Immune Alterations and Viral Reservoir Atlas in SIV-Infected Chinese Rhesus Macaques

Abstract

Background/objectives: Over the last decades, our projects have been dedicated to clarifying immunopathological and virological events associated with Human Immunodeficiency Virus (HIV) infection.

Methods: By using non-human primate models of pathogenic and non-pathogenic lentiviral infections, we aimed at identifying the cells and tissues in which the virus persists, despite antiretroviral therapy (ART). Indeed, the eradication of viral reservoirs is a major challenge for HIV cure.

Results: We present a series of results performed in rhesus macaques of Chinese origin deciphering the virological and immunological events associated with ART that can be of interest for people living with HIV.

Conclusions: This model could be of interest for understanding in whole body the clinical alteration that persist despite ART.

Keywords: B cell; CD4; SIV; Tfh; aids; apoptosis; cure; macaque; monocyte; reservoir.

Figure 1

(A) The Human Immunodeficiency Virus (HIV-1) pandemic in humans resulted from cross-species transmissions of a strain of Simian Immunodeficiency Virus that infects central African chimpanzees (Pan troglodytes troglodytes) (SIV_CPZ). Thus, SIVcpz is responsible for the emergence of the HIV-1 M and N groups. Furthermore, the infection of gorillas leading to the emergence of SIVgor is responsible for the emergence of the HIV-1 O group (see review [29]). SIVsmm from sooty mangabeys is associated with the emergence of HIV-2 in humans, and cross-species transmission to captive rhesus macaques in US primate centers is responsible for the emergence of the SIVmac. SIVs can also be isolated from mandrills (SIVmnd) and from African green monkeys (SIVagm). Whereas the majority of African NHPs manifest a benign course of natural SIV infection when infected with their species-specific SIV strain, monkeys of Asian origin, such as rhesus (Macaca mulatta), pigtailed (Macaca nemestrina), and cynomolgus (Macaca fascicularis) macaques, are susceptible to SIVmac infection. (B) Whereas in the blood, viremia is detected in both pathogenic and non-pathogenic non-human primate models of lentiviral infections, only humans and macaques demonstrate T cell immunodeficiency and AIDS. CD4 T cell apoptosis and immune activation characterize pathogenic lentiviral infections.

Figure 2

Impact of early antiretroviral therapy on the establishment of tissue and cellular reservoirs in SIVmac251-infected rhesus macaques of Chinese origin. Tissue and cellular atlas of viral reservoirs (VRs) in SIVmac251-infected RMs of Chinese origin. From the same individuals, an extensive exploration of lymphoid and myeloid VRs has been performed in blood [80,81] and from different tissues such as brain [82], lung [83], liver [83,84], spleen [80,81], axillary and inguinal lymph nodes (Ax LN and Ing LN) [80] and mesenteric lymph nodes (MLN) [80]. The presence (+) and the absence (−) of VRs is indicated. The nature of cells in which viral DNA has been detected is indicated: macrophages (Macro) and CD4 T cells (CD4). Nd: Not determined at the time of this publication. The references of the different manuscripts in which the results have been published are indicated.

Figure 3

T follicular helper cells and Simian Immunodeficiency Virus infection. (a) CD4 T cell differentiation. After antigen (Ag) presentation by the major histocompatibility complex (MHC) class II molecules expressed by antigen-presenting cells (APC) to the T cells expressing the T cell receptor (TCR), naïve T cells are activated, leading to their differentiation into central memory (CM), effector memory (EM) or terminally differentiated T (TDT) cells, as defined by the expression of CD45RA and CCR7 molecules. In addition, among EM, there is a subset of CD4 T cells, namely T follicular helper (Tfh) cells, that express the C-X-C chemokine receptor type 5 (CXCR5) and the programmed cell death protein 1 (PD-1) molecules. (b) T and B cell interaction. Tfh cells are essential for B cells by providing co-signals (CD40 and PDL-1) leading to the expression of transcriptional factors such as Bcl-6 (B-cell lymphoma 6) and Pax5 (Paired box protein 5) in B cells. In turn, B cell interaction provided co-signal to Tfh cells in inducing the transcription factors Bcl-6 and c-MAF, (musculoaponeurotic fibrosarcoma), which in turn led to the production of the interleukin 21 (IL-21) and sustained B cell activation and maturation. (c) B cell follicle. The formation of germinal centers depends at least in part on the interaction of Tfh and B cells. Confocal microscopy shows CXCR5, PD-1, and CD4 expressions from the spleen of a naïve rhesus macaque. (d) SIV replication. Viral replication is determined by in situ hybridization using a specific SIV nef probe (dark spots) demonstrating strong staining in the region of B cell follicles, as well as the accumulation of viral RNA in the follicular dendritic cell (FDC) network that may represent viral particles trapped at the surface of the FDCs.