NYTimes: ‘Cured of AIDS’? Not Yet
There is no way of knowing which HIV patients might kill the virus before it sinks deeper into their bodies, but experts agree on the clear benefits of early treatment. See link below for full article:
Mouse with human immune system may revolutionize HIV vaccine research
Animal model replicates human immune response against HIV
One of the challenges to HIV vaccine development has been the lack of an animal model that accurately reflects the human immune response to the virus and how the virus evolves to evade these immune responses. In the July 18 issue of Science Translational Medicine, researchers from the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard report that a model created by transplanting elements of the human immune system into an immunodeficient mouse addresses these key issues and has the potential to reduce significantly the time and costs required to test candidate vaccines.
"Our study showed not only that these humanized mice mount human immune responses against HIV but also that the ability of HIV to evade these responses by mutating viral proteins targeted by CD8 'killer' T cells is accurately reflected in these mice," says Todd Allen, PhD, senior author of the report. "For the first time we have an animal model that accurately reproduces critical host-pathogen interactions, a model that will help facilitate the development an effective vaccine for HIV." Recent studies by Allen's team and others have revealed that immune control of HIV is significantly limited by the ability of the virus to evade immune responses by rapidly mutating.
The traditional animal model for HIV research is the rhesus monkey, which can be infected with the related simian immunodeficiency virus (SIV). But differences in viral sequences between SIV and HIV and differences between the human and monkey immune systems limit the ability of the SIV model to directly replicate key interactions between HIV and the human immune system. Development of an effective HIV vaccine will require a greater understanding of how human immune responses succeed or fail to control HIV.
The current study was designed to test the humanized BLT mouse, a model created by transplanting human bone marrow stem cells, along with other human tissue, into mice lacking a functioning immune system. As noted by Andrew Tager, M.D. a co-author of the report and Director of the MGH Humanized Mouse Program, “multiple researchers have contributed to dramatic improvements in the ability of humanized mice to model human diseases. Earlier studies with BLT mice performed at the University of Texas Southwestern Medical Center, the MGH and elsewhere have demonstrated that this particular humanized mouse model reproduces many aspects of the human immune response. Timothy Dudek, PhD, of the Ragon Institute, lead author of the current study, explains, "Unlike normal mice, these humanized mice can be infected with HIV. But there has been little evidence regarding whether they reproduce the interaction between HIV and the human immune system, particularly the development of specific immune responses that exert control over HIV by targeting critical regions of the virus."
Co-senior author Andrew Tager, MD, of the MGH Center for Immunology and Inflammatory Diseases and his team created groups of humanized BLT mice using cells and tissues from human donors with different alleles, or versions, of the immune system's HLA molecules, which flag infected cells for destruction by CD8 T cells. Particular HLA alleles, such as HLA-B57, are more common in individuals naturally able to control HIV, and Tager’s group was able to generate some mice expressing this important protective allele.
Six weeks after the mice had been infected with HIV, the researchers found that the virus was rapidly evolving in regions known to be targeted by CD8 T cells. Their observation indicated that not only were the humanized mouse immune systems responding to HIV but also that the virus was mutating to avoid those responses in a manner similar to that seen in humans. In mice expressing the protective HLA-B57 allele, just as in human patients who control viral levels, CD8 responses were directed against an essential region of the virus, preventing viral mutation and allowing the animals to more effectively contain HIV.
"We now know that these mice appear to replicate the specificity of the human cellular response to HIV, and that the virus is attempting to evade these responses just as they do in humans," says Allen, an associate professor of Medicine at Harvard Medical School. "What we are currently studying is whether we can induce human HIV-specific immune responses in these animals by vaccination, which would provide a rapid, cost-effective model to test the ability of different vaccine approaches to control or even block HIV infection. If we can do this, we'll have a very powerful new tool to accelerate HIV vaccine development, one that also may be useful against other pathogens."
