Biodistribution Of HIV/SIV Latently Infected Cells And The Key Inhibition Factors Of HIV/SIV Virus Rebound

Acquired Immunodeficiency Syndrome (AIDS), result from Human Immunodeficiency Virus (HIV) infection, is one of most main infectious diseases in the world. Up to now, there is still 39 million of HIV-infected individual exist globally. Highly active antiretroviral therapy (HAART), can effectively reduce peripheral viral load of HIV infection, delay the occurrence of AIDS and prolong the life of those infected individuals, is currently the main weapon against HIV infection. But the immune system in patients with HAART cannot completely back to normal, and HAART cannot totally eliminate HIV virus from the body. The viral load will rebounded quickly in blood if treatment was interrupted. Some studies have shown that rebounded virus come from virus latently infected cells. And the effective HAART treatment can not fully remove HIV latently infected cells from the body. Thus, HIV latently infected cells are considered as the main obstacle to cure HIV infection.To achieve HIV cure, the researchers to explore a variety of treatment strategy to eliminate the latently infected cells, but the clinical effect and applicability of the above strategies are not very ideal. This indicates we don’t fully understand the mechanism of HIV latent, especially several key scientific questions remain breakthrough:1. the distribution in vivo of virus latently infected cells; 2. Inhibition factor of HIV rebound is unknown. To solve these key scientific issues, we did some researchs below.Part I. Biodistribution of HIV/SIV Latently Infected CellsTo cure HIV infection, we need to determine the in vivo distribution of virus latently infected cells. Firstly, the study established a novel detection strategy for latently infected cells. We compared the sorting effect of virus negative cells by cell surface staining with SIV p27/gp41 antibody or SmartFlare assay, active effects of immune cells by CD3/CD28 Dynabeads, LPS or PHA, analysis of latently infected cells by intracellular staining with SIV p27 antibody or FlowRNA technology. Base on the above data, we established a flow cytometry-based virus latently infected cells strategy (FlowVLIC). The FlowVLIC can obtain some data that were between the data form QVOA and provirus DNA-PCR test, more in line with the actual size of the HIV repository. Thereafter, virus latently infected cells of the RT-SHIV/rhesus monkey model were detected using the detection strategy, the results showed that the latently infected cells ware located mainly on the lymphoid tissue and intestinal tract and so on, on CD4+ memory cell. Further, this study also analysis the variation of env, rt sequence of latent virus, data indicated that the integration site of latent virus is related with cell types of latent virus. Therefore, this study initially identified in vivo distribution of HIV/SIV latently infected cells in non-human primate model.Part Ⅱ. The Key Inhibition Factors of HIV/SIV ReboundHIV functional cure would allow people with HIV to remain off ART for prolonged periods of time, perhaps years or decades. So, it is crucial to explore the key factors of viral suppression. We found a viral suppression model can be established efficiently using low-dose virus inoculation via mucosa, similar to HIV elite controllers. But the reason is unknown. In this study, A viral suppression model were established by SIVmac239 inoculation, and used to explore the mechanism of virus suppression from multiple angles. The study found that the cell immune response and humoral immune response of virus suppression animals didn’t increase. But there are significant differences in two groups on the innate immune response, suggests that innate immune responses may plays a role in viral suppression. In addition, the study also explores the role of the HIV/SIV target cell and the antiviral factor in this phenomenon. We found there is no significant difference in the target cell count and the expression and mutation of the inherent anti-viral cytokine between the two groups. Finally, the study explored the effect of infectious virus, we identified Transmitted/Founders (T/F) virus by SGA method, analyze the quantity and fitness of T/F virus by PASS assay. The result showed that the number of T/F virus in the virus suppression animals was less significantly than the normal control animals, and virus fitness of T/F virus from virus suppression animal were weaker significantly than normal control animals. These results suggest that the body’s innate immune response and virus characteristics have an important effect in the natural suppression of HIV.In summary, this study was to explore the in vivo distribution HIV/SIV latently infected cells and the mechanisms of virus suppression. The study provided research ideas and theoretical basis for the development of therapeutic strategies for HIV infection.