aftab A. Ansari, and Olaf Kutsch

Departments of Medicine and Genetics, The University of Alabama at Birmingham, Birmingham, AL; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA

While HIV-1 infection is associated with hyper-immune activation and systemic depletion of CD4+ T cells, SIV infection in sooty mangabeys or chimpanzees does not exhibit these hallmarks. Control of immune activation is thought to be one of the major components that govern species dependent differences in the disease pathogenesis. A previous study introduced the idea that the resistance of chimpanzees to SIVcpz infection induced hyper-immune activation could be the result of the expression of select sialic acid recognizing Ig-super family lectins (Siglec) by chimpanzee T cells. Siglecs, which are absent on human T cells, were reasoned to control levels of T cell activation in chimpanzees and thus suggested to account for the pathogenic differences in the course of SIVcpz or HIV-1 infection. As in human models of T cell activation, stimulation had been attempted using an anti-CD3 monoclonal antibody (mAb) (UCHT1; IgG1), but despite efficient binding, UCHT1 failed to activate chimpanzee T cells, an activation block that could be partially overcome by mAb-induced Siglec-5 internalization. We herein demonstrate that anti-CD3 mAb-mediated chimpanzee T cell activation is a function of the anti-CD3 mAb isotype and is not governed by Siglec expression. While IgG1 anti-CD3 mAbs fail to stimulate chimpanzee T cells, IgG2a anti-CD3 mAbs activate chimpanzee T cells in the absence of Siglec manipulations. Our results thus imply that prior to studying possible differences between human and chimpanzee T cell activation, a relevant model of chimpanzee T cell activation needs to be established.

The Plight of the Helpless: B Cell Dysfunction in HIV Infection Echoes T Cell Dysfunction

Last week, a research team led by Susan Moir from Anthony Fauci’s lab at NIAID published a potentially important paper on B cell dysfunction in HIV infection. It’s something of a sad commentary on the quality of science reporting in the mainstream media that, despite the issuance of a press release by NIAID, the study seems to have received no coverage whatsoever. Admittedly, immunology research can appear impenetrably arcane to the uninitiated, but it’s a shame that good science frequently goes uncovered while – as we’ve seen recently with stories on vaccine trials - misinformation about HIV research can get plastered across front pages.

Historically, research into the effects of HIV infection on B cell populations has been limited compared to the more extensive investigations into the impact of the virus on T cells. But over the past several years, Susan Moir and colleagues have conducted an impressive array of studies that have opened a window onto this obscure area of HIV pathogenesis. Many of the insights gained from these and other studies are described by Moir and Fauci in a free review in the special issue of the Journal of Allergy & Clinical Immunology mentioned in a prior post. What is fairly striking – although perhaps not entirely surprising - is that HIV infection appears to impact B cell populations in ways that are broadly similar to the effects of the virus on T cell populations. In both cases, HIV-induced immune activation appears to be driving the changes, which involve declines in the numbers of resting naïve and memory B cells and increases in the number of activated and dysfunctional B cells.

In this study, detailed evaluation of B cell phenotypes in people with HIV identified a subset of B cells that expressed high levels of inhibitory receptors (reminiscent of data on CTLA-4 and PD-1 expression on T cells in people with HIV) and displayed poor proliferative capacity. Analysis of the replicative history of these B cells suggests that they became dysfunctional and exhausted while en route differentiating from naïve to classical memory B cells. Interestingly, the population was enriched for HIV-specific responses, again echoing data showing that dysfunctional HIV-specific T cell responses accumulate over the course of disease (see for example this figure from a comprehensive analysis of HIV-specific CD4 and CD8 T cell responses in people at varying stages of disease progression; participant #21 - in whom around 18% of CD8 T cells and 3% of CD4 T cells make interferon gamma in response to HIV antigens - has a CD4 count of 181 and is the only participant with an AIDS diagnosis. The total number of HIV-specific T cells in this individual is actually certainly far greater because the capacity for interferon gamma production is lost by fully exhausted T cells and the consensus peptides used in the study do not capture the HIV sequence variation that occurs in an individual over time).

