The Role Of CD4⁺T Cells In Gut From Macaques At Chronic Stage With SHIV_SF162p3 Infection For Superinfection With SHIV-1157ipd3N4

Superinfection with HIV is the infection of an HIV seropositive individual with a second heterologous strain of the virus after infection with the first infecting strain is established. The superinfection resistance defines a phenomenon that immunodeficiency virus infection confers protection against a second immunodeficiency virus infection. Although there is accruing evidence for HIV superinfection, many studies have suggested that established infection can resist superinfection. The variables that may contribute to resistance to superinfection have not been well defined. Further dissection on protection against superinfection thought to be critical for developing other HIV vaccine approaches or antiviral strategies. The SHIV-infected nonhuman primate model provides an ideal means of studying the pathogenesis of HIV-1superinfection. In the present study, we use the SHIV-infected nonhuman primate model to study the protection against HIV superinfection.T lymphocytes play an important role in the adaptive immune response. Especially, change of memory cells’count and proportion is closely related to diseases. In this study, we collected data about the composition of T lymphocytes in a variety of lymphoid tissues of healthy Chinese-origin rhesus macaques. It is shown that the ratio of CD4+/CD8+T cells in lymph nodes showed higher than that in the peripheral blood and lowest in lamina propria. In the lymph nodes, most CD4+T cells were naive T cells while in the peripheral blood and lamina propria most CD4+T cells were memory T cells.28%of CD4+T cells in lamina propria expressing the CCR5that was the highest among all tissues. Our data provides a basic reference values for further research related to immunity or AIDS model by using macaques.Subsequently,12healthy Chinese-origin rhesus macaques were infected intravenously and intrarectally with SHIVSF162p3.During chronic infection, distribution and frequency of CD4+T cells in gut, peripheral blood and lymph nodes were analyzed. Comparing to the healthy macaques, CD4+T cells in these three tissues all decreased, while most part are CD4+Tcm cells. Especially CD4+Tcm cells decreased significantly in gut. Comparing to CD4+T cells, the proportion of CD4+Tcm cells in chronic infection was much more closed related to the peak viral loads of SHIVSF162p3in acute infection. For different tissues, CD4+Tcm cells in gut was most related to the the peak viral loads, and CD4+Tcm cells in peripheral blood followed, while CD4+Tcm cells in lymph nodes didn’t show too much relationship. It indicates that the massive of CD4+Tcm cells in the gut are destroyed by viral infection during the acute phase, and persist during the chronic phase. The decreases of CD4+T cells from lymph nodes at chronical SHIVF162p3infection was speculated due to the less recirculating lymphocytes rather than direct lymphocyte depletion.During chronica infection with SHIVSF162p3,12rhesus macaques were intravenously infected with SHIV-1157ipd3N4. The SHIV-1157ipd3N4and SHIVSF162p3are very similar at many areas, such as co-receptor tropism, ability of replication and injury for peripheral blood and mucosal.Of the12infected animals that were exposed to a heterologous virus, only5animals in resisted superinfection with the heterologous virus, there were no detectable SHIV-1157ipd3N4viral loads in these animals after exposure. In fact, a negative correlation was apparent between the peak viral loads of SHIVSF162p3following primary infection and the peak of SHIV-1157ipd3N4RNA levels following superinfection. It is indicated that the high replication level of first virus affected superinfection. Following SHIV-1157ipd3N4challenge, CD4+/CD8+T cells in gut of superinfection group induced significantly, and CD4+T cells increased quickly at the very beginning and then decreased sharply. CD4+T cells of macaques which got protection from first infection are no changed apparently. CD4+T cell counts in superinfection group were significantly higher than resisted group at d7post superinfection. CD4+Tcm cells in gut showed stronger trend which is similar with CD4+T cells.The relative resistance to superinfection was not correlated with CCR5expression level in peripheral blood and gut, SIV Gag-specific cellular immune responses and capacity of binding antibodies.The results indicate that both the SHIV superinfection and the protection against SHIV superinfection occur after the second viral challenge. The mechanism of this kind of protection can be two parts. One is related to inhibition by the established virus. Because of high efficiency of first virus, most cells are integrated. As soon as cells are activated, the first viruses are replicated rapidly. This can inhibit the replication of second virus. Another one is related to the inhibition of response of CD4+T cells and CD4+Tcm cells in gut by the first virus. After the CD4+T cells and CD4+Tcm cells couldn’t be activated and replicated, which provides less target cells for second virus.Overall, in this study, the phenotype and composition of T lymphocytes in a variety of lymphoid tissues in healthy Chinese-origin rhesus macaques were showed firstly. This can be a baseline for further experiments. We also analyzed the viral loads and the composition of CD4+T cells in gut, peripheral blood and lymph nodes from rhesus macaques before and after superinfection. All the results could be concluded that there are two possible mechanism of the protection against superinfection. This could be very useful for developing HIV vaccines.