Rapid development of isolate-specific neutralizing antibodies after primary HIV-1 infection and consequent emergence of virus variants which resist neutralization by autologous sera

Albert, Jan; Abrahamsson, Bengt; Nagy, K.; Aurelius, Elisabeth; Gaines, Hans; Nyström, Gunnel; Fenyõ, Éva Mária

doi:10.1097/00002030-199002000-00002

Cited by 373 publications

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“…The virus grows exponentially and declines as a function of the immune reaction. The latter is supposedly due to specific antibodies and/or to cytotoxic T cells (3,21,23,24). For simplicity, we here assume that the immune reaction is proportional to the concentration of HIV-specific CD4+ helper T cells.…”

Section: Models Of the Immune Response To Hivmentioning

confidence: 99%

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Diversity and virulence thresholds in AIDS

Boer¹,

Boerlijst²

1996

Models for Infectious Human Diseases

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We propose a model for the interaction between human immunodeficiency virus and the immune system. Two differential equations describe the interactions between one strain of virus and one clone of T lymphocytes. We use the model to generalize earlier results pertaining to the AIDS diversity threshold [Nowak, M. A., Anderson, R. M., McLean The development of AIDS is associated with the selective depletion of the most crucial cell type of the immune system: the CD4+ helper T cell. The human immunodeficiency virus (HIV) infects helper T cells by binding the gpl20 virus envelope glycoprotein to CD4+ molecules (1). The selective infection and death of CD4+ T cells provides a simple explanation for the impairment of the immune system (2, 3). This explanation, however, is widely debated (4-7).One hallmark of HIV infection is the long and variable incubation period. Although the processes of infection and immune activation have a short time scale, a typical time scale for the incubation period is 10 years (8). Another hallmark of HIV is its enormous genetic diversity. The dominant surface antigen for the immune response is the V3 loop of gpl20 (9,10). This V3 loop is hypervariable: virus isolates from one infected individual have genetically different V3 loops (11, 12). Since HIV accumulates one point mutation per genome during an average replication cycle (12,13), the genetic variability will grow exponentially. However, antigenic variability is not unique to HIV: several pathogens possess antigenic variability which lets them "run ahead" of the immune response.A recent model (14-17) combines these two hallmarks of AIDS in that it attributes the long and variable incubation period to genetic variability. The authors of the model coinedThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. the term "diversity threshold" for the critical variability beyond which the immune system is no longer capable of controlling the virus. The diversity threshold emerges mathematically from their simple and quite reasonable model. The diversity threshold (14-17) is a generic property of a wide variety of models. (See refs. 17 and 18 for recent reviews of mathematical models for the various pathogenic effects of HIV.)The virus quasispecies (19) not only increases in diversity but also evolves physiologically different strains. Virus strains evolve different replication rates, cytotrophisms, and antigenicities (20)(21)(22). Here we develop a model that allows us to study the relation between the diversity of the virus quasispecies and the "virulence" of each virus strain. We derive a dimensionless virulence parameter and show that it is involved in well-known local and global bifurcations. Models of the Immune Response to HIVOur models describe the interactions between one strain of virus vj, where j is the strain number, and the clone(s) of CD4+ T cells tj that recognizes thi...

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Section: Models Of the Immune Response To Hivmentioning

confidence: 99%

“…Virus strains evolve different replication rates, cytotrophisms, and antigenicities (20)(21)(22). Here we develop a model that allows us to study the relation between the diversity of the virus quasispecies and the "virulence" of each virus strain.…”

Section: Introductionmentioning

confidence: 99%

Diversity and virulence thresholds in AIDS

Boer¹,

Boerlijst²

1996

Models for Infectious Human Diseases

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“…(HBV: Carman et al, 1990;Harrison et al, 1991Harrison et al, , 1994Harrison & Zuckerman, 1992. HIV-1 : Albert et al, 1990;Arendrup et al, 1992Arendrup et al, , 1993Nara et al, 1990a, b;Tremblay & Wainberg, 1990;Montefiori et al, 1991;Watkins et al, 1993;Schreiber et al, 1994. ) …”

Section: Discussionmentioning

confidence: 99%

All rabbits immunized with type A influenza virions have a serum haemagglutination-inhibition antibody response biased to a single epitope in antigenic site B

