Genetic Approaches to Control of Influenza (1979)

GENETIC APPROACHES TO CONTROL OF INFLUENZA ROBERT M. CHANOCK and BRIAN R. MURPHY* There are few generalizations about die influenza viruses that meet the test of time, except, perhaps diat individuals who study these organisms intensively inevitably develop a deep sense of humility. Within die past few years three widely accepted laws describing the behavior of influenza A virus in man have been violated. The first law states: The emergence ofan influenza A virus widi novel surface antigens inevitably leads to pandemic spread of disease. In 1975 the swine influenza virus infected over 500 individuals within a short period at Fort Dix; the majority of persons in the United States and throughout die world lacked antibodies to tiiis virus, yet a pandemic did not follow. The second law states: Recycling ofan influenzaA virus subtype in man does not occur until most of the population lacks antibody and is completely susceptible to infection. In 1977, after a 21-yr period of quiescence, die HlNl subtype reemerged and caused extensive epidemics, despite the fact diat almost all persons over 25 yr ofage had been infected widi virus of tiiis subtype previously. The third law states: Only one subtype of influenza A virus circulates at any one time. In 1977, viruses ofboth the H3N2 and HlNl subtypes caused epidemics diroughout the world, often simultaneously. One wonders how a virus with such a limited genetic apparatus can make so many turns and twists in its pattern of infection and provide so many surprises to experts who are confident they understand its modus operandi. The history ofinfluenza A virus has been well documented as a result of local, national, and global efforts to track this agent through human populations and to define in exquisite detail changes in its two surface antigens, the hemagglutinin and neuraminidase glycoproteins. Very little of die epidemiology of influenza A virus and its pattern of antigenic variation has escaped our notice; however, at this time we are still unable to anticipate future antigenic changes and future epidemic behavior. In odier words, we know what die type A virus has done in die past, but we *Laboratory of Infectious Diseases, National Institute ofAllergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20014.© 1979 by The University of Chicago. 0031-5982/79/2222-0009$01.00 Perspectives in Biology andMedicine ¦ Winter 1979 · Part 2 | S37 lack the capacity to predict what it will do in the future. Nonedieless, there is cause for optimism, since a virtual explosion of new information concerning the anatomy and function of die influenza viruses has emerged during die past decade, and diese new insights will undoubtedly bring us closer to a complete understanding of die ecology of this important virus and to the development of more effective means of controlling influenzal disease. The influenza A virus has a segmented genome with each of its eight single-stranded RNA genes packaged separately [I]. The eight RNA genes fall into three size classes and range in molecular weight from 106 to 3 X 105 Daltons. Each gene codes for a distinct protein. Seven of the proteins are structural components ofthe virus, whereas the eighdi, the nonstructural or NS protein, is found only in infected cells. Segmentation of the viral genome makes it possible for the virus to undergo genetic recombination with high efficiency [2]. When a cell is infected by two influenza A viruses the genes of each virus are reproduced and packaged randomly into maturing virus particles. Thus, most viruses produced during mixed infection are recombinants. In a strict sense, tiiis is not recombination, but gene reassortment. The virus is bounded by a lipid bilayer into which are inserted two distinct types of glycoprotein projections, the hemagglutinin and neuraminidase antigens. The hemagglutinin is involved in attachmentof the virus to the host-cell surface, via neuraminic acid receptors, whereas die neuraminidase glycoprotein, which cleaves neuraminic acid, is required for release of the virus particle from die surface of die infected cell. The odier five virion proteins are located witiiin die virus and provide structural and enzymatic functions. The eight viral RNA segments (genes) are each coated with nucleoprotein (NP) to form helical RNP complexes. The large Pl, P2, and...