PASSIVE IMMUNE GLOBULIN THERAPY IN THE SIV MACAQUE MODEL - EARLY INTERVENTION CAN ALTER DISEASE PROFILE/

One of the major questions in AIDS is the role that the host immune sy stem and the virus play in the dynamics of infection and the developme nt of AIDS in an infected individual. In order to test the role of ant ibody in controlling viral infection, high-dose SIV-immune globulin wa s passively transferred to infected macaques early in infection. Immun e globulin purified from the plasma of an SIV-infected long-term non-p rogressor macaque (SIVIG) or a pool of normal immune globulin (normal Ig) was infused into SIVsmE660-infected macaques (170 mg/kg) at one an d fourteen days post infection. Animals were monitored for SIV-specifi c antibodies, viremia, plasma antigenemia, and clinical course. All an imals were infected by SIV. At 16 months post infection; five macaques in the combined control groups have been euthanized,one as a rapid pr ogressor with debilitating disease at 20 weeks post infection. Four ma caques from the comparison groups have signs of AIDS, accompanied by h igh and increasing levels of virus and p27 antigenemia. One of the ten control animals had a very low virus load in plasma and peripheral bl ood and lymph node mononuclear cells at all times tested and has remai ned disease-free. In the SIVIG treatment group, two macaques were euth anized at 18-20 weeks due to AIDS, rapid progressors to disease. Three macaques in the SIVIG group had an initial high level of virus in pla sma, peripheral blood mononuclear cells (PBMC), and lymph node mononuc lear cells (LNMC), which dropped to baseline at 6 weeks post infection and has remained very low or negative for 16 months, a disease profil e which has not been observed in untreated animals in this model to da te. These macaques have remained clinically healthy. The sixth treated animal is also healthy, with very low virus burden that is detectable only by nested set polymerase chain reaction (PCR). All SIVIG-treated macaques had no delectable p27 plasma antigenemia for the first 10 we eks of infection, demonstrating that the IgG effectively complexed wit h the virus. The immunological correlates in the treated animals inclu de development of de novo virus-specific antibodies and/or cytotoxic T cell (CTL), both of which are hallmarks of long term non-progressors. The two SIVIG-treated macaques that progress to disease rapidly had n o detectable de novo humoral immune responses, as is often seen in rap id HIV disease in humans. Envelope-specific and virus neutralizing ant ibodies alone were not sufficient to prevent disease progression, as t he plasma of both non-progressors as well as progressors had high tite rs of envelope-specific and neutralizing antibodies against SIVsmE660. Poor clinical prognosis was associated with moderate to high and incr easing virus loads in plasma, PBMC, and lymph nodes. Good clinical pro gnosis correlated with low or undetectable post acute viremia in the p eripheral blood and lymph nodes. We hypothesize that SIVIG reduced the spread of virus by eliminating or reducing plasma virus through immun e complexes during the first four to 8 weeks of infection and then mai ntaining this low level of viremia until the host immune response was capable of virus control. Reduction of virus burden early in infection by passive IgG can alter disease outcome in SIV infection of macaques . Modifications of this strategy may lead to effective early treatment of HIV-1 infection in humans.