Lambkin

Dimmock

1995

Journal of General Virology

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Nine rabbits were immunized with type A influenza virions and the epitope specificities of the secondary serum haemagglutination-inhibition (HI) antibody response were analysed with a panel of neutralizing monoclonal (MAb) antibody double escape mutants. Each of the latter was made by sequential selection using a MAb directed to an epitope of a discrete antigenic site, site A, site B or site D, of the haemagglutinin (HA). Thus the epitope reactivity of the escape mutants was represented as A+B-D -, A-B+D and A-B-D +. The HI antibody response of all antisera was biased to the site B epitope. In 9/12 antisera, obtained from seven rabbits immunized with whole virions, the site B epitope was predominant, representing 65-82% of the total HI antibody. The restriction of HI antibody was unaffected by strain of rabbit, route of inoculation (intravenous or subcutaneous), use of Freund's adjuvant, and up to four immunizing injections. In 3/7 rabbits immunized with whole virus, there was a HI antibody response to the HC2 (site A) or HC10 (site D) epitope, but not both, of equal magnitude to the site B epitope. The HI antibody response in one of the rabbits (#40) became more biased to the site B epitope between the third and fourth immunizing doses. Two further rabbits were immunized with virions which had been partially digested with bromelain and then purified from free HA. Both of these made equal HI antibody responses to the site B epitope and the site D epitope, possibly because their remaining HA spikes were better exposed. Overall, these data demonstrate an unexpected degree of restriction in the production of biologically relevant antibody, such that some rabbits (e.g. #45) mount an HI antibody response which is essentially epitope-specific. Implications for epitope specificity of HI antibody stimulated by human influenza vaccines, and also for the generation of antigenic drift variants are discussed. The reason for the non-responsiveness of the immune system to the many other HI epitopes of the HA is not known.

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“…However, these experiments have all required non-natural conditions, such as highly selected fractions of influenza antiserum [5][6][7][8], or low concentrations of foot-and-mouth disease virus [9,10], or HIV antiserum [11,12] and usually many sequential passages in the presence of the selecting antibody. In vivo escape mutants have arisen when vaccination of cattle with foot-and-mouth disease virus [13] or man with hepatitis B virus [14,15] or during persistent infection of man or non-human primates by HIV-1 [16][17][18][19], resulted in sub-protective immunity. In addition, our recent work has shown that some of the antisera (12 %) from mice immunized 2 or 3 times subcutaneously with inactivated whole influenza A virus were able to select escape mutants to an epitope in antigenic site A, and hence appeared to have an epitope-biased HA-specific secondary antibody response.…”

Section: Introductionmentioning

confidence: 99%

Selection of neutralizing antibody escape mutants with type A influenza virus HA-specific polyclonal antisera: possible significance for antigenic drift

1997

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Ten antisera were produced in rabbits by two or three intravenous injections of inactivated whole influenza type A virions. All contained haemagglutination-inhibition (HI) antibody directed predominantly to an epitope in antigenic site B and, in addition, various amounts of antibodies to an epitope in site A and in site D. The ability of untreated antisera to select neutralization escape mutants was investigated by incubating virus possessing the homologous haemagglutinin with antiserum adjusted to contain anti-B epitope HI titres of 100, 1000 and 10000 HIU/ml. Virus-antiserum mixtures were inoculated into embryonated hen's eggs, and progeny virus examined without further selection. Forty percent of the antisera at a titre of 1000 HIU/ml selected neutralizing antibody escape mutants as defined by their lack of reactivity to Mab HC10 (site B), and unchanged reactivity to other Mabs to site A and site D epitopes. All escape mutant-selecting antisera had a ratio of anti-site B (HC10)-epitope antibody[ratio ]other antibodies of [ges ]2·0[ratio ]1. The antiserum with the highest ratio (7·4[ratio ]1) selected escape mutants in all eggs tested in four different experiments. No antiserum used at a titre of 10000 HIU/ml allowed multiplication of any virus. All antisera used at a titre of 100 HIU/ml permitted virus growth, but this was wild-type (wt) virus. We conclude that a predominant epitope-specific antibody response, a titre of [ges ]1000 HIU/ml, and a low absolute titre of other antibodies ([les ]500 HIU/ml) are three requirements for the selection of escape mutants. None of the antisera in this study could have selected escape mutants without an appropriate dilution factor, so the occurrence of an escape mutant-selecting antiserum in nature is likely to be a rare event.

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Rapid development of isolate-specific neutralizing antibodies after primary HIV-1 infection and consequent emergence of virus variants which resist neutralization by autologous sera

Cited by 373 publications

References 0 publications

Diversity and virulence thresholds in AIDS

Diversity and virulence thresholds in AIDS

All rabbits immunized with type A influenza virions have a serum haemagglutination-inhibition antibody response biased to a single epitope in antigenic site B

Selection of neutralizing antibody escape mutants with type A influenza virus HA-specific polyclonal antisera: possible significance for antigenic drift

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