Immunization with a live, attenuated simian immunodeficiency virus vaccine leads to restriction of viral diversity in Rhesus macaques not protected from pathogenic challenge.
(17/1851)
Rhesus macaques immunized with simian immunodeficiency virus SIVmac239Deltanef but not protected from SIVmac251 challenge were studied to determine the genetic and biological characteristics of the breakthrough viruses. Assessment of SIV genetic diversity (env V1-V2) revealed a reduction in the number of viral species in the immunized, unprotected macaques, compared to the number in nonimmunized controls. However, no evidence for selection of a specific V1-V2 genotype was observed, and biologically cloned isolates from the animals with breakthrough virus were similar with respect to replication kinetics and coreceptor use in vitro. (+info)
Gastrointestinal epithelium is an early extrathymic site for increased prevalence of CD34(+) progenitor cells in contrast to the thymus during primary simian immunodeficiency virus infection.
(18/1851)
The objective of this study was to determine the effects of primary simian immunodeficiency virus (SIV) infection on the prevalence and phenotype of progenitor cells present in the gastrointestinal epithelia of SIV-infected rhesus macaques, a primate model for human immunodeficiency virus pathogenesis. The gastrointestinal epithelium was residence to progenitor cells expressing CD34 antigen, a subset of which also coexpressed Thy-1 and c-kit receptors, suggesting that the CD34(+) population in the intestine comprised a subpopulation of primitive precursors. Following experimental SIVmac251 infection, an early increase in the proportions of CD34(+) Thy-1(+) and CD34(+) c-kit+ progenitor cells was observed in the gastrointestinal epithelium. In contrast, the proportion of CD34(+) cells in the thymus declined during primary SIV infection, which was characterized by a decrease in the frequency of CD34(+) Thy-1(+) progenitor cells. A severe depletion in the frequency of CD4-committed CD34(+) progenitors was observed in the gastrointestinal epithelium 2 weeks after SIV infection which persisted even 4 weeks after infection. A coincident increase in the frequency of CD8- committed CD34(+) progenitor cells was observed during primary SIV infection. These results indicate that in contrast to the primary lymphoid organs such as the thymus, the gastrointestinal epithelium may be an early extrathymic site for the increased prevalence of both primitive and committed CD34(+) progenitor cells. The gastrointestinal epithelium may potentially play an important role in maintaining T-cell homeostasis in the intestinal mucosa during primary SIV infection. (+info)
The SIV-infected rhesus monkey model for HIV-associated dementia and implications for neurological diseases.
(19/1851)
The neuropathogenesis of human immunodeficiency virus (HIV)-associated dementia has remained elusive, despite identification of HIV as the causal agent. Although a number of contributing factors have been identified, the series of events that culminate in motor and cognitive impairments after HIV infection of the central nervous system (CNS) are still not known. Rhesus monkeys infected with simian immunodeficiency virus (SIV) manifest immunosuppression and CNS disease that is pathologically [L. R. Sharer et al. (1991) J. Med. Primatol. 20, 211-217] and behaviorally [E. A. Murray et al. (1992) Science 255, 1246-1249] similar to humans. The SIV model of HIV-associated dementia (HAD) is widely recognized as a highly relevant model in which to investigate neuropathogenesis. With better understanding of neuropathogenesis comes the opportunity to interrupt progression and to design better treatments for HAD. This becomes increasingly important as patients live longer yet still harbor HIV-infected cells in the CNS. The use of the SIV model has allowed the identification of neurochemical markers of neuropathogenesis important not only for HAD, but also for other inflammatory neurological diseases. (+info)
Replication capacity of simian immunodeficiency virus in cultured macaque macrophages and dendritic cells is not prerequisite for intravaginal transmission of the virus in macaques.
(20/1851)
In order to test the hypothesis that macrophages and dendritic cells (DCs) in mucosal tissue play an important role in heterosexual transmission of human immunodeficiency virus, the replication capacities of two simian immunodeficiency viruses (SIVs) were examined in cultured macrophages and DCs as well as in cultured PBMCs in vitro. The virus strains were a T cell-tropic SIV, SIVmac239, and a T cell- and macrophage-tropic (dual-tropic) SIV, SIVmac239/316E. The infectivities of these viruses to cynomolgus macaques by intravaginal inoculation were also compared. Although both virus strains replicated well in cultured PBMCs, SIVmac239 did not replicate in cultured macrophages, whereas SIVmac239/316E did. Both strains showed little replication in cultured DCs, but a high virus yield could be obtained when SIVmac239/316E-infected DCs were co-cultured with uninfected PBMCs. A mixture of these SIVs was inoculated intravaginally to three monkeys and the virus strain that first appeared through the vaginal mucosa was determined. The virus clones detected first in PBMCs, inguinal lymph nodes and vaginal wash cells (VWCs) after the virus inoculation were of SIVmac239 in all cases, except for one clone of SIVmac239/316E in VWCs of one monkey at one time-point. These results show that the infectivity of the virus in intravaginal transmission did not depend on the cell tropism in vitro of the virus. (+info)
Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs.