The theme that seems to be emerging from these data is that HIV, by preferentially infecting HIV-specific CD4 T cells, compromises the CD4 response from the very earliest stages of infection, and the lack of a fully functional HIV-specific memory CD4 T cell response deprives both HIV-specific B cells and HIV-specific CD8 T cells of the help they require to properly differentiate into memory cells. It would be interesting to know if the accumulation of dysfunctional HIV-specific T cell and B cell responses is linked to the loss of memory responses to opportunistic pathogens in people with AIDS.

In a related development, a new paper in the Journal of Immunology suggests that, despite their differences, the development of memory B cells and T cells is associated with gene transcription programs that have distinct similarities (abstract and link below).

The Journal of Experimental Medicine
Published online July 14, 2008
doi:10.1084/jem.20072683

BRIEF DEFINITIVE REPORT

Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals

Susan Moir1, Jason Ho1, Angela Malaspina1, Wei Wang1, Angela C. DiPoto1, Marie A. O'Shea1, Gregg Roby1, Shyam Kottilil1, James Arthos1, Michael A. Proschan2, Tae-Wook Chun1, and Anthony S. Fauci1
1 Laboratory of Immunoregulation and 2 Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, MD 20892

Human immunodeficiency virus (HIV) disease leads to impaired B cell and antibody responses through mechanisms that remain poorly defined. A unique memory B cell subpopulation (CD20hi/CD27lo/CD21lo) in human tonsillar tissues was recently defined by the expression of the inhibitory receptor Fc-receptor-like-4 (FCRL4). In this study, we describe a similar B cell subpopulation in the blood of HIV-viremic individuals. FCRL4 expression was increased on B cells of HIV-viremic compared with HIV-aviremic and HIV-negative individuals. It was enriched on B cells with a tissuelike memory phenotype (CD20hi/CD27–/CD21lo) when compared with B cells with a classical memory (CD27+) or naive (CD27–/CD21hi) B cell phenotype. Tissuelike memory B cells expressed patterns of homing and inhibitory receptors similar to those described for antigen-specific T cell exhaustion. The tissuelike memory B cells proliferated poorly in response to B cell stimuli, which is consistent with high-level expression of multiple inhibitory receptors. Immunoglobulin diversities and replication histories were lower in tissuelike, compared with classical, memory B cells, which is consistent with premature exhaustion. Strikingly, HIV-specific responses were enriched in these exhausted tissuelike memory B cells, whereas total immunoglobulin and influenza-specific responses were enriched in classical memory B cells. These data suggest that HIV-associated premature exhaustion of B cells may contribute to poor antibody responses against HIV in infected individuals.

The Journal of Immunology, 2008, 181: 1859-1868.

Identification of an Evolutionarily Conserved Transcriptional Signature of CD8 Memory Differentiation That Is Shared by T and B Cells

W. Nicholas Haining, Benjamin L. Ebert, Aravind Subrmanian, E. John Wherry, Quentin Eichbaum, John W. Evans, Raymond Mak, Stephen Rivoli, Jennifer Pretz, Jill Angelosanto, John S. Smutko, Bruce D. Walker, Susan M. Kaech, Rafi Ahmed, Lee M. Nadler and Todd R. Golub

After Ag encounter, naive lymphocytes differentiate into populations of memory cells that share a common set of functions including faster response to Ag re-exposure and the ability to self-renew. However, memory lymphocytes in different lymphocyte lineages are functionally and phenotypically diverse. It is not known whether discrete populations of T and B cells use similar transcriptional programs during differentiation into the memory state. We used cross-species genomic analysis to examine the pattern of genes up-regulated during the differentiation of naive lymphocytes into memory cells in multiple populations of human CD4, CD8, and B cell lymphocytes as well as two mouse models of memory development. We identified and validated a signature of genes that was up-regulated in memory cells compared with naive cells in both human and mouse CD8 memory differentiation, suggesting marked evolutionary conservation of this transcriptional program. Surprisingly, this conserved CD8 differentiation signature was also up-regulated during memory differentiation in CD4 and B cell lineages. To validate the biologic significance of this signature, we showed that alterations in this signature of genes could distinguish between functional and exhausted CD8 T cells from a mouse model of chronic viral infection. Finally, we generated genome-wide microarray data from tetramer-sorted human T cells and showed profound differences in this differentiation signature between T cells specific for HIV and those specific for influenza. Thus, our data suggest that in addition to lineage-specific differentiation programs, T and B lymphocytes use a common transcriptional program during memory development that is disrupted in chronic viral infection.

