Pathogenesis of simian AIDS in rhesus macaques inoculated with the SRV-1 strain of type D retrovirus.

Type D retrovirus was isolated from rhesus macaques with simian acquired immunodeficiency syndrome (SAIDS) and transmitted to healthy rhesus macaques with tissue culture medium containing the virus. The clinical, immunologic, and lymph node morphologic changes were observed in 9 rhesus macaques for 52 weeks after inoculation. A spectrum of clinical signs developed including early death, persistent SAIDS, and apparent remission. Animals that died or developed persistent SAIDS had characteristic lymphoid depletion, persistently depressed peripheral blood mononuclear cell (PBMC) mitogenic response, and decreased serum immunoglobulins. The SAIDS retrovirus (SRV) was recovered from PBMC of 8 of the animals after inoculation. Virus could not be recovered from PBMC of one animal in remission, but this animal developed serum-neutralizing antibodies to SRV after inoculation. Seven of the animals seroconverted to SRV after inoculation, all 9 were seronegative for human T-lymphotropic virus-III, and 5 animals tested were seronegative to human T-lymphotropic virus-I. These findings support the etiologic role of the type D retrovirus in SAIDS and further define the pathogenesis of this disease.

Early events in tissues during infection with pathogenic (SIVmac239) and nonpathogenic (SIVmac1A11) molecular clones of simian immunodeficiency virus.

The extent of virus replication, tissue distribution, localization of virus within tissues, and the presence of pathological lesions was examined early after experimental infection of rhesus monkeys with simian immunodeficiency virus (SIV). Three strains of SIV were used: molecularly cloned pathogenic SIVmac239; molecularly cloned nonpathogenic SIVmac1A11; and uncloned pathogenic SIVmac. The major targets of infection in all animals at 2 weeks postinoculation were the thymus and spleen. The distribution of virus within lymphoid organs varied with the viral inoculum: nonpathogenic SIVmac1A11 was present primarily within lymphoid follicles and in the thymic cortex; SIVmac239 was present primarily within periarteriolar lymphoid sheaths in the spleen, the paracortex of lymph nodes, and the medulla of the thymus; uncloned SIVmac was present in all these areas but tended to parallel the distribution of SIVmac239. Animals inoculated with nonpathogenic SIVmac1A11 had fewer SIV-positive cells by in situ hybridization and after 13 weeks postinoculation, virus was undetectable in any tissue from these animals. No significant pathological abnormalities were recognized in animals inoculated with this nonpathogenic virus. In contrast, nearly half of the animals inoculated with either SIVmac or SIVmac239 developed significant pathological lesions, including opportunistic infections by 13 weeks postinoculation, highlighting the virulence of these viruses. Our results indicate marked differences in tissue distribution between pathogenic and nonpathogenic molecular clones of SIV during the acute phase of infection. The most striking differences were the absence of SIVmac1A11 from the central nervous system and thymic medulla. The prominent early involvement of the thymus suggests that infection of this organ is a key event in the induction of immune suppression by SIV.

Protection of macaques against infection with simian type D retrovirus (SRV-1) by immunization with recombinant vaccinia virus expressing the envelope glycoproteins of either SRV-1 or Mason-Pfizer monkey virus (SRV-3).

Rhesus macaques were immunized with live vaccinia virus recombinants expressing the envelope glycoproteins (gp70 and gp22) of simian type D retrovirus (SRV), serotype 1 or 3. All of the animals immunized with either the SRV-1 env or the SRV-3 env vaccinia virus recombinant developed neutralizing antibodies against the homologous SRV. In addition, both groups developed cross-reactive antibodies and were protected against an intravenous live-virus challenge with SRV-1. The four control animals immunized with a vaccinia virus recombinant expressing the G protein of respiratory syncytial virus were not protected against the same SRV-1 challenge. Although SRV-1 and SRV-3 immune sera showed cross-neutralization, they failed to neutralize a separate, more distantly related serotype, SRV-2, in an in vitro assay. These findings are consistent with the known degree of serologic and genetic relatedness of these three SRV strains.

Asymptomatic infection of the central nervous system by the macaque immunosuppressive type D retrovirus, SRV-1.

