The journal Cold Spring Harbor Perspectives is offering several free review articles on HIV research, see abstracts and links below.
Richard A. Koup and Daniel C. Douek
Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
Vaccines are arguably the most powerful medical intervention in the fight against infectious diseases. The enormity of the global human immunodeficiency virus type 1 (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic makes the development of an AIDS vaccine a scientific and humanitarian priority. Research on vaccines that induce T-cell immunity has dominated much of the recent development effort, mostly because of disappointing efforts to induce neutralizing antibodies through vaccination. Whereas T cells are known to limit HIV and other virus infections after infection, their role in protection against initial infection is much less clear. In this article, we will review the rationale behind a T-cell-based vaccine approach, provide an overview of the methods and platforms that are being applied, and discuss the impact of recent vaccine trial results on the future direction of T-cell vaccine research.
Robert F. Siliciano1 and Warner C. Greene2
1Department of Medicine, Johns Hopkins University School of Medicine, Howard Hughes Medical Institute, Baltimore, Maryland 21205
2Gladstone Institute of Virology and Immunology, Department of Medicine, Microbiology and Immunology, University of California, San Francisco, California 94158
HIV-1 can establish a state of latent infection at the level of individual T cells. Latently infected cells are rare in vivo and appear to arise when activated CD4+ T cells, the major targets cells for HIV-1, become infected and survive long enough to revert back to a resting memory state, which is nonpermissive for viral gene expression. Because latent virus resides in memory T cells, it persists indefinitely even in patients on potent antiretroviral therapy. This latent reservoir is recognized as a major barrier to curing HIV-1 infection. The molecular mechanisms of latency are complex and include the absence in resting CD4+ T cells of nuclear forms of key host transcription factors (e.g., NFκB and NFAT), the absence of Tat and associated host factors that promote efficient transcriptional elongation, epigenetic changes inhibiting HIV-1 gene expression, and transcriptional interference. The presence of a latent reservoir for HIV-1 helps explain the presence of very low levels of viremia in patients on antiretroviral therapy. These viruses are released from latently infected cells that have become activated and perhaps from other stable reservoirs but are blocked from additional rounds of replication by the drugs. Several approaches are under exploration for reactivating latent virus with the hope that this will allow elimination of the latent reservoir.
Peter D. Kwong, John R. Mascola and Gary J. Nabel
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
The development of a highly effective AIDS vaccine will likely depend on success in designing immunogens that elicit broadly neutralizing antibodies to naturally circulating strains of HIV-1. Although the antibodies induced after natural infection with HIV-1 are often directed to strain-specific or nonneutralizing determinants, it is now evident that 10%–25% of HIV-infected individuals generate neutralizing antibody responses of considerable breadth. In the past, only four broadly neutralizing monoclonal antibodies had been defined, but more than a dozen monoclonal antibodies of substantial breadth have more recently been isolated. An understanding of their recognition sites, the structural basis of their interaction with the HIV Env, and their development pathways provides new opportunities to design vaccine candidates that will elicit broadly protective antibodies against this virus.
Paul M. Sharp1 and Beatrice H. Hahn2
1Institute of Evolutionary Biology and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom
2Departments of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Acquired immunodeficiency syndrome (AIDS) of humans is caused by two lentiviruses, human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2). Here, we describe the origins and evolution of these viruses, and the circumstances that led to the AIDS pandemic. Both HIVs are the result of multiple cross-species transmissions of simian immunodeficiency viruses (SIVs) naturally infecting African primates. Most of these transfers resulted in viruses that spread in humans to only a limited extent. However, one transmission event, involving SIVcpz from chimpanzees in southeastern Cameroon, gave rise to HIV-1 group M—the principal cause of the AIDS pandemic. We discuss how host restriction factors have shaped the emergence of new SIV zoonoses by imposing adaptive hurdles to cross-species transmission and/or secondary spread. We also show that AIDS has likely afflicted chimpanzees long before the emergence of HIV. Tracing the genetic changes that occurred as SIVs crossed from monkeys to apes and from apes to humans provides a new framework to examine the requirements of successful host switches and to gauge future zoonotic risk.
Published in Advance September 14, 2011, doi: 10.1101/cshperspect.a007385
Robin J. Shattock1 and Zeda Rosenberg2
1Centre for Infection and Immunity, Division of Clinical Sciences, St George’s, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom
2International Partnership for Microbicides, 8401 Colesville Road, Suite 200, Silver Spring, Maryland 20910
Microbicides represent a potential intervention strategy for preventing HIV transmission. Vaginal microbicides would meet the need for a discreet method that women could use to protect themselves against HIV. Although early-generation microbicides failed to demonstrate efficacy, newer candidates are based on more potent antiretroviral (ARV) products. Positive data from the CAPRISA 004 trial of tenofovir gel support use in women and represent a turning point for the field. This article reviews current progress in development of ARV-based microbicides. We discuss the consensus on selection criteria, the potential for drug resistance, rationale for drug combinations, and the use of pharmacokinetic (PK)/pharmacodynamic (PD) assessment in product development. The urgent need for continued progress in development of formulations for sustained delivery is emphasized. Finally, as the boundaries between different prevention technologies become increasingly blurred, consideration is given to the potential synergy of diverse approaches across the prevention landscape.
Published in Advance September 7, 2011, doi: 10.1101/cshperspect.a007153
Nichole R. Klatt1, Guido Silvestri2 and Vanessa Hirsch1
1Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland 20892
2Department of Pathology and Laboratory Medicine, Emory University School of Medicine, and Yerkes National Primate Research Center, Atlanta, Georgia 30322
The simian immunodeficiency viruses (SIVs) are a diverse group of viruses that naturally infect a wide range of African primates, including African green monkeys (AGMs) and sooty mangabey monkeys (SMs). Although natural infection is widespread in feral populations of AGMs and SMs, this infection generally does not result in immunodeficiency. However, experimental inoculation of Asian macaques results in an immunodeficiency syndrome remarkably similar to human AIDS. Thus, natural nonprogressive SIV infections appear to represent an evolutionary adaptation between these animals and their primate lentiviruses. Curiously, these animals maintain robust virus replication but have evolved strategies to avoid disease progression. Adaptations observed in these primates include phenotypic changes to CD4+ T cells, limited chronic immune activation, and altered mucosal immunity. It is probable that these animals have achieved a unique balance between T-cell renewal and proliferation and loss through activation-induced apoptosis, and virus-induced cell death. A clearer understanding of the mechanisms underlying the lack of disease progression in natural hosts for SIV infection should therefore yield insights into the pathogenesis of AIDS and may inform vaccine design.