Margaret I. Johnston

HIV vaccine research: the way forward.

The need to broaden research directed at answering fundamental questions in HIV vaccine discovery through laboratory, nonhuman primate (NHP), and clinical research has recently been emphasized. In addition, the importance of attracting and retaining young researchers, developing better NHP models, and more closely linking NHP and clinical research is being stressed. In an era of a level budget for biomedical research at the U.S. National Institutes of Health (NIH), HIV/AIDS vaccine research efforts will need to be carefully prioritized such that resources to energize HIV vaccine discovery can be identified. This article summarizes progress and challenges in HIV vaccine research, the priorities arising from a recent summit at NIAID, and the actions needed, some already under way, to address those priorities.

An HIV vaccine--challenges and prospects.

An HIV vaccine has thus far been elusive. Drs. Margaret Johnston and Anthony Fauci remain cautiously optimistic that a substantial increase in our understanding of HIV infection and disease will lead to creative ideas about how to design an effective HIV vaccine. Dr. Anthony Fauci discusses the 30-year search for an HIV vaccine, recent setbacks, and prospects for future success. Dr. Fauci is the director of the National Institute of Allergy and Infectious Diseases, Bethesda, MD.

HIV-1 Vaccines and Adaptive Trial Designs

Development of an HIV vaccine could be accelerated by testing candidate vaccines using adaptive clinical trial designs. Developing a vaccine against the human immunodeficiency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.

HIV Vaccine Development — Improving on Natural Immunity

Since our natural immune response to HIV infection is ineffective, a key goal for an HIV vaccine is to induce a response different from that induced by natural infection — an “unnatural immunity,” involving production of broadly neutralizing antibodies.

Activation of human and mouse 2-5A synthetases and mouse protein P1 kinase by nucleic acids: Structure-activity relationships and correlations with inhibition of protein synthesis and interferon induction

The natural occurrence of fully double-stranded RNA (dsRNA) of high molecular weight in viruses, virus-like particles in fungi, as intermediates in the replication of RNA and DNA viruses has suggested some possible biological role for such molecules [ 11. Interest in dsRNA as a possible regulatory signal has been generated by the observations that dsRNA is a potent interferon inducer [2] and a powerful inhibitor

Progress in the development of an HIV vaccine

Despite the remarkable advances that have been made in the last 20 years regarding the molecular virology, pathogenesis and epidemiology of HIV, the development of an effective HIV vaccine remains an elusive goal. The major reason for this is that we have not determined a correlate of immunity. The various explanations for this include integration of the virus into the host cell genome, infection of long-lived immune cells, HIV genetic diversity (especially in its envelope), persistent high viral replication releasing up to 10 billion viral particles per day and/or production of immunosuppressive products or proteins. However, there is evidence that the host can be protected: some highly exposed persons have remained uninfected; the relatively low incidence of mother to child (fetus) transmission; the initial effective immune response that significantly, if temporally, reduces viral loads; some infected persons are long-term non-progressors; experimental vaccines and passive immunisation have proven effective in experimental animals; and finally, successful vaccine development against other viral infections. At this time, the experimental vaccine pipeline is quite robust and ranges from HIV proteins (although the first such vaccine, recombinant gp120 made on Chinese hamster ovary cells, failed to protect volunteer men having sex with men [MSM]) to DNA vaccines and various novel delivery strategies. Perhaps the greatest impediment is the requirement to test these experimental vaccines in resource-poor developing countries that, at present, lack the necessary infrastructure for performing large, long-term, scientifically valid studies.

Oligo(2′–5′)adenylate synthetase in human lymphoblastoid cells

The enzyme oligo(2′–5′)adenylate synthetase, when activated by double-stranded RNA, polymerizes ATP into the novel oligonucleotide (2′–5′)ppp(Ap)nA. We describe conditions for assay of this enzyme in crude extracts of a human lymphoblastoid cell line, Namalwa. The production of (2′–5′)ppp(Ap)nA by Namalwa extracts was 3–5 times greater than the production by extracts of interferon pretreated mouse L cells, and 700 fold higher than the production by extracts of untreated mouse L cells. The relatively high level of oligo(2′–5′)adenylate synthetase in Namalwa cells was not attributable solely to their constitutive secretion of low levels of interferon. Analysis of the size distribution of the oligomers formed at different times suggested that the enzyme can add ATP to a free pppApA. Infection by Newcastle disease virus or treatment with interferon raised the apparent synthetase levels only marginally. Experiments that employed antibody to interferon suggested that the interferon must be externalized from the NDV-infected cell to induce maximal synthetase levels.