Expression of the Duffy Antigen Receptor for Chemokines May Impact Susceptibility to HIV Infection

A new and complex study has identified a possible genetic influence on susceptibility to HIV acquisition that preferentially impacts Africans and people of recent African descent. The paper is available free on the website of the journal Cell Host & Microbe (link below). As best I can discern, the major points are as follows:

• The Duffy Antigen Receptor for Chemokines (DARC) on red blood cells can bind a slew of different chemokines and also HIV itself (X4-using HIV isolates much more than R5-using isolates).

• A genetic change (called a single nucleotide polymorphism or SNP) can lead to a lack of DARC receptors on red blood cells. This SNP is very common in Africans and people of recent African descent, because it once protected against a form of malaria caused by the pathogen Plasmodium vivax. Data indicates the SNP is present in around 60% of African Americans and 90% of Africans.

• In a large cohort of African American individuals from the US military, having the DARC-negative SNP was associated with a significantly increased risk of having HIV infection, even in multivariate analyses controlling for various confounding variables. However, the confidence intervals on the multivariate analyses appear to approach a relative risk of 1.0 at the low end (in other words, based on the numbers in this study, it is within the bounds of possibility that the SNP has little impact on susceptibility). The result appears to rest on the finding that perhaps ~60% of 814 HIV-negative African Americans lacked the DARC receptor compared to ~70% of 470 HIV-infected African Americans.

• If the result holds up, the fact the SNP is nearly ubiquitous among African populations could contribute to the higher incidence of HIV infection on that continent (the researchers estimate it might explain ~11%).

• The absence of the DARC receptor is associated with lower levels of CCL5 (formerly called RANTES), a chemokine with strong anti-HIV activity, providing a possible mechanistic explanation of the finding. A prior study has reported that persistently exposed, uninfected sex workers have ten-fold higher levels of CCL5 in the genital tract compared to both infected individuals and uninfected study participants who had recently started sex work and thus had little prior exposure to HIV. Higher CCL5 production has also been reported in highly exposed but uninfected gay men.

• Although at first blush it might sound paradoxical, the absence of DARC was also associated with a slight but significant slowing of disease progression in the HIV-infected members of the study cohort. The researchers suggest that this is likely explained by the association between the presence of DARC and higher levels of pro-inflammatory chemokines such as CCL2. Once infection occurs, the authors propose, the presence of DARC may exacerbate immune activation due to this association with elevated levels of pro-inflammatory chemokines (immune activation is the single strongest predictor of the pace of disease progression in people with HIV). While this hypothesis remains speculative, the authors argue it is supported by an association they have reported previously; in that case, a SNP that increases CCL2 levels in European Americans was shown to be linked to reduced susceptibility to acquisition of HIV infection and also faster disease progression in infected individuals. Another non-exclusive possibility raised by the authors is that the absence of DARC slows progression by preventing transfer of DARC-bound HIV particles to CD4 T cells.

In discussing their results, the study authors acknowledge that there is a possibility that the associations they have observed are connected to an unknown factor or factors that are linked to the DARC SNP, and stress that confirmation of these results in other cohorts will be necessary to ensure they are valid. If it does turn out that there is a protective effect mediated by elevated levels of CCL5, this information could potentially assist vaccine development, as it would suggest that using adjuvants that elevate CCL5 levels and/or inducing HIV-specific T cell responses that produce CCL5 could be useful strategies for HIV vaccines.

Cell Host and Microbe, Vol 4, 52-62, 17 July 2008

Article

Duffy Antigen Receptor for Chemokines Mediates trans-Infection of HIV-1 from Red Blood Cells to Target Cells and Affects HIV-AIDS Susceptibility

Weijing He,1,2,9 Stuart Neil,3,9 Hemant Kulkarni,1,2,9 Edward Wright,3,9 Brian K. Agan,4,5,6,7 Vincent C. Marconi,4,5,7 Matthew J. Dolan,4,5,6,7,∗∗∗ Robin A. Weiss,3,∗∗ and Sunil K. Ahuja1,2,8,∗