Tager is an assistant professor of Medicine and Dudek a research fellow in Medicine at Harvard Medical School. Additional co-authors are Daniel No, Lena Fadda, Priyasma Bhoumik, Christian Boutwell, Karen Power, Adrianne Gladden, Laura Battis, Elizabeth Mellors, and Marcus Altfeld of the Ragon Institute; Edward Seung, Vladimir Vrbanac, Trevor Tivey and Andrew Luster, MGH Center for Immunology and Inflammatory Diseases; and Xiaojiang Gao, National Cancer Institute. The study was supported by grants from the National Institutes of Health, the Ragon Institute, the Harvard University Center for AIDS Research and the National Cancer Institute.
HIV-specific CD4 cells that control viral levels
Ragon Institute of MGH, MIT and Harvard
A subpopulation of the immune cells targeted by HIV may play an important role in controlling viral loads after initial infection, potentially helping to determine how quickly infection will progress. In the February 29 issue of Science Translational Medicine, a team of researchers from the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard describe finding a population of HIV-specific CD4 T cells – cells traditionally thought to direct and support activities of other immune cells – that can directly kill HIV-infected cells.
"We observed the emergence of CD4 T cells able to kill HIV-infected cells in those patients who are able to control viral replication soon after acute infection," says Hendrik Streeck, MD, PhD, a Ragon Institute faculty member and senior author of the report. "These cells appear very early in HIV infection, and we believe they may set the stage for the course of the disease."
The primary role of CD4 T cells is to assist other cells of the immune system; and their importance is illustrated by how completely the immune response collapses after the cells, the main cellular targets of HIV, are destroyed. Ironically, CD4 cells that are specifically targeted against HIV are preferentially infected and depleted by the virus.
However, although HIV-specific CD4 cells have not been a major focus of vaccine research, these cells may have an important role in controlling HIV infection. "Every successful licensed vaccine induces CD4 T cell responses to some extent," Streeck explains, "and we know from many other viral infections that the success of the immune system in gaining control is best achieved in the presence of strong CD4 T cell responses."
To investigate whether CD4 T cell responses are important in the early control of HIV infection, the Ragon Institute team enrolled a group of 11 volunteers who were in the earliest stages of HIV infection, a time when viral levels are exceedingly high. A year into the study, participants were divided into two groups based on the level of HIV in their bodies – one group was able to keep HIV at low levels while the other group apparently had no immune control over HIV replication. Retrospective analysis of samples taken throughout the year showed striking differences in the CD4 T cell responses in both groups. While the HIV-specific CD4 responses in the group that did not control HIV replication quickly dropped and stayed low, the same response increased significantly in participants able to effectively control the virus, suggesting a role for HIV-specific CD4 cells in viral control.
Additional experiments revealed that the HIV-specific CD4 T cell responses showed activity associated with cell-killing and could even destroy HIV-infected macrophages – an unusual function for CD4 T cells, which have traditionally been seen as helper cells. In addition, the researchers determined that the presence of a specific cell-death protein called granzyme A prominently distinguished HIV-specific CD4 cells of participants maintaining a lower "viral set point" from those less able to control viral levels.
To validate these findings, the researchers examined a larger group of HIV-infected individuals and found that those with higher levels of granzyme A in their HIV-specific CD4 T cell response immediately after infection progressed more slowly to AIDS and did not require antiretroviral therapy as quickly as did those with lower levels of the protein. "The key baseline difference between these two groups has to do with the quality, not the quantity, of the HIV-specific CD4 T cell response," explains Streeck, an assistant professor of Medicine at Harvard Medical School. "In those who progressed to a lower viral set point, the early CD4 response was dominated by granzyme A expression, which was highly predictive of the rate of disease progression."
Associating a particular CD4 T cell activity with more successful suppression of viral levels suggests that inducing such responses with a vaccine may be beneficial, Streeck notes. In addition, the association of granzyme A expression with a more effective HIV-specific CD4 cell response suggests that measuring levels of the protein may allow prediction of disease outcome at the earliest stages of infection, something which is not currently possible. Future studies will need to explore the mechanisms underlying the cell-killing activities of the CD4 cell response and the functional and prognostic role of granzyme A.