Executive summary and recommendations from the WHO/UNAIDS/IAVI expert group consultation on 'Phase IIB-TOC trials as a novel strategy for evaluation of preventive HIV vaccines', 31 January-2 February 2006, IAVI, New York, USA

This report summarizes the discussions and recommendations from a consultation held in New York City, USA (31 January–2 February 2006) organized by the joint World Health Organization–United Nations Programme on HIV/AIDS HIV Vaccine Initiative and the International AIDS Vaccine Initiative. The consultation discussed issues related to the design and implementation of phase IIB ‘test of concept’ trials (phase IIB-TOC), also referred to as ‘proof of concept’ trials, in evaluating candidate HIV vaccines and their implications for future approval and licensure. The results of a single phase IIB-TOC trial would not be expected to provide sufficient evidence of safety or efficacy required for licensure. In many instances, phase IIB-TOC trials may be undertaken relatively early in development, before manufacturing processes and capacity are developed sufficiently to distribute the vaccine on a large scale. However, experts at this meeting considered the pressure that could arise, particularly in regions hardest hit by AIDS, if a phase IIB-TOC trial showed high levels of efficacy. The group largely agreed that full-scale phase III trials would still be necessary to demonstrate that the vaccine candidate was safe and effective, but emphasized that governments and organizations conducting trials should consider these issues in advance. The recommendations from this meeting should be helpful for all organizations involved in HIV vaccine trials, in particular for the national regulatory authorities in assessing the utility of phase IIB-TOC trials in the overall HIV vaccine research and development process.

Structure-Activity Correlations of Natural Products with Anti-HIV Activity

The search for safe and effective therapies to treat infections caused by the human immunodeficiency virus (HIV) and related opportunistic infections (OI’s) are among the highest priorities of the National Institutes of Health. The Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID) supports rational drug design and targeted drug discovery for HIV and the OI’s through investigator-initiated research grants including the National Cooperative Drug Discovery Group programs.

DOUBLE-STRANDED RNA AND 2′,5′-OLIGOADENYLATES: COMPANIONS IN INTERFERON ACTION?

ABSTRACT A number of oligonucleotides have been synthesized and evaluated as antagonists of the protein synthesis inhibitory effects of 2-5A in order to gain information on the oligonucleotide structural features involved in binding to the 2-5A-activated endoribonuclease. The base moieties, the ribose-phosphate backbone and the 5′-monophosphate group of p5′A2′p5′A2′p5′A are strategic regions for binding to the endonuclease; however, rather extensive modification of the 2′-terminal ribose unit is possible without adversely affecting interaction with the endonuclease. Analogues of p5′A2′p5′A2′p5′A, p5′A2′p5′ A2′p5′A2′p5′A or ppp5′A2′p5′A2′p5′A2′p5′A, in which the 2′-terminal ribose has been modified to an N-hexylmorpholine ring have significantly enhanced activity as antagonists of 2-5A action or as inhibitors of protein synthesis. Such analogues are much more resistant to degradation by the phosphodiesterase activity found in L cell extracts. These analogues of p5′A2′p5′A2′p5′A are also effective antagonists of the inhibition of protein synthesis caused by dsRNA in extracts of interferon-treated L cells, and their use demonstrates that 2-5A is the primary mediator of inhibition caused by dsRNA. In accord with this finding, the synthetic dsRNA, poly(A). poly(dUfl), an activator of the protein P 1 kinase but not the 2-5A synthetase, was a potent inhibitor of protein synthesis in rabbit reticulocyte lysates, but was without discernable activity in extracts of interferon-treated L cells. Thus, phosphorylation of eIF-2α and/or protein does not appear to be a sufficient condition for protein synthesis inhibition in extracts of interferon-treated L cells.