Early attempts with candidate HIV-1
vaccines based entirely or partially on the use of recombinant
envelope proteins gp120 or gp160 (gp120 & gp41) have
failed to elicit neutralizing antibodies against primary
HIV-1 isolates1,2. Therefore, redesigned alternative vaccine
approaches have been developed. Most vaccines currently under
development are designed to stimulate strong T-cell-mediated
immune responses to HIV. These include several viral vector-based
live attenuated vaccines combined or not with a DNA prime
and/or a recombinant antigen boost3. The interest for vaccines
capable of eliciting neutralizing antibodies has recently
gained a new interest4. It has been postulated that past
failures to elicit neutralizing antibodies with the viral
glycoproteins may be due in part to the use of recombinant
monomeric gp41, gp120 or gp160 molecules that were improperly
folded and did not expose the neutralization epitopes. It is
well known that HIV-1 may evade neutralizing antibodies and
cytotoxic T-cell responses (CTL) through a variety of mechanisms.
Therefore, discovering way to trigger a broad neutralizing
immune response that could overcome viral immune escape is
of prime importance.
Furthermore, none of the HIV vaccines under development takes
into consideration the possible autoimmunity issue due to cross-reactivity
between HIV-1 antigens and host proteins. Molecular mimicry
between HIV-1 glycoproteins and key immune-regulatory molecules
might induce persistent autoreactivity resulting in deregulation
of immunocompetent cells. Indeed, autoantibodies with various
specificities (anti-IL-25,6, anti-MHC class II7, anti alpha-actin8,
anti-complement factor H9, anti-IFNa/b10,11, platelet glycoprotein
gpIIIa12, etc.) can be found at early stages of HIV-1 infection
and might contribute to the eventual development of AIDS.
Ideally, viral proteins used as vaccine candidates should be
devoid of mimicry with host proteins in order to prevent the
potential induction of autoimmune reactions. However, it is
neither assured that a significant number of vaccines would
mount such an immune response as the immune tolerance to self
would have to be broken, nor is it known if, were such a response
to occur, it would be of physiological significance at early
time points. On a long-term basis, however, tolerance to self
is known to gradually and naturally wane with time, as pre-established
or newly appearing auto-reactive T cells significantly expand
because regulatory CD4+CD25+ T cells progressively become unable
to control their proliferation. This defect is seen in elderly
persons13. As a result of vaccination at a younger age, weak
to strong autoimmune-associated pathologies might develop at
an advanced age, depending of the initial cell pool and self-antigen
specificities. In view of that potential human health problem,
we think that eliminating viral mimicry while maintaining maximal
antigenicity is an important point to consider when designing
a safe and efficacious vaccine against HIV/AIDS. |