The aetiological agent of spontaneously occurring simian acquired immune deficiency syndrome (SAIDS) in rhesus monkeys (Macaca mulatta) at the California Primate Research Center is a type D retrovirus designated SAIDS retrovirus serotype 1 (SRV-1). SRV-1 DNA and RNA have previously been detected in the brains of rhesus monkeys with SAIDS in the absence of viral antigen or neuropathological lesions. In this study we further define the relationship between SRV-1 and the central nervous system (CNS) in rhesus monkeys by examining the CNS for infectious SRV-1, viral antigen and anti-SRV-1 antibodies. In addition, cerebrospinal fluid (CSF) was assayed for alterations in IgG and albumin levels, IgG/albumin ratios and cell count in comparison to uninfected control animals. No differences in CSF parameters were detected between infected and uninfected animals except for the presence of infectious SRV-1 which was isolated from the CSF from 13 out of 19 (68%) viraemic rhesus monkeys. The probable source of this virus was the choroid plexus, where approximately 1 in 1000 surface epithelial cells were found to contain viral antigen by immunohistochemistry. Antibodies against SRV-1 were not detected in the CSF even when present in the serum. Neither infectious virus nor viral antigen were found in the brain parenchyma of any animal examined. Thus infection of the CNS by SRV-1 appears to be subclinical without an intrathecal immune response. This may be related to the apparent restriction of productive infection in the CNS to cells of the choroid plexus.

Immune response of rhesus macaques to recombinant simian immunodeficiency virus gp130 does not protect from challenge infection.

Simian immunodeficiency virus (SIV) infection of rhesus macaques is a model for human immunodeficiency virus (HIV) infection in humans. Inactivated and modified live whole-virus vaccines have provided limited protective immunity against SIV in rhesus macaques. Because of safety concerns in the use of inactivated and live whole-virus vaccines, we evaluated the protective immunity of vaccinia virus recombinants expressing the surface glycoprotein (gp130) of SIVmac and subunit preparations of gp130 expressed in mammalian cells (CHO). Three groups of animals were immunized with recombinant SIV gp130. The first group received SIV gp130 purified from genetically engineered CHO cells (cSIVgp130), the second group was vaccinated with recombinant vaccinia virus expressing SIVmac gp130 (vSIVgp130), and the third group was first primed with vSIVgp130 and then given a booster immunization with cSIVgp130. Although anti-gp130 binding antibodies were elicited in all three groups, neutralizing antibodies were transient or undetectable. None of the immunized animals resisted intravenous challenge with a low dose of cell-free virus. However, the group primed with vSIVgp130 and then boosted with cSIVgp130 had the lowest antigen load (p27) compared with the other groups. The results of these studies suggest that immunization of humans with HIV type 1 surface glycoprotein may not provide protective immunity against virus infection.

Prevention of simian acquired immune deficiency syndrome with a formalin-inactivated type D retrovirus vaccine.

Experimental induction of simian acquired immune deficiency syndrome (SAIDS) by inoculation of juvenile rhesus monkeys with a type D retrovirus was prevented by immunization with Formalin-killed whole SAIDS retrovirus serotype 1 containing the adjuvant threonyl muramyl-dipeptide. All six immunized animals developed neutralizing antibody after three injections, while six age-matched cagemates receiving adjuvant alone were antibody free. All 12 monkeys were challenged intravenously with a potentially lethal dose of SAIDS retrovirus serotype 1. The six immunized animals failed to develop persistent viremia and remained clinically normal 8 months postchallenge. In contrast, five of six nonvaccinates developed persistent viremia, four of six developed clinical SAIDS, and two of six died with SAIDS at 10 weeks and 8 months postchallenge, respectively. These results show that prevention of a common spontaneous retrovirus-induced immunosuppressive disease in macaques is now possible by vaccination.

Isolation of a new serotype of simian acquired immune deficiency syndrome type D retrovirus from Celebes black macaques (Macaca nigra) with immune deficiency and retroperitoneal fibromatosis.

A new serotype of simian acquired immune deficiency syndrome (SAIDS) retrovirus (type 2) belonging to the D genus of retroviruses is associated with a SAIDS occurring spontaneously in a colony of Celebes macaques (Macaca nigra) and rhesus macaques (Macaca mulatta) at the Oregon Regional Primate Research Center. This syndrome resembles SAIDS in M. mulatta at the California Primate Research Center, which is associated with a similar type D retrovirus (type 1). However, at the Oregon Center, SAIDS is distinguished by the occurrence of retroperitoneal fibromatosis in some of the affected monkeys. Type 2 virus was isolated from seven of seven macaques with SAIDS, retroperitoneal fibromatosis, or both and from one of six healthy macaques. The new strain is closely related to SAIDS retrovirus type 1 and Mason-Pfizer monkey virus but can be distinguished by competitive radioimmunoassay for minor core (p10) antigen and by genomic restriction endonuclease cleavage patterns. Neutralization tests indicate that type 1 and type 2 SAIDS retroviruses are distinct serotypes. Therefore, separate vaccines may be necessary to control these infections in colonies of captive macaques.