TAG HIV Basic Science, Vaccines, and Cure Project Blog

HLA Alleles Associated with Control of HIV Replication Ape Chimpanzee MHC

A very interesting paper from the new issue of AIDS reports that MHC (HLA) alleles associated with control of HIV replication in humans show significant similarities to chimpanzee MHC. Furthermore, in both cases these alleles predict broad targeting of epitopes in the SIV/HIV Gag protein, echoing a slew of recent studies indicating broad CD8 T cell responses to Gag are critical for efficient immunological control of HIV.

The authors note that “the predicted similarity in binding specificity between chimpanzee and protective HLA molecules clearly supports the hypothesis that the MHC class I repertoire of chimpanzees has been formed under selective pressure induced by an HIV-like virus.” They conclude by stating: “our results indicate that the binding motifs of protective HLA and chimpanzee molecules are directed towards peptides able to elicit effective CD8 T-cell responses against HIV-1 and that similarity to chimpanzee MHC specificity plays a central role in controlling HIV-1 viral load in humans.”

AIDS. 22(11):1299-1303, July 11, 2008.

BASIC SCIENCE

Humans with chimpanzee-like major histocompatibility complex-specificities control HIV-1 infection.

Hoof, Ilka; Kesmir, Can; Lund, Ole; Nielsen, Morten

Abstract:

Background: Major histocompatibility complex (MHC) class I molecules allow immune surveillance by presenting a snapshot of the intracellular state of a cell to circulating cytotoxic T lymphocytes. The MHC class I alleles of an HIV-1 infected individual strongly influence the level of viremia and the progression rate to AIDS. Chimpanzees control HIV-1 viral replication and develop a chronic infection without progressing to AIDS. A similar course of disease is observed in human long-term non-progressors.

Objective: To investigate if long-term non-progressors and chimpanzees have functional similarities in their MHC class I repertoire.

Methods: We compared the specificity of groups of human MHC molecules associated with different levels of viremia in HIV-1 infected individuals with those of chimpanzee.

Results and conclusion: We demonstrate that human MHC with control of HIV-1 viral load share binding motifs with chimpanzee MHC. Moreover, we find that chimpanzee and human MHC associated with low viral load are predicted to elicit broader Gag-specific immune responses than human MHC associated with high viral load, thus supporting earlier findings that Gag-specific immune responses are essential for HIV-1 control.

Th17 Cells in SIV Infection

One of the studies of Th17 cells that was presented recently at CROI (covered on the blog previously) has now been published in the new journal, Mucosal Immunology. Full text of the paper is available free of charge.

Mucosal Immunology (2008) 1, 279–288; doi:10.1038/mi.2008.14; published online 7 May 2008

Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques

V Cecchinato, C J Trindade, A Laurence, J M Heraud, J M Brenchley, M G Ferrari, L Zaffiri, E Tryniszewska, W P Tsai, M Vaccari, R Washington Parks, D Venzon, D C Douek, J J O'Shea and G Franchini

Abstract

Loss of CD4+ T cells in the gut is necessary but not sufficient to cause AIDS in animal models, raising the possibility that a differential loss of CD4+ T-cell subtypes may be important. We found that CD4+ T cells that produce interleukin (IL)-17, a recently identified lineage of effector CD4+ T-helper cells, are infected by SIVmac251in vitro and in vivo, and are found at lower frequency at mucosal and systemic sites within a few weeks from infection. In highly viremic animals, Th1 cells predominates over Th17 T cells and the frequency of Th17 cells at mucosal sites is negatively correlated with plasma virus level. Because Th17 cells play a central role in innate and adaptive immune response to extracellular bacteria, our finding may explain the chronic enteropathy in human immunodeficiency virus (HIV) infection. Thus, therapeutic approaches that reconstitute an adequate balance between Th1 and Th17 may be beneficial in the treatment of HIV infection.