1 Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, San Antonio, TX 78229, USA
2 Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA
3 Division of Infection and Immunity, University College London, London, UK
4 Infectious Disease Clinical Research Program, Uniformed Services University, Bethesda, MD 20814, USA
5 Infectious Disease Service, Wilford Hall United States Air Force Medical Center, Lackland Air Force Base, TX 78236, USA
6 Henry M. Jackson Foundation, Wilford Hall United States Air Force Medical Center, Lackland Air Force Base, TX 78236, USA
7 San Antonio Military Medical Center, Fort Sam Houston, TX 78234, USA
8 Department of Microbiology and Immunology, and Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA

Duffy antigen receptor for chemokines (DARC) expressed on red blood cells (RBCs) influences plasma levels of HIV-1-suppressive and proinflammatory chemokines such as CCL5/RANTES. DARC is also the RBC receptor for Plasmodium vivax. Africans with DARC −46C/C genotype, which confers a DARC-negative phenotype, are resistant to vivax malaria. Here, we show that HIV-1 attaches to RBCs via DARC, effecting trans-infection of target cells. In African Americans, DARC −46C/C is associated with 40% increase in the odds of acquiring HIV-1. If extrapolated to Africans, ∼11% of the HIV-1 burden in Africa may be linked to this genotype. After infection occurs, however, DARC-negative RBC status is associated with slower disease progression. Furthermore, the disease-accelerating effect of a previously described CCL5 polymorphism is evident only in DARC-expressing and not in DARC-negative HIV-infected individuals. Thus, DARC influences HIV/AIDS susceptibility by mediating trans-infection of HIV-1 and by affecting both chemokine-HIV interactions and chemokine-driven inflammation.

Enhancing T Cell Memory with IL-7

The latest issue of Immunology & Cell Biology features an interesting commentary by Jared Purton and colleagues on the use of the cytokine IL-7 to enhance memory T cell responses. So far, attempts to improve DNA vaccine immunogenicity using cytokines have proven largely unsuccessful, but emerging data suggests that the timing of administration may be a critical variable. Purton and colleagues cite a recent study showing that administering IL-7 during the contraction phase of a CD8 T cell response can enhance memory CD8 T cell formation in mice, and propose that these results might be further improved using an approach they have developed which complexes IL-7 with an anti-IL-7 monoclonal antibody (both study abstracts are appended below).

Interestingly, at CROI earlier this year, data was presented from a phase I trial of IL-7 in people with HIV infection showing that administration of the cytokine was associated with changes in the functional profile of HIV-specific memory CD4 T cell responses. Although the follow-up is only short-term, the numbers of HIV-specific memory CD4 T cell capable of producing IL-2 were significantly increased among IL-7 recipients, a phenomenon not seen in studies of other cytokines. Hopefully future studies will elucidate how this relates to observations regarding the influence of IL-7 on CD8 T cell memory. A phase I trial of a glycosylated form of IL-7 with improved pharmacokinetics is slated to start soon, details can be found in the clinicaltrials.gov listing.

This issue of Immunology & Cell Biology also contains a special feature on the determination of T cell fate by dendritic cells, which includes several free access reviews including Geography and plumbing control the T cell response to infection by Kamal Khanna and Leo Lefrançois and Dendritic cell behaviour in vivo: lessons learned from intravital two-photon microscopy by Lois Cavanagh and Wolfgang Weninger.

Immunology and Cell Biology (2008) 86, 385–386; doi:10.1038/icb.2008.30

News and Commentary

Enhancing T cell memory: IL-7 as an adjuvant to boost memory T-cell generation

Jared F Purton, Chris E Martin and Charles D Surh

Correspondence: Dr JF Purton, Scripps Research Institute, IMM-26, La Jolla, CA 92037, USA.

Cytokines play a central role in regulating the homeostasis of naïve and memory T cells and their responses to pathogens. Surprisingly, not much is known about the ability of exogenously administered cytokines to affect the formation of memory T cells. In a recent study, Nanjappa et al.1 have shown that infusion of interleukin (IL)-7 during the contraction phase of a T-cell response can augment the accumulation of functional viral-specific memory T cells. As the formation of a large pool of memory T cells is the main goal of vaccination, these findings suggest that cytokines could be applied therapeutically to enhance vaccine efficacy.

