Morphine potentiates neuropathogenesis of SIV infection in rhesus macaques.

Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Opiates are well known to modulate immune responses by preventing the development of cell-mediated immune responses. Their effect on the pathogenesis of HIV-1 infection however remains controversial.

Rhesus macaque model of chronic opiate dependence and neuro-AIDS: longitudinal assessment of auditory brainstem responses and visual evoked potentials.

Our work characterizes the effects of opiate (morphine) dependence on auditory brainstem and visual evoked responses in a rhesus macaque model of neuro-AIDS utilizing a chronic continuous drug delivery paradigm. The goal of this study was to clarify whether morphine is protective, or if it exacerbates simian immunodeficiency virus (SIV)-related systemic and neurological disease. Our model employs a macrophage tropic CD4/CCR5 coreceptor virus, SIV(mac)239 (R71/E17), which crosses the blood-brain barrier shortly after inoculation and closely mimics the natural disease course of human immunodeficiency virus infection.

Effect of morphine on the neuropathogenesis of SIVmac infection in Indian Rhesus Macaques.

Morphine is known to prevent the development of cell-mediated immune (CMI) responses and enhance expression of the CCR5 receptor in monocyte macrophages. We undertook a study to determine the effect of morphine on the neuropathogenesis and immunopathogenesis of simian immunodeficiency virus (SIV) infection in Indian Rhesus Macaques. Hypothetically, the effect of morphine would be to prevent the development of CMI responses to SIV and to enhance the infection in macrophages.

Active simian immunodeficiency virus (strain smmPGm) infection in macaque central nervous system correlates with neurologic disease.

Simian immunodeficiency virus strain smmPGm can induce neuropathology in macaques and is a model for the development of human HIV-related brain injury. For quantitative studies of proviral presence and expression in the central nervous system (CNS), we inoculated 8 macaques intravenously with the virus. Three animals were necropsied 2 to 4 weeks after development of infection, and we obtained lymphoid tissue biopsies from 5 animals before 5 weeks after infection.

A noninfectious simian/human immunodeficiency virus DNA vaccine that protects macaques against AIDS.

Simian/human immunodeficiency virus SHIV(KU2) replicates with extremely high titers in macaques. In order to determine whether the DNA of the viral genome could be used as a vaccine if the DNA were rendered noninfectious, we deleted the reverse transcriptase gene from SHIVKU2 and inserted this DNA (DeltartSHIVKU2) into a plasmid that was then used to test gene expression and immunogenicity. Transfection of Jurkat and human embryonic kidney epithelial (HEK 293) cells with the DNA resulted in production of all of the major viral proteins and their precursors and transient export of a large quantity of the Gag p27 into the supernatant fluid.

Simian human immunodeficiency virus-associated pneumonia correlates with increased expression of MCP-1, CXCL10, and viral RNA in the lungs of rhesus macaques.

Pulmonary disorders are the most frequent cause of death in HIV-1-infected individuals with AIDS and remain important even in the current era of potent antiretroviral therapy. Macaques infected with Simian/Human Immunodeficiency Virus (SHIV) develop pulmonary disease and concurrent opportunistic infections similar to those observed in HIV-infected individuals, thereby providing an excellent working model to elucidate the pathogenesis of the human lung disease. Since chemokines play a crucial role in the recruitment of inflammatory cells to tissues, we investigated the relationship between respiratory disease and the levels of chemokines, monocyte chemotactic protein-1 (MCP-1) and CXCL10, in the lungs of SHIV-infected rhesus macaques.

Inhibition of pathogenic SHIV replication in macaques treated with antisense DNA of interleukin-4.

Interleukin-4 is implicated in the pathogenesis of HIV-induced AIDS and causes enhancement of replication of virus strains that use the CXCR4 (X4) coreceptor. In this study, we explored the effects of interleukin-4 (IL-4) antisense (AS) DNA on replication of X4, simian human immunodeficiency viruses, SHIV(KU-2) and SHIV89.6P.

Protection against late-onset AIDS in macaques prophylactically immunized with a live simian HIV vaccine was dependent on persistence of the vaccine virus.

This is a 5-year follow-up study on 12 macaques that were immunized orally with two live SHIV vaccines, six with V1 and six with V2. All 12 macaques became persistently infected after transient replication of the vaccine viruses; all were challenged vaginally 6 mo later with homologous pathogenic SHIV(KU-1). Two of the V1 group developed full-blown AIDS without evidence of vaccine virus DNA in tissues.

Role of interleukin-4 and monocyte chemoattractant protein-1 in the neuropathogenesis of X4 simian human immunodeficiency virus infection in macaques.