Of Animal Models and CD8 T Cells: A Perspective & Review in Nature Medicine

The new issue of Nature Medicine includes a perspective piece regarding the use of the macaque/SIV model in HIV vaccine research and a comprehensive review of knowledge regarding CD8 T cell efficacy in vaccination and disease. In their perspective, David Watkins, Dennis Burton, Esper Kallas, John Moore and Wayne Koff offer concrete recommendations regarding criteria for advancing HIV vaccine candidates toward efficacy trials (reproduced below). The authors reiterate that a challenge of vaccinated macaques with SIVmac239 predicted the outcome of the Merck trial better than studies using the SIV/HIV hybrid SHIV89.6P; however, they add that “because no macaque study has predicted a positive result in humans (as there have been none), one must exercise caution in interpreting nonhuman primate challenge studies.” This statement may deserve reevaluation in the context of the data that has emerged from the STEP trial indicating that vaccination enhanced the impact of known favorable HLA alleles on viral load control, seemingly echoing the significant impact on SIV viral load that was seen in vaccinated macaques bearing the favorable Mamu A*01 allele (although this result was seen with Merck’s DNA/Ad5 and not Ad5 alone).

In a comprehensive review regarding CD8 T cells, Victor Appay, Daniel Douek and David Price describe the advances that are being made in understanding the factors that contribute to an efficacious, protective response. The authors stress that it is now widely recognized that simply measuring the magnitude of the CD8 T cell response to a given antigen cannot discriminate between potentially effective and ineffective CD8 T cells; in their words “we have come to realize that the ways in which we currently monitor immunogenicity actually provide very limited information.” Also highlighted in the review are recent data indicating that low antigen densities appear to induce more functional and effective CD8 T cells, which prompts the cautionary statement that “it should be borne in mind that recurrent immunizations and boosting with high-dose antigen, conducted with the aim of achieving maximum immunogenicity as determined by solely quantitative measures, may have adverse effects; specifically, effective vaccine-induced T cells could become exhausted through the loss of replicative capacity and apoptotic deletion.” It is also gratifying that the review emphasizes the importance of using “immunomonitoring” to guide the design and delivery of vaccines in order to optimize vaccine-induced T cell responses; TAG has also been arguing this point in the context of HIV vaccine candidates. The authors conclude by stating: “The failure of the Merck STEP trial represents a turning point for the field of vaccination. However, far from embodying the end of the T cell vaccine strategy, it heralds a new era in vaccine research based on comprehensive immunomonitoring.”

Suggested criteria for advancing HIV vaccine candidates into efficacy trials (from Watkins et al):

1. Safety and immunogenicity trials in humans. The vaccine candidate should be shown to be safe and immunogenic in phase 1 and 2a trials. Immunogenicity should be based on validated assays that should show that a vast majority of volunteers immunized with the vaccine show positive responses. The quality and/or quantity of the immune responses to a CMI vaccine should be markedly improved over those elicited by the Merck Ad5 product.

2. Protection conferred by an analogous vaccine in the SIV–rhesus macaque challenge model. Whenever feasible, the analogous SIV vaccine should be designed and tested in rhesus macaques before advancing the candidate to a phase 2 screening test of concept (STOC) trial (see point 3 below). This may not always be possible, as some candidate vaccines—for example, epitope-based concepts, some bacterial-vectored delivery systems and some viral vectors that are species-specific for humans—cannot be appropriately modeled in SIV–nonhuman primate challenge studies. For those candidate vaccines that can be evaluated in the SIV–rhesus macaque model, the vaccine should suppress viral load by a minimum of 1.5 logs (peak and set point) compared to control macaques when tested for its efficacy against a heterologous repeated low-dose mucosal SIV challenge.

3. Protection of humans in a STOC trial. STOC trials could rapidly screen a limited number of leading HIV-1 vaccine candidates, enabling the most promising to be prioritized to large-scale, phase 3 efficacy licensing trials. The primary endpoint of a STOC trial is plasma HIV-1 RNA viral load at set point (about 3–6 months after infection) in participants who become infected with HIV-1. In a STOC trial, 30 incident HIV-1 infections are enough to detect a minimum of a one-log suppression of viral load with sufficient statistical power. Any candidate vaccines that show a 1.5-log suppression of viral load for longer than 1 year should be considered for advancement to phase 3 licensing trials.