J. Clin. Invest. 118(3): 1027-1039 (2008). doi:10.1172/JCI32020.

Research Article

Effects of IL-7 on memory CD8+ T cell homeostasis are influenced by the timing of therapy in mice

Som G. Nanjappa1, Jane H. Walent1, Michel Morre2 and M. Suresh1

1Department of Pathobiological Sciences, University of Wisconsin–Madison, Madison, Wisconsin, USA.
2Cytheris Inc., Issy-Les-Moulineaux, France.

Address correspondence to: M. Suresh, 2015 Linden Drive, Department of Pathobiological Sciences, University of Wisconsin–Madison, Madison, Wisconsin 53706, USA.

Received for publication March 5, 2007, and accepted in revised form November 28, 2007.

IL-7 is integral to the generation and maintenance of CD8+ T cell memory, and insufficient IL-7 is believed to limit survival and the persistence of memory CD8+ T cells. Here, we show that during the mouse T cell response to lymphocytic choriomeningitis virus, IL-7 enhanced the number of memory CD8+ T cells when its administration was restricted to the contraction phase of the response. Likewise, IL-7 administration during the contraction phase of the mouse T cell response to vaccinia virus or a DNA vaccine potentiated antigen-specific CD8+ memory T cell proliferation and function. Qualitatively, CD8+ T cells from IL-7–treated mice exhibited superior recall responses and improved viral control. IL-7 treatment during the memory phase stimulated a marked increase in the number of memory CD8+ T cells, but the effects were transient. IL-7 therapy during contraction of the secondary CD8+ T cell response also expanded the pool of memory CD8+ T cells. Collectively, our studies show differential effects of IL-7 on memory CD8+ T cell homeostasis and underscore the importance of the timing of IL-7 therapy to effectively improve CD8+ T cell memory and protective immunity. These findings may have implications in the clinical use of IL-7 as an immunotherapeutic agent to bolster vaccine-induced CD8+ T cell memory.

J Immunol. 2008 Jun 1;180(11):7265-75.

IL-7/anti-IL-7 mAb complexes restore T cell development and induce homeostatic T Cell expansion without lymphopenia.

Boyman O, Ramsey C, Kim DM, Sprent J, Surh CD.

Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.

IL-7, a member of the common gamma-chain family of cytokines, is essential for B and T lymphocyte development and homeostasis of mature T cell subsets. Thus, naive and memory T cells are both dependent on IL-7 for survival and homeostatic proliferation under lymphopenic conditions. In line with prior findings with IL-2, we show in this study that the biological activity of IL-7 in vivo is greatly increased by association with. Under in vivo conditions, IL-7/mAb complexes displayed 50- to 100-fold higher activity than free IL-7 and induced massive expansion of pre-B cells. IL-7/mAb complexes also increased thymopoiesis in normal mice and restored thymopoeisis in IL-7-deficient mice. For mature T cells, IL-7/mAb complexes induced marked homeostatic proliferation of both naive and memory CD4(+) and CD8(+) cell subsets even under normal T cell-replete conditions. Finally, IL-7/mAb complexes were able to enhance the magnitude of the primary response of Ag-specific naive CD8(+) cells. The strong stimulatory activity of IL-7/mAb complexes could be useful for treatment of immunodeficiency and cancer.

JACI Special Issue on AIDS, Prospects for Eradication Review

The Journal of Allergy & Clinical Immunology’s new issue has a special focus on HIV/AIDS, in recognition of the upcoming International AIDS Conference in Mexico City. There are several free full-text articles, including this review by Lin Shen and Robert Siliciano that summarizes recent evidence indicating ART can completely suppress viral replication, and mulls the implications for efforts to eradicate HIV infection.

Journal of Allergy & Clinical Immunology
Volume 122, Issue 1, Pages 22-28 (July 2008)

Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection

Lin Shen, MD, Robert F. Siliciano, MD, PhD

Although highly active antiretroviral therapy (HAART) can reduce HIV-1 viremia to levels that are below the limit of detection of clinical assays, the virus persists in reservoirs, and trace levels of free virions can be found in the plasma. Whether this residual viremia represents ongoing cycles of replication continuing despite HAART or simply the release of virus from stable reservoirs has been controversial. Here we summarize the evidence that HAART can stop ongoing cycles of replication. The evidence comes from a detailed analysis of the residual viremia, which shows it to be archival and nonevolving in character. In addition, new pharmacodynamic measures incorporating a previously ignored slope parameter have provided the first real indication of how well HAART actually suppresses viral replication in vivo. Together, these results argue that the ultimate theoretical potential of HAART to control viral replication has already been reached. Progress toward eradication of the infection will require novel approaches to target the stable reservoirs that persist even when viral replication is completely halted.

