Immunotherapy for Infectious Diseases

Passive Immunotherapy for HIV Infection 207
The anti-CD4 monoclonal antibody B4 was found to protect all three chimpanzees
challenged intravenously with a primary HIV-1 isolate and three of four macaques
challenged intravenously with SIV mac257 (72).
Mascola et al. (105) studied the activity of combinations of antibodies in protecting
macaques against intravenous challenge with an SHIV containing the envelope of the
primary isolate HIV-89.6. Three of six animals given HIVIG together with the monoclonal
antibodies 2F5 and 2G12 were protected from infection; one of three given 2F5
and 2G12 together were protected. The animals that became infected had lower viremias
than IVIG-treated controls and maintained near normal CD4 counts. The three monkeys
that received 2F5, 2G12, or HIVIG alone, respectively, developed high viremias
but had slower falls in their CD4 cell counts and more benign clinical courses than controls
(105).
Protection was easier to achieve against vaginal challenge with SHIV89.6 (106).
Four of five monkeys receiving HIV IG/2F5/2G12, two of five receiving 2F5/2G12,
and two of four receiving 2G12 alone were completely protected from infection. Again,
the six animals that became infected had lower plasma viral RNA levels and smaller
declines in CD4 lymphocyte counts than control animals. Although the number of animals
studied was small, and the progesterone-treated monkey model is not completely
comparable to the natural human situation, these experiments suggest that antibody
may be more protective against mucosal viral exposure than intravenous challenge
(106). This suggestion is supported by the finding that neutralizing antibody inhibits
HIV infection of dendritic cells and subsequent spread to T-cells (90). Since dendritic
cells in the mucosa are likely to be the initial targets of HIV infection, antibody could
play an important role in protecting against the initial establishment of infection (90).
Antibody protection against mucosal infection was also demonstrated in an SHIVvpu�
study in macaques (107). The triple monoclonal antibody combination of F105,
2F5, and 2G12 given 5 days before cesarean section and immediately after completely
protected the infants of four pregnant macaques from an oral SHIV challenge. The four
adult macaques were also protected from an intravenous SHIV challenge 3 days post
partum. Since the monoclonal antibodies used in this experiment were of the IgG1
type, it appears that antibodies of the secretory IgA type are not necessary for mucosal
protection from viral infection (107).
Preexposure Studies in SCID Mice
Severe combined immunodeficient (SCID) mice lack functional T- and B-lymphocytes
(108). Human peripheral blood lymphocyte (hu-PBL-SCID) or fetal human thymic or
lymph tissue (hu-thy-SCID or SCID-hu) can be engrafted into the peritoneum of these
animals (109,110). The intraperitoneal injection of HIV-1 into hu-PBL-SCID mice leads
to sustained infection of the human xenograft (111). Antibody given intraperitioneally
rapidly distributes into the blood (112). Thus, the hu-PBL-SCID mouse provides a simple,
inexpensive animal model to test passive antibody protection strategies. Large numbers
of animals can be involved in these studies.
On the other hand, the immunocompromised nature of these animals does not mimic
the natural human state when humans are exposed to virus. Furthermore, most human
infections occur via the intravenous or mucosal route, not intraperitoneally. Nonetheless,
with these limitations in mind, several useful observations have been made.