4. Feasibility for large-scale manufacture and distribution. Candidate vaccines that have fulfilled criteria 1 and 2 or 1 and 3 should be advanced to phase 3 licensing and efficacy trials, provided that they can be manufactured on a large enough scale to enable their widespread distribution if they turn out to be effective.

Perspective abstract

Nature Medicine 14, 617 - 621 (2008)
Published online: 5 June 2008 | doi:10.1038/nm.f.1759

Nonhuman primate models and the failure of the Merck HIV-1 vaccine in humans

David I Watkins, Dennis R Burton, Esper G Kallas, John P Moore & Wayne C Koff

Abstract

The adenovirus type 5 (Ad5)-based vaccine developed by Merck failed to either prevent HIV-1 infection or suppress viral load in subsequently infected subjects in the STEP human Phase 2b efficacy trial. Analogous vaccines had previously also failed in the simian immunodeficiency virus (SIV) challenge–rhesus macaque model. In contrast, vaccine protection studies that used challenge with a chimeric simian-human immunodeficiency virus (SHIV89.6P) in macaques did not predict the human trial results. Ad5 vector–based vaccines did not protect macaques from infection after SHIV89.6P challenge but did cause a substantial reduction in viral load and a preservation of CD4+ T cell counts after infection, findings that were not reproduced in the human trials. Although the SIV challenge model is incompletely validated, we propose that its expanded use can help facilitate the prioritization of candidate HIV-1 vaccines, ensuring that resources are focused on the most promising candidates. Vaccine designers must now develop T cell vaccine strategies that reduce viral load after heterologous challenge.

Review abstract

Nature Medicine 14, 623 - 628 (2008)
Published online: 5 June 2008 | doi:10.1038/nm.f.1774

CD8+ T cell efficacy in vaccination and disease

Victor Appay, Daniel C Douek & David A Price

Abstract

Much effort has been devoted to the design of vaccines that induce adaptive cellular immunity, in particular CD8+ T cells, which have a central role in the host response to viral infections and cancers. To date, however, the development of effective T cell vaccines remains elusive. This is due, in part, to the lack of clearly defined correlates of protection and the inherent difficulties that hinder full characterization of the determinants of successful T cell immunity in humans. Recent data from the disparate fields of infectious disease and tumor immunology have converged, with an emphasis on the functional attributes of individual antigen-specific T cell clonotypes, to provide a better understanding of CD8+ T cell efficacy. This new knowledge paves the way to the design of more effective T cell vaccines and highlights the importance of comprehensive immunomonitoring.

Comparing T Cell Responses to DNA/Ad5 and Ad5/Ad5 Prime-Boost Approaches

In a new paper just published online by the Journal of Virology, researchers from Merck present the first direct comparisons of the functional profiles of T cell responses induced by a DNA priming immunization followed by an Ad5 vector boost and an Ad5 prime/Ad5 boost regimen (as was used in the STEP trial). Merck’s original plan was to develop the DNA/Ad5 approach, but they subsequently decided to pursue Ad5 alone because the immunogenicity of the two strategies – when measured by interferon gamma ELISpot – appeared similar.

The data in the J. Virology paper indicate that the DNA/Ad5 regimen induced CD4 T cell responses in a significantly greater proportion of recipients and the CD4 and CD8 T cells induced by this approach displayed more functions, particularly in terms of IL-2 production, when compared to Ad5/Ad5. Although it might be a stretch to criticize Merck’s decision to drop the DNA prime based on the functional measures (which were not well characterized at the time), the issue of the proportion of recipients developing CD4 T cell responses does raise questions about the company's transparency during the development process. At no point can I recall Merck acknowledging clearly that there was a significant difference in the proportion of CD4 T cell responders between the DNA/Ad5 and Ad5/Ad5 approaches, and data presentations at meetings and conferences focused almost exclusively on CD8 T cell responses. The potential importance of CD4 T cell help was well appreciated at the time the DNA prime was discontinued.

Correction: embarrassingly, I realized that I recently posted a 2005 CROI abstract to the blog in which Danny Casimiro from Merck reported that only ~30% of Ad5 recipients developed HIV-specific CD4 responses; my original statement above regarding Merck not disclosing this data is erroneous. It would be more accurate to say that I don't recall seeing the CD4 data presented before the STEP trial began.