HLA-Driven HIV Mutations and Viral Load

Two new papers add to the recent welter of studies indicating that T cell immune responses can pressure HIV into mutating in ways that compromise viral fitness. Much of this data has been generated by a productive and novel collaboration between immunologists affiliated with Bruce Walker’s lab at Partners AIDS Researcher Center in Boston and a team of data crunchers at Microsoft led by David Heckerman. Heckerman was interviewed by CNET about the project last year.

JVI Accepts, published online ahead of print on 2 July 2008

J. Virol. doi:10.1128/JVI.00580-08

CENTRAL ROLE OF REVERTING MUTATIONS IN HLA ASSOCIATIONS WITH HIV VIRAL SETPOINT

Philippa C Matthews*, Andrew Prendergast, Alasdair Leslie, Hayley Crawford, Rebecca Payne, Christine Rousseau, Morgane Rolland, Isobella Honeyborne, Jonathan Carlson, Carl Kadie, Christian Brander, Karen Bishop, Nonkululeko Mlotshwa, James D Mullins, Hoosen Coovadia, Thumbi Ndung'u, Bruce D Walker, David Heckerman, and Philip JR Goulder*

Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford OX1 3SY, UK; Department of Microbiology, University of Washington School of Medicine, Seattle, Washington 98195-8070, USA; Miscrosoft Research, One Microsoft Way, Redmond, WA 9805; Partners AIDS Research Center, Massachusetts General Hospital, 13th St, Bldg 149, Charlestown, Boston, MA 02129, USA; HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa; Howard Hughes Medical Institute, Chevy Chase, MD, USA

Much uncertainty still exists over what T cell responses need to be induced by an effective HIV vaccine. Previous studies have hypothesised that the effective CD8+ T cell responses are those driving the selection of escape mutations that reduce viral fitness and therefore revert post-transmission. In this study, we adopted a novel approach to define better the role of reverting escape mutations in immune control of HIV infection. This analysis of sequences from 710 study subjects with chronic C-clade HIV-1 infection demonstrates the importance of mutations that impose a fitness cost on control of viraemia. Consistent with previous studies, the viral setpoints associated with each HLA-B allele are strongly correlated with the number of Gag-specific polymorphisms associated with the relevant HLA-B allele (r=-0.56, p=0.0034). The viral setpoints associated with each HLA-C allele were also strongly correlated with the number of Pol-specific polymorphisms associated with the relevant HLA-C allele (r=-0.67, p=0.0047). However, critically, both these correlations were dependent solely on the polymorphisms identified as reverting. Therefore, despite the inevitable evolution of viral escape, viraemia can be controlled through the selection of mutations that are detrimental to viral fitness. The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses.

AIDS. 22(11):1277-1286, July 11, 2008.

Human leukocyte antigen-specific polymorphisms in HIV-1 Gag and their association with viral load in chronic untreated infection.

Brumme, Zabrina L; Tao, Iris; Szeto, Sharon; Brumme, Chanson J; Carlson, Jonathan M; Chan, Dennison; Kadie, Carl; Frahm, Nicole; Brander, Christian; Walker, Bruce; Heckerman, David; Harrigan, P Richard

Objective: Selection of specific human leukocyte antigen (HLA)-restricted cytotoxic T-lymphocyte (CTL) escape mutations in key Gag epitopes has been associated with loss of HIV immune control on an individual basis. Here we undertake a population-based identification of HLA-associated polymorphisms in Gag and investigate their relationship with plasma viral load.

Design: Cross-sectional analysis of 567 chronically HIV subtype B-infected, treatment-naive individuals.
Methods: HLA class I-associated Gag substitutions were identified using phylogenetically corrected analysis methods featuring a multivariate adjustment for HLA linkage disequilibrium and a q-value correction for multiple tests. Presence of HLA-associated substitutions and markers of HIV disease status were correlated using Spearman's rank test.

