Immunotherapy for Infectious Diseases

212 Jacobson
clinical isolates, which are more resistant than laboratory-adapted strains to neutralization
by antibodies.
Successful animal protection studies usually have utilized 10 MID 50s of virus as the
challenge inoculum to be neutralized. It is likely that natural human exposures consist
of inocula far smaller, probably on the order of �1 MID 50 (115). On the other hand,
natural host antibody responses are usually inadequate to protect and control HIV
infection durably. Exogenous administration of protective quantities of more potent targeted
antibodies seems to be technically feasible and practical in the clinical setting.
Undoubtedly, the doses of anti-HIV antibodies required for treatment must be
greater than those required for prevention, perhaps 2–3 logs greater (23). A Pediatrics
AIDS Foundation-sponsored workshop on HIV passive immunization recommended
that the criteria for advancing candidate anti-HIV monoclonal antibodies to human trials
include a requirement for 90% in vitro neutralization of most clinical isolates at
concentrations of 5–10 �g/mL. It was felt that these concentrations could be safely
reached in the sera of patients after administration of monoclonal antibody preparations
(137). Comparable levels have been associated with protection in animal studies. However,
several hu-PBL-SCID mouse experiments have demonstrated that doses associated
with >99% in vitro neutralization activity are required for successful protection
(115). Treatment of infection, as opposed to prevention of infection, is likely to require
even higher doses and/or potency. No clear therapeutic antiviral benefit has been seen
with the antibody preparations studied to date, but monoclonal antibodies with potent
neutralizing activity against clinical isolates have not yet gone into clinical trials.
In addition to neutralizing activity, the ability of antibodies to activate complementmediated
lysis of free virus and infected cells, as well as ADCC against infected cells,
would be attractive features. These activities were found to be important in hu-PBL-
SCID mouse protection studies (114, 123).
Monoclonal antibodies will need to be administered in combination to obtain synergistic
potency, reduce dosage requirements, counteract any infection enhancement
activity of any antibodies in the combination, and prevent the emergence of mutant
viral strains resistant to neutralization.
The host immune response to natural infection with HIV involves both humoral and
cellular components. The response is partially effective in controlling viral replication but
not in eradicating infection in most circumstances. Enhancing either arm of the immune
response should prove beneficial. Passively administered antibodies might prove to be
particularly useful in protection against the initial infection of dendritic cells, as well as
monocytes and lymphocytes and might thus protect against the establishment of the
infection. In addition, research in this area should identify HIV epitopes targeted by antibodies
and cytotoxic T lymphocytes that will aid in the design of effective vaccines.
REFERENCES
1. Albert J, Abrahamsson B, Nagy K, et al. Rapid development of isolate-specific neutralizing
antibodies after primary HIV-1 infection and consequent emergence of virus variants
which resist neutralization by autologous sera. AIDS 1990; 4:107–112.
2. Robert-Guroff M, Goedert JJ, Naugle CL, Jennings AM, Blattner WA, Gallo RC. Spectrum
of HIV-1 neutralizing antibodies in a cohort of homosexual men: results of a 6 year
prospective study. AIDS Res Hum Retroviruses 1989; 5:343–350.