JVI Accepts, published online ahead of print on 4 June 2008
J. Virol. doi:10.1128/JVI.00620-08

DNAgag/Ad5gag and Ad5gag/Ad5gag Vaccines Induce Distinct T cell Response Profiles

Kara S. Cox, James H. Clair, Michael T. Prokop, Kara J. Sykes, Sheri A. Dubey, John W. Shiver, Michael N. Robertson, and Danilo R. Casimiro

Department of Vaccine Basic Research, Merck Research Laboratories, West Point, PA USA; Biostatistics and Research Decision Sciences, Merck Research Laboratories, West Point, PA USA; Infectious Disease Vaccines Clinical Research, Merck Research Laboratories, Upper Gwynedd, PA USA

Abstract

Results from Merck's phase II Ad5-gag/pol/nef test-of-concept trial showed that the vaccine lacked efficacy against HIV infection in a high-risk population. Among the many questions to be explored following this outcome are whether or not 1) the Ad5 vaccine induced the quality of T cell responses necessary for efficacy and 2) the lack of efficacy in the Ad5 vaccine can be generalized to other vector approaches intended to induce HIV-1 specific T cell responses. Here we present a comprehensive evaluation of the T cell response profiles from cohorts of clinical trial subjects who received the HIV CAM-1 gag insert delivered by either a DNA priming followed by Ad5 boosting regimen (N=50) or homologous Ad5/Ad5 prime/boost regimen (N=70). The samples were tested using a statistically qualified 9-color intracellular cytokine staining assay measuring IL-2, TNF, MIP1, and IFN-N production and expression of CD107a. Both vaccine regimens induced CD4+ and CD8+ HIV gag-specific T cell responses which variably expressed several intracellular markers. Several trends were observed in which the frequencies of HIV-1 specific CD4+ T cells and IL-2 production from antigen-specific CD8+ T cells in the DNA/Ad5 cohort were more pronounced than in the Ad5/Ad5 cohort. Implications of these results in future vaccine development will be discussed.

Presentations from the May 21-23 HIV Vaccine Trials Network (HVTN) Meeting

The HVTN has laudably made available the Powerpoint files of presentations from their recent meeting in DC. Of particular interest, Surojit Sarkar from Emory presents data indicating that - as suggested by the longitudinal data from trials of Merck's HIV vaccine - CD8 T cell responses induced by Ad5 vectors do no contract in the way that typically occurs during the development of protective memory T cell responses, and that this is associated with the persistence of the vector. As a result, Ad5-induced CD8 T cell responses appear functionally compromised and display poor proliferative capacity and protective efficacy in Sarkar's murine studies.

David Watkins also contrasts the breadth of T cell responses that he observes in macaque vaccine studies (6-18 CD8 T cell epitopes) with those observed in the Merck vaccine efficacy trial (3 CD8 T cell epitopes), and several other presenters discuss strategies for improving the number of epitopes targeted by HIV-specific T cell responses. Based on a prior comment to this blog by Ian York, it is to be hoped that members of relevant NIH study sections are being educated about the potential importance of improving the breadth of vaccine-induced T cell responses in humans.

Reviewing Mucosal HIV Transmission

In the June issue of Nature Reviews Immunology, Florian Hladik and Juliana McElrath review the current state of knowledge regarding mucosal transmission of HIV infection. Access to the full text of the paper is free of charge but requires registration with the Nature website.

Nature Reviews Immunology 8, 447-457 (June 2008) | doi:10.1038/nri2302

Setting the stage: host invasion by HIV

Florian Hladik & M. Juliana McElrath

Abstract

For more than two decades, HIV has infected millions of people worldwide each year through mucosal transmission. Our knowledge of how HIV secures a foothold at both the molecular and cellular levels has been expanded by recent investigations that have applied new technologies and used improved techniques to isolate ex vivo human tissue and generate in vitro cellular models, as well as more relevant in vivo animal challenge systems. Here, we review the current concepts of the immediate events that follow viral exposure at genital mucosal sites where most documented transmissions occur. Furthermore, we discuss the gaps in our knowledge that are relevant to future studies, which will shape strategies for effective HIV prevention.