ScienceDaily (June 17, 2008) — A protein related to heart disease and
Alzheimer's is found to be a factor in HIV. The apolipoprotein (apo) E4 isoform
has been implicated in neurodegeneration in Alzheimer's disease, cardiovascular
disease, and stroke. Now, investigators at the Gladstone Institutes, the
University of California, San Francisco, the University of Texas Health Science
Center at San Antonio, and the Infectious Disease Clinical Research Program,
Uniformed Services University, Bethesda, Maryland have shown that this troubling
protein is a risk factor for AIDS progression rates and promotes entry of HIV
into cells.
The study was published in the June 16 issue of the Proceedings of the National
Academy of Sciences USA (PNAS).
"The apoE4 protein is the greatest known genetic risk factor for Alzheimer's
disease," said Gladstone president and study author Robert W. Mahley. "However,
its role in infectious diseases has been less well-defined."
ApoE has three isoforms that differ by only one amino acid. Yet this seemingly
small sequence difference has profound implications for the structure and
function of the protein. ApoE4 has an extra intramolecular bond that results in
a more compact structure, and it also is more likely to be
unstable--characteristics that have been linked to its deleterious effects.
Although the apoE3 gene is the most prevalent in all human populations, with
frequencies of 50%á²%, the genetic variant that leads to production of apoE4 is
also widely distributed; its prevalence is 15%á€%.
The different effects of the apoE isoforms in other settings led the
investigators to hypothesize that a similar difference might exist in HIV
infection.
To test this hypothesis, Dr. Mahley teamed up with Trevor Burt and Joseph M.
McCune of the University of California, San Francisco, Brian Agan and Matthew
Dolan of the Infectious Disease Clinical Research Program, and Sunil Ahuja of
the University of Texas Health Science Center at San Antonio to examine a large
and well-characterized cohort of 1267 HIV-positive subjects of European and
African American descent and 1132 ethnically matched seronegative controls. The
goal was to study the interactions between apoE and HIV in tissue culture.
Several questions were of great interest. Does apoE genotype affect disease
progression? Do apoE isoforms influence cell entry by HIV in a manner concordant
with the impact of the corresponding APOE alleles on HIV disease progression? Do
the genetic variants of apoE convey differential susceptibility to
HIV-associated dementia, a condition that shares many pathogenic and clinical
features with Alzheimer's disease?
The researchers found a much faster disease course and progression to death in
patients with two copies of the apoE4 allele than in patients with two copies of
the apoE3 allele. The corresponding apoE4 isoform enhanced in vitro HIV
fusion/cell entry of HIV strains that use both the CCR5 and CXCR4 chemokine
coreceptors to enter the cell. However, the apoE4 gene did not increase the
incidence of HIV-associated dementia.
"A large body of evidence suggests that the amphipathic helical domains of
apolipoproteins act as fusion inhibitors," said Dr. Mahley. "We speculate that
these domains in apoE inhibit HIV infection in a manner analogous to the
clinical HIV fusion inhibitor Enfurvitide. Our findings suggest apoE4 is less
efficient than apoE3 at inhibiting fusion of HIV to target cells."
Polymorphisms in host genes significantly affect susceptibility to HIV-1
infection and the rate of disease progression. The study of these polymorphisms
has increased the understanding of HIV pathogenesis and informed the development
of new antiviral therapeutics.
The findings from this study show that apoE is a determinant of the pathogenesis
of HIV/AIDS and raise the possibility that current efforts in the Gladstone
Center for
Translational Research to convert apoE4 to an "apoE3-like" molecule for the
treatment of Alzheimer's disease might also have clinical applicability in HIV
disease.
"Although we suspected that apoE4 had a role in infectious disease, this aspect
of the study is very exciting for us because we already have studies under way
to find small molecules that make apoE4 more like apoE3," said Dr. Mahley. "Now
those potential new drugs may have more value than we originally thought."
Additional members of the research team were Weijing He and Hemant Kulkarni of
the University of Texas Health Science Center at San Antonio, Jeffrey E. Mold of
the University of California, San Francisco, Marielle Cavrois and Yadong Huang
of the Gladstone Institutes, and Vincent C. Marconi of the Uniformed Services
University of Health Sciences.
Adapted from materials provided by Gladstone Institutes, via EurekAlert!, a
service of AAAS.