The lead author of the Science Translational Medicine report is Damien Soghoian of the Ragon Institute. Additional co-authors are Michael Flanders, Kailan Sierra-Davidson, Sam Butler, Thomas Pertel, PhD, Srinika Ranasinghe, PhD, Madelene Lindqvist, Isaiah Davis, Kimberly Lane, Alicja Piechocka-Trocha, Abraham Brass, MD, PhD, and Bruce Walker, MD, Ragon Institute of MGH, MIT and Harvard; Heiko Jessen, MD, Practice Jessen-Jesse-Stein, Berlin, Germany; Jenna Rychert, MD, and Eric Rosenberg, MD, MGH Infectious Disease Unit; and Jason Brenchley, PhD, National Institutes of Health. The study was funded by the National Institute for Allergy and Infectious Diseases of the National Institutes of Health.
The Early Capture HIV Cohort Study (ECHO)
The identification of individuals with very acute HIV-1 infection, just days after exposure to HIV-1, is critical for a better understanding of the earliest events that occur following HIV-1 acquisition. The MHRP RV217 protocol, Early Capture HIV Cohort (ECHO), implemented a unique approach for acute HIV-1 infection diagnosis. This study is based in populations in Thailand, Uganda, Kenya and Tanzania with the hope to study HIV-1 prevalence, incidence, host genetics and viral diversity in acute HIV-1 infection. The goal is to enroll 150 individuals with acute infection within the 3-5 days of exposure to HIV-1 (Fiebig stages I-III).
The study population is followed for two years and consists of individuals who are thought to be at high risk for HIV-1 infection. Throughout the study, these high risk individuals provide blood samples by finger stick twice a week in microvette vials. Using the very sensitive technique of Gen-Probe’s HIV RNA Assay, the blood samples are then used to test for the presence of HIV-1 RNA. The ability to obtain samples during the antibody negative stage provides the opportunity to study the early viral evolution and its relation to innate immunity.
Several studies have suggested that events occurring in very early acute HIV-1 infection influence the ultimate control of viremia and the prognosis of the disease. ECHO provides the opportunity for classification of the founding virus and the understanding of host control among these high risk individuals. This cohort will be followed up for two years which will provide data on the level of viral replication and decline of CD4+ T cell numbers. It also gives researchers the opportunity to determine the relationship between early immunological and virological events, viral load set point and clinical outcome throughout the acute and early phase of the infection. These data will be very relevant for vaccine design.
AIDS Vaccine Conference 2011
Features Oral and Poster Presentations from Ragon Institute's Acute P01 Investigators
The 2011 AIDS Vaccine conference, held in Bangkok, Thailand, was organized by the Global HIV Vaccine Enterprise, a collaboration in an effort to advance HIV vaccine research. This conference is the largest scientific meeting, which focuses exclusively on HIV vaccine research and annually brings together scientists from across the world engaged in AIDS vaccine research and development. The conference featured oral and poster presentations by a number of investigators from the Ragon Institute who participate in the effort to develop a protective HIV-1 vaccine. These included several presentations by investigators involved in the Acute HIV-1 Infection research efforts at the Ragon Institute that are directly supported by an NIH Program Project Grant. Below we have listed these oral and poster presentations:
Antiviral Activity of NK Cells in HIV-1 Infection
Identification of Escape-Refractory Subdominant CD8 Epitopes for Common HLA Alleles CL Boutwell, C Oniangue-Ndza, A Schneidewind, H Streeck, A Seese, E Mellors, K Murthy, K Power, M Kemper, T Dudek, BD Walker, M Altfeld, TM Allen
HIV-Specific Cytolytic CD4+ T-Cell Responses During Acute HIV-1 Infection Predict Disease Outcome DZ Soghoian, H Jessen, S Cutler, M Flanders, S Ranasinghe, M Lindqvist, I Davis, K Lane, J Rychert, ES Rosenberg, BD Walker, H Streeck
