Age-dependent Differential Expression Of HIV-1 Viral Protein And Plasma Cytokine In HIV-1 Transgenic Rat

PartⅠAge-dependent differential expression of HIV-1 viral protein in HIV-1 transgenic ratBackground:The HIV-1 transgenic(HIV-1Tg) rat was developed about a decade ago as a model of AIDS-related pathology and immune dysfunction.Recently,the HIV-1Tg rat was shown to be a valuable rodent model for studying pathologies similar to those seen in HIV-1-infected patients given highly anti-retroviral therapy(HAART),where,even though viral replication may be under control,HIV-1 viral proteins are continuously present.It is now recognized that not all HIV-1 disease manifestations can be attributed to viral infection of target cells alone.There is evidence that HIV-1-related proteins can independently cause organ dysfunction,either by their mere presence,or by a change in the expression. In the HIV-1Tg rat,HIV-1-related pathologies become more prominent with advancing age. We demonstrate that the developing HIV-1Tg rat maintains lower body weight compared with the F344 control rat.Aim:Establish the expression profile of the HIV-1 viral proteins tat,gp120,nef and vif in peripheral organs and brain areas of the HIV-1 Tg rat;Determine if expression of these HIV-1 viral proteins in HIV-1 Tg rats 10-11 months of age differs from HIV-1 Tg rats 2-3 months of age.Method:We developed highly specific real-time PCR assays to evaluate the expression of the HIV-1 proteins,tat,gp120,nef and vif in the immune and nervous systems of young(2-3 mo old) versus mature(10-11 mo old) HIV-1Tg rats.Result:In the 2-3 mo old HIV-1Tg rats,mRNA expression of those four viral proteins was greatest in the spleen;whereas in the 10-11 mo old rats,HIV-1 viral protein mRNA levels were greatest in the cerebellum and spinal cord.Tat,gp120,nef,and vif mRNA levels in the spleens of the 2-3 mo old HIV-1Tg rats were significantly greater than those in the 10-11 mo old rats(p＜0.01).Conversely,viral protein mRNA levels in the spinal cord, cerebellum,and striatum in the 10-11 mo old HIV-1Tg rats were significantly greater than in the 2-3 mo old animals(p＜0.01).Interestingly,in the prefrontal cortex,tat and nef expression was significantly greater at 2-3 mo of age than at 10-11 mo of age(p＜0.05).Conclusion:These findings indicate that there may be age-dependent differential expression of various HIV viral proteins,with a switch from peripheral immune organs to the CNS,even when the animals are still pre-symptomatic.Our study also demonstrates that this noninfectious rat can be a useful model simulating HIV-1 infected individuals that are on HAART therapy. PartⅡPlasma Cytokine Profiles in the Aging HIV-1 Transgenic RatBackground:Using transgenic(Tg) animal models for the study of the pathogenesis of HIV-1 associated complications could be a reproducible and cost effective approach.The HIV transgenic rodents develop similar pathology as that seen in HIV-1/AIDS patients. Recently,the HIV-1Tg rat was shown to be a valuable rodent model for studying pathologies similar to those seen in HIV-1-infected patients given highly anti-retroviral therapy(HAART),where,even though viral replication may be under control,HIV-1 viral proteins are continuously present.The viral proteins,Tat,Nef,Rev,and gp120,have been shown to stimulate cytokine production.Importantly,long-term control of HIV infection has been shown to restore balance to expression of Th1/Th2 cytokine expression levels to that of non-HIV infected individuals.These complex interactions between HIV and the host immune system ultimately result in a state of severe immunodeficiency if viral replication cannot be controlled by HAART.This non-infectious animal model expresses spliced and unspliced viral transcripts in lymph nodes,spleen,thymus,and peripheral blood cells.However,a complete Th1/Th2 cytokine expression profile has yet to be established. In addition,in the HIV-1Tg rat,HIV-1-related pathologies become more prominent with advancing age.Aim:Establish the expression profile of the Th1/Th2 cytokines(IL-4,IL-5,KC/GRO, IFNγ,TNFα,IL-1β,and IL-13) in plasma of the HIV-1 Tg rat;Determine if expression of these cytokines in HIV-1 Tg rats 10-11 months of age differs from HIV-1 Tg rats 2-3 months of age.Method:We utilized an MSD rat cytokine multiplex assay to establish a baseline Th1/Th2 cytokine(IL-4,IL-5,KC/GRO,IFNγ,TNFα,IL-1β,and IL-13) expression profile in the plasma in both 2-3 month and 10-11 month old HIV-1 Tg rats and Fischer F344 rats.Result:KC/GRO expression in 2-3 month old HIV-1Tg rats elevated significantly as compared with age-matched F344,but at 10-11 months old,although there was no significant difference between HIV-1Tg and F344 rats,the trend of difference between them is the same with at 2-3 months old;a reduction in plasma IFNγwas detected in 10-11 month old HIV-1Tg rats as compared with age-matched F344.Expression profile of most of cytokines detected in our study,except IFNγ,exhibited age-dependence.Conclusion:Combining partⅠand partⅡresults,we suggest that the synergistic action of age and HIV-1 viral proteins led to the cytokine expression profile in 10-11 month old HIV-1Tg rats.Thus,further understanding of the cellular origins and the molecular mechanisms of age-related HIV-1 viral protein-associated inflammation and the interaction of these two factors in HIV-1Tg rats could advance our ability to develop strategies in improving quality of health in the elderly HIV infected patients.