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...

Chimeric simian/human immunodeficiency virus (SHIV) consists of the env, vpu, tat, and rev genes of human immunodeficiency virus type 1 (HIV-1) on a background of simian immunodeficiency virus (SIV). We derived a SHIV that caused CD4 ؉ cell loss and AIDS in pig-tailed macaques (S.

Calcitonin (CT) inhibits secretion of PRL when administered intravenously in rats and humans. It also inhibits PRL release from cultured rat anterior pituitary (AP) cells. Recent evidence suggests that CT-like immunoreactive peptide is synthesized and released from the AP gland. However, its physiological role in the regulation of PRL secretion has not been understood. Present studies tested the role of endogenous pituitary CT (pit-CT) in the regulation of PRL secretion in vivo by passive immunization. In the first group of experiments, ovariectomized (ovx) adult female rats were administered either preimmune or anti-salmon CT (sCT) serum, and their serum PRL levels were analyzed at various time points up to 3 h. A second group of experiments examined the effects of anti-sCT serum and dopamine on PRL release from cultured rate AP cells. In the next group of experiments, the regional distribution of pit-CT secretion was examined in different sections of the AP gland. In the last set, CT-like activity of AP extract was tested in neonatal rat kidney cells, which respond to CT with an increase in cAMP accumulation. These experiments also tested whether anti-sCT serum reduces AP extract-induced increase in cAMP accumulation. The results suggest that anti-sCT serum dramatically increased serum PRL levels (by 5-fold) of ovx rats within 30 min of administration. The serum PRL levels declined gradually after the peak. However, a significant increase in serum PRL levels was maintained by the anti-sCT serum for the duration of the experiment. The anti-serum also induced a significant increase in PRL release from cultured AP cells when added to the presence or absence of dopamine. The distribution profile of pit-CT within the AP gland suggests that the release of pit-CT immunoreactivity was significantly greater in the inner sections, and anti-sCT serum also caused greater increase in PRL release in these sections. Finally, AP extract and sCT stimulated cAMP accumulation in neonatal rat kidney cells, and anti-sCT serum significantly reduced AP extract-induced cAMP accumulation. These results demonstrate that pit-CT is an important regulator of tonic PRL secretion in female rats and can potently inhibit PRL secretion even in the presence of dopamine.

We inoculated four rhesus macaques with molecularly cloned simian immunodeficiency virus SIVmac239/17E env, a chimeric virus whose env gene was derived from the brain of an SIV-encephalitic macaque. Blood and lymphoid tissues had high frequencies of infected cells. The virus was neuroinvasive, but productive virus replication did not occur in the brain, and animals did not develop encephalitis.