Recent studies on the coreceptor usage of human immunodeficiency virus (HIV) strains associated with acquired immunodeficiency syndrome (AIDS) dementia have shown that both X4 and R5 viruses are involved in the process. The disease is associated with enhanced virus replication and monocyte chemoattractant protein (MCP)-1 production in macrophages in the brain. Using the macaque model of the disease, the authors show here that X4, macrophage-tropic simian human immunodeficiency virus (SHIV) required the enhancing effect of interleukin (IL)-4 to achieve equivalent concentrations of virus and MCP-1 that are produced in macrophages infected with R5 viruses alone.

Microarray analysis of cytokine and chemokine genes in the brains of macaques with SHIV-encephalitis.

Human immunodeficiency virus (HIV)-encephalitis results from a cascade of viral-host interactions that lead to cytokine and chemokine imbalance, which then leads to neuropathologic manifestations of the disease. These include macrophage/microglia activation, astrocytosis and neuronal dysfunction or death. As the molecular mechanisms of this process are poorly understood, we used Atlas human cytokine or cytokine receptor microarray analysis to highlight gene expression profiles that accompanied encephalitis in Simian human immunodeficiency virus (SHIV) 89.

Systemic infection and limited replication of SHIV vaccine virus in brains of macaques inoculated intracerebrally with infectious viral DNA.

SHIV deleted in two accessory genes, DeltavpuDeltanef SHIV(PPC), functioned well as a vaccine against later challenge with highly pathogenic SHIV(KU), and it was able to reach the brain after oral inoculation of live virus. In this study, the proviral genome cloned into a plasmid was inoculated as DNA intracerebrally and spread systemically. Few regions of the brain had detectable proviral DNA by real-time PCR.

Immunization of macaques with live simian human immunodeficiency virus (SHIV) vaccines conferred protection against AIDS induced by homologous and heterologous SHIVs and simian immunodeficiency virus.

To evaluate the vaccine potential of SHIVs attenuated by deletion of viral accessory genes, seven rhesus macaques were sequentially immunized with Delta vpu Delta nefSHIV-4 (vaccine-I) followed by Delta vpuSHIV(PPC) (vaccine-II). Despite the absence of virological evidence of productive infection with the vaccine strains, based on analysis of infectivity among peripheral blood mononuclear cells (PBMC) of the vaccinated animals, all seven animals developed binding as well as neutralizing antibodies against both vaccine-I and -II. The animals also developed vaccine virus-specific CTLs that recognized homologous as well as heterologous pathogenic SHIVs and SIV, and also soluble inhibitory factors that blocked the in vitro replication of the vaccine strains and different challenge viruses.

Neuropathogenesis of lentiviral infection in macaques: roles of CXCR4 and CCR5 viruses and interleukin-4 in enhancing monocyte chemoattractant protein-1 production in macrophages.

Neurological disease associated with lentiviral infection occurs mainly as a consequence of primary replication of the virus or a combination of the virus infection and replication of opportunistic pathogens in the central nervous system. Recent studies have shown that whereas the disease can be caused by CCR5 tropic viruses alone, its induction by CXCR4 (X4) tropic viruses occurred usually in association with infections caused by opportunistic pathogens and in the presence of a Th2 cytokine, interleukin (IL)-4.(1,2) Further, X4-mediated neurological disease developed preferentially in rhesus compared to pig-tailed macaques.

Presence of Intact vpu and nef genes in nonpathogenic SHIV is essential for acquisition of pathogenicity of this virus by serial passage in macaques.

Use of the macaque model of human immunodeficiency virus (HIV) pathogenesis has shown that the accessory genes nef and vpu are important in the pathogenicity of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV). We examined the ability of two nonpathogenic SHIVs, SHIV(PPC) and DeltavpuDeltanefSHIV(PPC), to gain pathogenicity by rapid serial passage in macaques. In this study, each virus was passaged by blood intravenously four times at 4-week intervals in macaques.

Innate differences between simian-human immunodeficiency virus (SHIV)(KU-2)-infected rhesus and pig-tailed macaques in development of neurological disease.

Neurological disease associated with HIV infection results from either primary replication of the virus or a combination of virus infection and replication of opportunistic pathogens in the CNS. Recent studies indicate that the primary infection is mediated mainly by viruses that utilize CCR5 as the coreceptor; it is not known whether the syndrome can be mediated by viruses that use the CXCR4 coreceptor. The macaque model of the disease using simian immunodeficiency virus (SIV) has confirmed that CCR5-using viruses such as SIV(mac)251 can cause primary disease in the CNS.