Results: We have created a gene-wide map of HLA class I-associated substitutions in HIV-1 subtype B Gag. This features 111 HLA-associated substitutions occurring at 51 of 500 Gag codons, more than 50% of which occur within published and/or putative HLA-restricted CTL epitopes. A modest inverse correlation was observed between the total number of HLA-associated Gag polymorphic sites within each individual and plasma viral load in chronic untreated infection (R = -0.17, P < 0.0001), supporting the hypothesis that a broad ability to target Gag in vivo contributes to viral control. A modest positive correlation was observed between the proportion of these sites exhibiting HLA-associated substitutions and plasma viral load (R = 0.09, P = 0.03), consistent with a loss of viremia control with the accumulation of CTL escape mutations.

Conclusion: Results contribute to our understanding of immune-driven viral adaptation and suggest that the accumulation of CTL escape mutations in Gag results in clinically detectable consequences at the population level. These data have implications for HIV vaccines.

Naive CD4 T Cell Depletion, Microbial Translocation & Immune Activation

An interesting new basic immunology paper in PNAS suggests that decreased naïve T cell numbers are associated with microbial translocation (the transfer of normally harmless “friendly” gut bacteria across the mucosa) and that this, in turn, exacerbates naïve T cell depletion by causing immune activation. The authors argue that the output of naïve T cells by the thymus is required for the maintenance of immunological détente with gut bacteria and that the cessation of thymic output (induced artificially in this paper by genetic manipulation and the administration of poly I:C) disrupts this balance leading to increases in lipopolysaccharide binding protein (LBP) that are indicative of microbial translocation in mice. Microbial translocation has recently been implicated as a cause of immune activation in HIV infection, but the cause has been suggested to be early depletion of gut "memory" CD4 T cells. This new paper suggests that the depletion of naive T cells - a well-described consequence of HIV infection - could also contribute.

The study may also have implications for efforts to untangle the relationship between cause and effect when it comes to immune activation in HIV infection; data indicates that persistent immune activation despite ART is associated with poor immune reconstitution and the general assumption has been that the activation is playing a causative role. This new data suggests that immune activation could also possibly result from poor immune reconstitution (e.g. slow naïve T cell repletion due to poor thymic output). Therapies such as IL-7, which recent studies indicate can enhance naïve T cell repletion, might therefore conceivably reduce immune activation, and this can be explored in ongoing and planned studies.

Published online on June 18, 2008, 10.1073/pnas.0803732105
PNAS | June 24, 2008 | vol. 105 | no. 25 | 8691-8696

Article
BIOLOGICAL SCIENCES / IMMUNOLOGY

Ablation of thymic export causes accelerated decay of naïve CD4 T cells in the periphery because of activation by environmental antigen

Christine Bourgeois*,, Zhenyue Hao, Klaus Rajewsky,¶, Alexandre J. Potocnik*, and Brigitta Stockinger*,¶
*Division of Molecular Immunology, The National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom; The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Research Institute, Toronto, ON, Canada M5G2C1; and Immune Disease Institute, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115

Contributed by Klaus Rajewsky, April 17, 2008 (received for review March 4, 2008)

A model of chemical thymectomy by inducible Rag ablation was used to study peripheral T cell homeostasis. Induction of Rag ablation was efficient and complete, leading to cessation of thymic T cell production within 3–4 weeks. The decay of peripheral T cells became apparent with a delay of an additional 2–3 weeks and was entirely accounted for by loss of naïve T cells, whereas numbers of memory phenotype and regulatory T cells were not decreased. Naïve CD4 T cells decayed with an average half-life of 50 days, whereas naïve CD8 T cells exhibited a considerably longer half-life. The rapid decay of naïve CD4 T cells was not caused by intrinsic survival differences compared with naïve CD8 T cells, but was caused by changes in the lymphopenic environment resulting in higher microbial load and consequential activation. This finding suggests that in lymphopenic conditions involving compromised thymic function replenishment and survival of a naïve CD4 T cell repertoire may be severely curtailed because of chronic activation. Such a scenario might play a role in the aging immune system and chronic viral infection, such as HIV infection, and contribute to loss of CD4 T cells and impaired immune function. As our data show, continued replenishment with cells from the thymus seems to be required to maintain efficient gut mucosal defense.