(21/1851)
Infection of macaques with chimeric simian-human immunodeficiency virus (SHIV) provides an excellent in vivo model for examining the influence of envelope on HIV-1 pathogenesis. Infection with a pathogenic CCR5 (R5)-specific enveloped virus, SHIVSF162P, was compared with infection with the CXCR4 (X4)-specific SHIVSF33A.2. Despite comparable levels of viral replication, animals infected with the R5 and X4 SHIV had distinct pathogenic outcomes. SHIVSF162P caused a dramatic loss of CD4+ intestinal T cells followed by a gradual depletion in peripheral CD4+ T cells, whereas infection with SHIVSF33A.2 caused a profound loss in peripheral T cells that was not paralleled in the intestine. These results suggest a critical role of co-receptor utilization in viral pathogenesis and provide a reliable in vivo model for preclinical examination of HIV-1 vaccines and therapeutic agents in the context of the HIV-1 envelope protein. (+info)
Simian immunodeficiency virus disease course is predicted by the extent of virus replication during primary infection.
(22/1851)
To elucidate the relationship between early viral infection events and immunodeficiency virus disease progression, quantitative-competitive and branched-DNA methods of simian immunodeficiency virus (SIV) RNA quantitation were cross-validated and used to measure viremia following infection of rhesus macaques with the pathogenic SIVmac251 virus isolate. Excellent correlation between the methods suggests that both accurately approximate SIV copy number. Plasma viremia was evident 4 days postinfection, and rapid viral expansion led to peak viremia levels of 10(7) to 10(9) SIV RNA copies/ml by days 8 to 17. Limited resolution of primary viremia was accompanied by relatively short, though variable, times to the development of AIDS (81 to 630 days). The persistent high-level viremia observed following intravenous inoculation of SIVmac251 explains the aggressive disease course in this model. Survival analyses demonstrated that the disease course is established 8 to 17 days postinfection, when peak viremia is observed. The most significant predictor of disease progression was the extent of viral decline following peak viremia; larger decrements in viremia were associated with both lower steady-state viremia (P = 0.0005) and a reduced hazard of AIDS (P = 0.004). The data also unexpectedly suggested that following SIVmac251 infection, animals with the highest peak viremia were better able to control virus replication rather than more rapidly developing disease. Analysis of early viral replication dynamics should help define host responses that protect from disease progression and should provide quantitative measures to assess the extent to which protective responses may be induced by prophylactic vaccination. (+info)
A case of intestinal Mycobacterium simiae infection in an SIV-infected immunosuppressed rhesus monkey.
(23/1851)
Although Mycobacterium simiae was identified and classified more than three decades ago, only a few cases are mentioned in the current literature. After experimental simian immunodeficiency virus infection, a 9-year-old female rhesus monkey (Macaca mulatta) developed progressive immunosuppression and gastrointestinal disease very similar to the clinical and pathomorphologic features of Johne's disease, which is caused by M. paratuberculosis. Acid-fast-positive bacteria reacted immunohistochemically with antibodies against M. paratuberculosis and M. bovis but were not useful for differentiation because of a high degree of cross-reactivity. In contrast to immunohistochemistry and histopathology, biochemical methods and cycle sequencing analysis of the 16S ribosomal RNA identified M. simiae as the disease-causing pathogen. This case demonstrates the importance of molecular biological methods for the diagnosis of M. simiae infection in monkeys. (+info)
A highly pathogenic simian/human immunodeficiency virus with genetic changes in cynomolgus monkey.
(24/1851)
A highly pathogenic simian/human immunodeficiency virus (SHIV), designated C2/1, was obtained by serum passages in cynomolgus monkeys of p-SHIV, an SHIV strain that contains the env gene of pathogenic human immunodeficiency virus type 1 89.6. CD4+ lymphocyte depletion was induced within 1 week of the SHIV-C2/1 infection in peripheral blood as well as in various lymphoid organs in all the animals tested, with symptoms of diarrhoea and no increase in body weight, followed by intense viraemia. Serum antibody against Env protein was detected from 4 weeks after the virus infection, while the anti-Gag antibody response was absent in the SHIV-C2/1-infected animals. In contrast, both anti-Gag and anti-Env antibody responses were present in animals infected with p-SHIV or the non-pathogenic SHIV-MN. Sequencing of the env gene of isolates of SHIV-C strains showed conserved amino acid changes in the Env C2 and V3 regions that included changes to negatively charged amino acids, in the cytoplasmic region of gp41 that included a 42 amino acid deletion, and in the Nef protein. The pathogenic SHIV-C2/1-monkey model suggests that virus-specific pathogenicity in SHIV infection may be associated with the absence of anti-Gag antibody responses in animals and may be caused by genetic changes during serum passage in vivo. (+info)