Immunosenescence And Pathogenesis In Early SIV Infection Of Aged Chinese Rhesus Macaque

The elderly infected with HIV-1 are increasingly becoming a noticeable group for HIV/AIDS research, given their high mortality, rapid AIDS progression and poor immune restoration even under treatment. The most possible contributor to this phenomenon is believed to be immunosenescence. In fact, A variety of HIV-induced immunologic alterations is similar to that seen in uninfected old people, including an accelerated reduction in the T-cell and the B-cell renewal, an accumulation of terminally differentiated memory cells with poor proliferative responses and shortened replication history, constricted diversity within the T-cell and B-cell repertoire and a reduced responsiveness to vaccines, they are associated with accelerated HIV disease progression, increased risk for non-AIDS comorbidities and unsatisfactory treatment. On the other hand, immunosenescence in normal aging has strong associations with morbidity and mortality in the elderly and results in a poor response to vaccination and an increased susceptibility to infection in the elderly. Thus, immunosenescence coming from both HIV-1 infection and normal aging may explain the accelerated AIDS development and poor clinical outcomes in older HIV-1-infected patients.However, most of these findings lack evidentiary support from longitudinal studies throughout the entire course of HIV-1 infection. The key to solving the problem is finding appropriate animal models for the elderly AIDS. In the past 50 years and more, macaques, most are Indian rhesus macaque (InRM), cynomolgus monkey and pig-tailed macaque, have served an important role in the researches of pathogenic mechanisms and the developments of vaccines or drugs for more than 70 human infectious diseases, notably for HIV infection and AIDS. Moreover, as a long-lived species of non-human primates and sharing greater genetic and physiological similarities with humans than rodent models, macaques offer more distinct advantages to research the effect of immunosenescence. Existing data have shown that rhesus macaques could be a robustly translational model in researches on age-related changes of immune system.Chinese rhesus macaques (ChRM) are extensive used in human disease models in recent years to resolve the shortage of Indian rhesus macaques. They are much valuable for HIV/AIDS model researches as they closely mimic both of treated and untreated HFV infected humans. Compared to SFV-infected InRM and pig-tailed macaques, SIV-infected ChRM are more adaptable to HIV/AIDS researches as their slower disease progression and more effective anti-retroviral therapy. Furthermore, there are numerous evidences that aged macaques are susceptible to a lot of infections and AIDS cases of SIV natural hosts occur most frequently in aged animals. Thus it is most possible that ChRM will act as a valuable animal model for researches on interactions between immunosenescence and HIV/SFV infection. However, up to the present day there still has few basic information about the features of immunosenescence in ChRM and no aged animal AIDS models. So we studied the immunosenescence of ChRM, established the AIDS model of aged ChRM and research the pathogenesis of elderly AIDS, finally to support for the clinical therapy of elderly AIDS.In the first study, we designed a cross-sectional experiment to determine age-related phenotypic changes in circulating T cells and B cells of Chinese rhesus macaques ranging from 2 to 24 years of age. Here Chinese rhesus macaques showed an expectant homology of immunosenescence with humans, such as decreased B cells and naive T cells, accumulation of CD8+effector memory T cells, turnover of naive lymphocytes to memory subsets and differences in sex. Furthermore, we found some potential markers of immunosenescence, including increased frequency of PD-1+CD4+T cells and CD95+B cells. Furthermore, ChRM have a progressive reduction of CD4/CD8 ratio and aged males have the severest immune risk profiles marked by lowest CD4/CD8 and naive/EM ratio more similar to humans compared to Indian rhesus macaques. It is suggested that ChRM could act as a favourable model for researches on immunosenescence.In the second study, we intensively compared the immunological, virological and gene-expressed dynamics between 6 young and 12 old ChRM throughout the early SIVmac239 infection (3 months post infection) to find the characteristics of elderly AIDS and explore the mechanisms within interactions between immunosenescence and elderly AIDS. After 42 days post infection,4 old ChRM gradually died of AIDS complications. Old ChRM showed a faster AIDS development and a higher risk for AIDS development than young macaques as their rapidly elevated plasma viral load, fast loss of CD4+T cells and serious inversion of CD4/CD8 ratio during acute infection. The low frequency of naive CD4+T cells prior to infection and the violent proliferation of naive lymphocytes after infection strongly predicted increased disease progression, which suggested that naive T cells play an important role in immune protection during early SIV infection and old ChRM have lost control of disease progression as their less naive lymphocytes. Moreover, a robust host response with defective regulation in old ChRM was associated with rapidly elevated homeostatic proliferation and loss of naive CD4+ T cells. This compensation mechanism could partially delay the depletion of naive CD4+ T cells, but in fact enhanced the immune activation and inflammation and accelerated disease progression of hosts. Overall, we demonstrated that SIV-infected old ChRM may be a favorable model for the pathogenesis research of elderly AIDS and the therapeutic strategies of elderly AIDS should focus on the reverse of immunosenescence and the effective control of abnormal immune response.