AIDSWEEKLY Plus, 25 March 1996 issue; Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588
Daniel J. DeNoon, Senior Editor

Hyperimmune plasma from healthy people with HIV infection could prevent disease in some people recently exposed to the virus, monkey studies show.

The data also provide a tantalizing glimpse into the unknown: the correlates of protective immunity against HIV. Lack of this knowledge currently hamstrings HIV vaccine research.

The experiments showed that macaque monkeys experimentally infected with HIV's cousin, simian immunodeficiency virus (SIV), are protected against disease if they are quickly treated with hyperimmune plasma from other SIV infected monkeys that have not yet developed immune deficiency.

By temporarily suppressing SIV replication, the SIV specific polyclonal immunoglobulin (Ig), dubbed SIVIG, provided a window of opportunity for the animals to develop effective anti-SIV immune responses of their own. A minority of animals did not develop such responses and developed disease despite SIVIG therapy.

"The finding that immune responses are required to maintain low viral load is very important to vaccine research," said researcher Nancy Haigwood, senior principal scientist at Bristol-Myers Squibb Research Center, Seattle, Washington. "It is now important to define what these responses are."

Haigwood made her remarks in an invited address to the Eighth Annual Meeting of the National Cooperative Vaccine Development Groups for AIDS (NCVDG), held February 11-15, 1996, in Bethesda, Maryland.

Haigwood noted that hepatitis B virus and some animal lentiviruses - relatives of HIV - can be successfully treated with passive immunotherapy. In humans, strong anti-HIV humoral immunity is associated with longer survival.

An HIV immunoglobulin preparation, manufactured by North American Biologicals, Miami, Florida, under the name HIVIG, has shown promise in Phase I and II clinical trials.

The SIVIG used in the Haigwood studies was purified from animals that did not progress to disease despite being infected for at least six years with pathogenic SIV. All donor animals had high titers of SIV neutralizing antibodies.

In their experiment, Haigwood and colleagues infected 16 macaques with pathogenic SIV. On days 1 and 14 after infection, six of the animals received SIVIG and six received intravenous immunoglobulin prepared from normal animals. The remaining monkeys received no treatment.

After receiving SIVIG, the treated animals exhibited anti- SIV antibody levels similar to those seen in the untreated animals only 12 weeks after infection. Unlike the untreated monkeys, none of the treated animals had detectable serum levels of SIV p27 antigen.

Four of the six SIVIG recipients remained healthy; the remaining two died quickly of AIDS-like symptoms. Only one of the control animals remained healthy during the course of the study, and that animal has recently developed symptoms, Haigwood said.

All of the SIVIG-treated animals that remained healthy had blunted SIV viral titers that remained low over more than 18 months of observation.

Cytotoxic lymphocytes specific for SIV appeared in four animals, but not all of these monkeys were in the SIVIG treatment group.

Survival in all groups was strongly correlated with the appearance of de novo anti-SIV immune responses. The two SIVIG recipients that died did not develop such responses.

But in the absence of SIVIG treatment, even a strong immune response to SIV was not enough: the one untreated animal that developed anti-SIV immune responses survived longer than its companions but eventually developed disease.

"De novo immune responses are necessary but not sufficient to control the virus," Haigwood concluded.

"What we're hypothesizing is that we are providing them with a very effective antibody. The result is that virus is suppressed until the development of effective immunity."

Haigwood noted that it is essential to define this window of opportunity if HIVIG treatment is to be considered for people recently exposed to HIV.

"This is an extremely useful tool to explore the relationship between the immune response and viral load," said session chair James Bradac.

Haigwood flatly concluded that immune-based therapies for HIV should be pursued.

"The hope is that HIVIG and a vaccine could be given together," she said.

HIVIG is prepared from plasma donated by specially selected donors who carry HIV but have no symptoms of AIDS. These donors must have high CD4(+) lymphocyte counts to demonstrate that their immune systems have not yet been compromised by the disease. The preparation of the HIVIG includes multiple steps to inactivate HIV.

HIVIG was originally developed and tested under an National Heart, Lung, and Blood Institute (NHLBI) contract with the New York Blood Center in the late 1980s.

The Institute subsequently sponsored a pilot study with chimpanzees that showed HIVIG to be effective in preventing infection prior to exposure to HIV.

A Phase III HIVIG trial exploring the ability of the treatment to prevent mother-to-infant HIV transmission was originally scheduled to begin in the spring of 1992, but the original supplier of the HIVIG withdrew. In late June 1993, NHLBI awarded a contract to the Immunotherapy Division of North American Biologicals Inc. to supply the drug. A Phase III clinical trial began October 1993.

"Clearly we are going to have to combine passive antibodies plus vaccine if we are going to prevent [mother-to- infant] transmission," said Diane Wara of the University of California, San Francisco, at the December 1995 meeting of the AIDS Clinical Trials Groups (see AIDS Weekly Plus, December 18, 1995). "This is where the future lies: to give vaccines within two weeks of birth combined with appropriate HIVIG spiked with monoclonal antibodies."

Copyright (c) 1995 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.

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Copyright © 1996 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.