VARIABLE GENE USE AND PNEUMOCOCCAL IMMUNITY IN AIDS

Project: Research project

Project Details

Description

DESCRIPTION (adapted from abstract of applicant): Human antibodies to capsular
polysaccharide of Streptococcus pneumoniae (PPS) express genes from the VH3
gene subgroup. SinceVH3 gene expression is often reduced in the setting of HIV
infection and PPS-derived vaccines are poorly immunogenic in HIV-infected
individuals, we have hypothesized that decreased expression of the
immunoglobulin genes used in antibodies to PPS contributes to PPS vaccine
failure in the setting of HIV infection. The structure-function relationship of
human antibodies to most pneumococcal serotypes has not been fully
investigated. The studies that are proposed in this application are designed to
characterize the variable gene use and epitope specificity of human antibodies
to two common serotypes of S. pneumoniae, serotypes 8 and 23F, and to use this
information to develop probes to determine the specificity of vaccine elicited
antibodies to PPS 8 and 23F from individuals with and without HIV infection.
The specific aims are: 1) To determine the molecular structure of human Mab to
PPS 8 and 23F generated in transgenic mice reconstituted with human
immunoglobulin loci; 2) To characterize the Mabs to PPS 8 and 23F produced in
aim one as protective, non-protective or disease enhancing against pneumococcal
infection in mice and as opsonic in vitro; 3 ) To use Mabs with functional
efficacy as defined in aim two to isolate peptide mimetics of PPS 8 and 23F
epitopes, and to use the peptides to determine if PPS-elicited antibodies in
patients sera recognize protective, non-protective or disease enhancing
epitopes. Studies are proposed to examine the hypothesis that protective
antibodies to PPS can be distinguished by their variable gene use and
specificity and that the production of antibodies to certain epitopes ,which
are derived from VH3 genes, is impaired in the setting of HIV infection.
Knowledge gained from these studies will help us to understand the
structure-function relationship for antibodies to S. pneumoniae in patients
with HIV infection, and to identify possible correlates of PPS vaccine failure
and the requirements for more effective anti-pneumococcal vaccines.

Significance: Infection with pneumococcus has become a major cause of morbidity
and mortality in AIDS. In the past, AIDS-associated infections were easily
treated with antibiotics however, penicillin resistant isolates have emerged in
the 1990's. This emergence of antibiotic resistant pneumococcus has increased
the need for vaccination of high-risk groups such as HIV+ persons. However,
available pneumococcal vaccines are poorly immunogenic in HIV+ persons. Thus,
the goal of this proposal, which is to identify the molecular and biological
basis of human antibody responses to peumococcal vaccination in normal
volunteers and HIV+ persons, is very significant. The information gained from
the proposed studies could lead to better vaccines for pneumococcus in
immunocompromised hosts and importantly, will contribute to the understanding
of how antibodies function in resistance to S. pneumoniae.

Approach: This is the second revision of this application. Since the last
review of this application the author has published 1 manuscript and has two
others in press having to do with this application. The first publication
describes the generation of a protective human Mab to PPS 8. The second,
describes the generation of human antibodies to PPS 3 in XenoMouse mice. The
third describes the molecular response of HIV-infected and HIV-uninfected
subjects to Pneumovax. Thus, the author has made excellent progress even though
she is not funded to do this work. This indicates commitment, enthusiasm and
capability of the author to carry out this work. he P.I. has responded to the
previous criticisms and has written a strong and significant application. One
previous concern was that if HIV-infected individuals can not produce VH3 and
only VH3 ab are protective that little of this information will be useful to
make patients more resistant to pneumococcus. The PI points out that the goal
of this application is not to characterize VH3 expression in HIV-infected
individuals, but to determine whether they do or do not produce antibodies to
pneumococcal capsular polysaccharides with defined epitope specificity. The
PI's response and revisions to other reviewer's comments also strengthen the
1
ZRG-1 AARR- 4 (01) 3 1 R01 AI45459-01A2
March 2000 Pirofski, Liise-Anne


proposal. In addition, because of the subject of this application, the initial
applications were difficult to follow. This revised version is clearer and the
additions the PI has made are helpful. It is much more apparent what the PI
really wants to accomplish. This is important since the reviewers agreed that
this was a difficult application to read, mainly because of the subject matter
and the specialized nature of the work.

Innovation: The overall approach utilized in solving this problem takes
advantage of established methods. The author has used these methods in the
study of Cryptococcus so that the overall strategy is somewhat proven. Use of
the XenoMouse is considered innovative. There are relatively few laboratories
interested in antibody-mediated resistance. This makes this work somewhat
unique.

Investigator: Dr. Pirofski is well qualified to carry out the proposed
research. She has published studies utilizing most of the methods in the
proposal. Dr. John McKitrick is a consultant and brings expertise in the
microbiology of S. pneumoniae.

Environment: The P.I. is at Albert Einstein and has several other researchers
nearby that have expertise in many of the methods she will utilize. She is in
an excellent environment to accomplish this proposal.

In summary, the subject of this proposal is timely and significant. The
emergence of antibiotic resistant S. pneumoniae infections in AIDS patients
requires the development of more efficient means of immunizing these
individuals. The PI has made excellent progress on this project despite not
being funded in this area. Studies proposed in this application could provide
valuable information for developing more immunogenic vaccines for HIV+ persons.
Simply put, this work needs to be done.
StatusFinished
Effective start/end date7/1/006/30/01

Funding

  • National Institute of Allergy and Infectious Diseases: $370,125.00

ASJC

  • Microbiology (medical)
  • Infectious Diseases
  • Molecular Medicine
  • Virology
  • Immunology

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