final program.qxd - Parallels Plesk Panel

OP 2.3
Research Priorities In HIV Immunology ?
Marie-Lise GOUGEON,
Unité Immunité Antivirale, Biothérapie et Vaccins, Institut Pasteur, Paris
The pathogenic and physiologic processes leading to AIDS remain a conundrum. Upon
transmission to a new host, HIV targets effector memory T cells, resulting in acute,
massive depletion of these cells from mucosal sites, including gut. Does this early
depletion compromise the regenerative capacity of immune cells? Mucosal depletion is
closely followed by the onset of generalized immune activation. What is the cause of
chronic immune activation? Does it reflect a homeostatic response, or activation by
mucosal antigens, or "bystander effects" of innate and adaptive immune response to HIV
replication, involving cytokines, self-antigens and foreign microorganisms? Because
persistent activation progressively disrupts the functional organization of the immune
system, reducing its regenerative capacity and facilitating viral evolution that leads to
AIDS, it is important to resolve this issue and to design strategies to target host
mechanisms that contribute to loss of immune functions.
The characterization of innate immune cells and the way they control HIV infection is
another important research area. Natural killer (NK) cells can contribute to the host
immune response to HIV infection through cytolytic and non cytolytic mechanisms, and
genetic and functional studies of exposed, uninfected individuals indicate a protective role
for NK cells in the early stage of HIV infection. Interaction with dendritic cells (DC) and
priming for the adaptive immune response is another important function of NK cells.
HIV induces several alterations in NK-cell phenotype and function in vitro and in vivo, but
further research is warranted to determine the role of NK cells in the control of HIV
viraemia, in the development of mucosal immunity and in protection against mucosal
infection, in order to specifically target NK cells with new molecules that would activate
them to lyse HIV-infected target cells in vivo. With regard to vaccine development, further
delineation of the immune correlates of protection during natural infection and after
vaccination is a fundamental task. Recent data suggest that the effectiveness of virusspecific
immune responses is not exclusively based on the quantity but rather on the
quality of CD4 and CD8 T cells. Indeed, the control of virus replication by HIV-specific cell
mediated immunity is suggested by several observations i.e. virus-specific CD8 T cells are
detected in individuals who were exposed to HIV but remained uninfected, depletion of
CD8 T cells results in a loss of virus control in monkeys infected with SIV, the
preservation of HIV-specific helper CD4 T cell responses is associated with virus control
after interruption of antiviral therapy during primary infection, HIV-specific CD4 and CD8
responses are preserved in LTNP and the memory T cell responses are qualitatively
similar to the EBV and CMV-specific immune responses that control both infections.
Nevertheless, definitive experimental evidence that certain types of immune response are
indeed immune correlates of protection are needed before current candidate vaccines can
be moved into large efficacy trials. Concerning humoral immunity, it is still unclear whether
neutralizing antibodies have a substantial role in the control of chronic steady-state
viraemia, but their limited effect may be related to the very rapid evolution of the virus and
the selection of variants that are resistant to the most broadly neutralizing antibodies.
A number of questions have to be solved: what is the impact of HIV-induced B cell
maturation defects on the viral escape from neutralizing antibodies? Is it possible to
design immunogens capable of inducing protective neutralizing antibodies by active
vaccination ? how to induce high titers of neutralizing antibodies? Determining the
correlates of immune protection provides insight the mechanisms of protection, although
it does not prove cause and effect. In addition, the correlates of protection involved in
preventing disease progression during natural infection with HIV do not necessarily reflect
those that would be protective in the presence of pre-existing vaccine-induced immunity.
Therefore, more basic research is still needed to elucidate the mechanisms of immune
control of HIV infection and the correlates of vaccine protection.
“ Focusing FIRST on PEOPLE “ 38 w w w . i s h e i d . c o m