Important Contribution of Subdominant HIV-Specific CD8 T Cell Responses to Early Control of HIV Replication Streeck, D Kwon, M Addo, M Flanders, I Davis, S Cutler, J Rychert, K Lane, B Yassine-Diab, J Routy, S Little, H Jessen, A Kelleher, F Hecht, R Sekaly, E Rosenberg, B Walker, T Allen, M Altfeld
Frequent and Strong NK Responses to HIV-1 Env Peptides in Individuals with Acute and Chronic HIV-1 Infection CF Thobakgale, L. Fadda, K. Lane, F. Pereyra, B.D. Walker, T. Allen, M. Altfeld
Differential Regulation of Various TLR Pathways in Acute and Chronic HIV-1 Infection J Chang, A Lacas, RJ Lindsay, E Doyle, K Axten, BD Walker, F Pereyra, T Allen, M Altfeld
Different Cytokine Profiles Induced by HIV-1 and HIV-1-Derived TLR Ligands in Monocytes and mDCs RP Simmons, E Groden, JJ Chang, R Lindsay, L Fadda, JD Lifson, K Lane, K Axten, E Rosenberg, T Allen, M Altfeld
Dysregulation of Tim-3 Expression on NK Cells in Chronic HIV-1 Infection S Jost, UY Moreno-Nieves, J Reardon, I Toth, A Piechocka-Trocha, G Alter, M Altfeld, MM Addo
Increased Plasma Levels of Hemoxygenase-1 (HO-1) and Presence of HO-1-Specific Regulatory T Cells in Acute HIV-1 Infection M Angin, A Fathi, M King, MM Addo
Preexposure Prophylaxis Reduces HIV Acquisition A recent study has found that the use of preexposure antiviral treatment (termed preexposure prophylaxis or "PrEp") can be highly successful in preventing HIV infection in men-who-have-sex-with-men (MSM). Dr. Ken Mayer, Medical Research Director and Co-chair of the Fenway Institute, is one of the Principal Investigators on the iPrEx study, which included nearly 2,500 participants from the United States as well as Peru, Ecuador, Brazil, Thailand, and South Africa. The iPrEx study consented HIV- uninfected men who reported having sex with men as well as engaging in risky sexual behaviors. The study participants were randomized to either oral doses of a combination pill containing tenofovir (TDF) and emtricitabine (FTC) or a placebo pill. The results of this study indicated that subjects provided with preexposure antiviral treatments or "PrEp" had 44% reduction in HIV acquisition. Furthermore, the study showed that among those participants who took the drug at least 90% of the time, HIV acquisition was further reduced by 73%. Those who took the drug less than 90% of the time had a 21% reduction in HIV acquisition. Both the placebo pill and the PrEp groups showed similar rates of serious adverse events, suggesting that the use of FTC-TDF was well tolerated, although nausea was reported more frequently during the first four weeks of the PrEp group. These promising results suggest that combining PrEp with behavioral interventions has the potential to maximize the reduction of HIV incidence in MSM.
Preexposure Prophylaxis Reduces HIV Acquisition
A recent study has found that the use of preexposure antiviral treatment (termed preexposure prophylaxis or "PrEp") can be highly successful in preventing HIV infection in men-who-have-sex-with-men (MSM). Dr. Ken Mayer, Medical Research Director and Co-chair of the Fenway Institute, is one of the Principal Investigators on the iPrEx study, which included nearly 2,500 participants from the United States as well as Peru, Ecuador, Brazil, Thailand, and South Africa. The iPrEx study consented HIV- uninfected men who reported having sex with men as well as engaging in risky sexual behaviors. The study participants were randomized to either oral doses of a combination pill containing tenofovir (TDF) and emtricitabine (FTC) or a placebo pill. The results of this study indicated that subjects provided with preexposure antiviral treatments or "PrEp" had 44% reduction in HIV acquisition. Furthermore, the study showed that among those participants who took the drug at least 90% of the time, HIV acquisition was further reduced by 73%. Those who took the drug less than 90% of the time had a 21% reduction in HIV acquisition. Both the placebo pill and the PrEp groups showed similar rates of serious adverse events, suggesting that the use of FTC-TDF was well tolerated, although nausea was reported more frequently during the first four weeks of the PrEp group. These promising results suggest that combining PrEp with behavioral interventions has the potential to maximize the reduction of HIV incidence in MSM.