Immunotherapy for Infectious Diseases

76 Kunert and Katinger
that so-called neutralizing antibodies are not detectable during the acute phase of virus
clearance after primary infection of seronaive individuals, whereas cellular immune
responses are clearly found (42,43).
During the chronic phase of HIV-1 infection, serum antibodies capable of neutralizing
primary virus isolates in vitro are detectable. Long-term survivors apparently tend
to have higher levels of those neutralizing antibodies than so-called fast progressors
(44). There is also evidence that the presence of maternal neutralizing antibodies correlates
with reduced transmission of HIV-1 to the neonate. Indirect epidemiologic evidence
suggests that mucosal virus transmission plays a major role during intrapartum
infection of the infant (45).
Nevertheless, the putative roles of neutralizing antibodies in prevention of infection or
their beneficial contribution to the control of established viremia and disease progression
remain to be established in clinical trials rather than by academic reasoning. The observation
that HIV-1 appears to escape from neutralizing antibodies in vivo cannot be clarified
by simple in vitro neutralization tests, which are inappropriate to simulate the complex
in vivo dynamics of the battle between the immune system and a highly adaptive virus.
Standard in vitro neutralization tests, even when done with primary virus isolates passaged
on primary cells, do not reflect the complex interactive in vivo background matrix. Interactions
with the complement system, antibody-mediated cellular immune responses, and
other important in vivo derived and profound accessory factors are neglected.
It is well established that during the chronic phase of viremia the virus alters its
(co)receptor tropism, and therefore neutralizing antibodies recognizing different epitopes
(either so-called linear, structural, or complex epitopes) might be useful in prevention
of infection or (therapeutic) control of viremia in different phases of progression.
It is also established that viruses shedd in vivo are loaded with various cytoplasmatic
and envelope proteins as well as with components contributed from the plasma of the
host (46). Little is known about the contribution of those host factors to either increased,
or reduced or altered infectivity of the virus and its sensitivity to neutralizing antibodies
in vitro or in vivo. At least it has become evident that the glycoprotein complex of
HIV-1 isolates propagated in peripheral blood mononuclear cells (PBMCs) differs from
that of T-cell line-adapted (TCLA) HIV-1 strains in various respects. The so-called primary
HIV-1 isolates are generally less sensitive to neutralization by antibodies directed
to certain domains on the gp120 envelope such as the CD4 binding domain and the V3
loop. It has even been noted that neutralizing monoclonal antibodies directed against
these domains and also polyclonal HIV-1-specific antibodies derived from human
donors (HIVIG) may enhance virus entry. One may even speculate that ADE is a strategy
common to closely related lentivirus such as HIV-1, HIV-2, and simian immunodeficiency
virus (SIV) in order to escape from neutralizing antibodies (47).
On the other hand, it has been shown in extensive studies that the human monoclonal
antibody 2F5 (48), which binds to a conserved epitope on the ectodomain of the HIV-
1 envelope protein gp41, is capable of inhibiting virus entry and shows no ADE phenomena.
This antibody is obviously blocking an essential step in the process of virus
entry of both TCLA- and PBMC-derived viruses (49). One might therefore conclude
that such types of neutralizing monoclonal antibodies and combinations thereof, which
do not mediate ADE phenomena, may represent the most suitable candidates for passive
immune intervention.