TRANSGENIC MOUSE MODELS FOR HIV INFECTION

Project: Research project

Project Details

Description

DESCRIPTION (adapted from applicant's abstract): The development of
vaccines capable of eliciting an immune response protective against HIV
infection has been hampered by the lack of a small animal model susceptible
to HIV infection. Despite the identification of CD4 as the primary cellular
receptor for HIV, expression of human CD4 transgene alone did not render
mice susceptible to HIV infection. The mechanistic basis for this
restriction has recently been clarified by the demonstration that, in
addition to CD4, HIV must interact with another member of the chemokine
receptor superfamily, such as CCR5, to start the process of membrane fusion
and viral penetration. The investigators have initiated studies examining
the susceptibility of mice to HIV infection using mice that they developed
that are transgenic for human CD4 and CCR5. Therefore, they propose to
expand on these studies and to develop mice transgenic for human CD4 and
other human chemokine receptors as a model for studying the role of the
immune system in controlling HIV infection and for evaluating HIV vaccines.
Because HIV infection of mouse cells is also compromised by defective
function of HIV regulatory genes such as tat and rev, the usefulness of
these transgenic mice for studying HIV infection will require the generation
of isolates of HIV that are better suited for growth in mouse cells. One
approach the investigators will use to generate these isolates will be to
adapt HIV for growth in mouse cells by serial in vivo or in vitro passage.
Another approach that will be used will be to construct HIV clones with
alternative regulatory sequences designed to circumvent post-penetration
blocks that impede HIV replication in murine cells. After generating the
transgenic mice and permissive HIV isolates, they will use a genetic
approach to delineate the immune responses necessary and sufficient for
protection against HIV infection. The transgenic mice will be bred into
mouse lines homozygous for targeted disruptions of various critical immune
response genes such as class I MHC, class II MHC, perforin and u-M, and then
infected with HIV. This will enable the investigators to develop a genetic
approach for studying the mechanisms of immune protection and pathogenesis
of HIV infection.
StatusFinished
Effective start/end date9/30/979/29/00

ASJC

  • Immunology