By animal-to-animal passage of simian/human immunodeficiency virus (SHIV) in pig-tailed macaques, we have developed a macaque model of human immunodeficiency virus type 1 (HIV-1) disease in humans. Passaging was begun with a chimeric virus containing the env gene of HIV-1 HXBc2 and the gag and pol genes of simian immunodeficiency virus SIVmac239. SHIV was passaged serially in cohorts of two macaques each, using bone marrow-to-bone marrow transfers at 5, 5, and 16 weeks for passages 2, 3, and 4, respectively. The fifth passage was done by using cell-free virus isolated from cerebrospinal fluid of a passage 4 macaque. The virus became more virulent with each passage. Virus replication was restricted in all three animals in passages 1 and 2 but not in five of the six animals in passages 3, 4, and 5. In these animals, intense virus replication in the lymphoid tissues resulted in almost total elimination of CD4 ؉ T cells within weeks of inoculation, and three of these animals developed AIDS in less than 1 year. The more uniform virus-host interaction initiated by the cell-free virus in the passage 5 animals contrasted with a more variable pattern of disease initiated by infectious bone marrow cells during earlier passages. The virulent cell-free SHIV can now be used to screen the efficacy of vaccines directed against the envelope of HIV-1. Human immunodeficiency virus type 1 (HIV-1) can infect nonhuman primates such as chimpanzees but does not cause disease in these animals (16). This is a major impediment to understanding the mechanisms of pathogenesis of HIV-1 infection and has also retarded efforts to evaluate the efficacy of anti-HIV drugs and vaccines. At present, simian immunodeficiency virus SIVmac infection in macaques is the best-characterized model of HIV-1 disease (3). HIV-2 infection in baboons represents another useful model (1). SIVmac and HIV-2 are closely related viruses, but both have genetic, antigenic, and structural features in their env genes that clearly distinguish them from HIV-1. Chimeric simian/human immunodeficiency viruses (SHIVs) that bear the envelope of HIV-1 and are infectious in macaques potentially offer a solution to this problem. However, SHIVs have so far proven avirulent in macaques (2, 9, 13, 15, 17). Since the bone marrow (BM) of SIVmac-infected macaques has high virus burdens (7) and since specific pathogenic viral genotypes can be selected by serial passage of infectious BM in animals (14), we hypothesized that similar passaging of SHIV-infected BM cells would also result in selection of pathogenic genotypes of this virus. We report here on derivation of a pathogenic SHIV by using this procedure and the initial characterization of the disease process caused by this virus. MATERIALS AND METHODS Passage in macaques. SHIV, obtained as described below, was used to begin passaging in young (7 to 19 months old) rhesus (Macaca mulatta) and pig-tailed (Macaca nemestrina) macaques (Fig. 1). Macaques were housed in American Association for Laboratory Animal Care-accredited facilities an...
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