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Lymph Node Cellular and Viral Dynamics in Natural Hosts and Impact for HIV Cure Strategies


Lymph Node Cellular and Viral Dynamics in Natural Hosts and Impact for HIV Cure Strategies

Nicolas Huot et al. Front Immunol.


Combined antiretroviral therapies (cARTs) efficiently control HIV replication leading to undetectable viremia and drastic increases in lifespan of people living with HIV. However, cART does not cure HIV infection as virus persists in cellular and anatomical reservoirs, from which the virus generally rebounds soon after cART cessation. One major anatomical reservoir are lymph node (LN) follicles, where HIV persists through replication in follicular helper T cells and is also trapped by follicular dendritic cells. Natural hosts of SIV, such as African green monkeys and sooty mangabeys, generally do not progress to disease although displaying persistently high viremia. Strikingly, these hosts mount a strong control of viral replication in LN follicles shortly after peak viremia that lasts throughout infection. Herein, we discuss the potential interplay between viral control in LNs and the resolution of inflammation, which is characteristic for natural hosts. We furthermore detail the differences that exist between non-pathogenic SIV infection in natural hosts and pathogenic HIV/SIV infection in humans and macaques regarding virus target cells and replication dynamics in LNs. Several mechanisms have been proposed to be implicated in the strong control of viral replication in natural host's LNs, such as NK cell-mediated control, that will be reviewed here, together with lessons and limitations of in vivo cell depletion studies that have been performed in natural hosts. Finally, we discuss the impact that these insights on viral dynamics and host responses in LNs of natural hosts have for the development of strategies toward HIV cure.

Keywords: HIV; NK cells; SIV; T cells; inflammation; lymph nodes; natural hosts; viral control.


Figure 1
Figure 1
Viral and host immune cell dynamics in lymph nodes (LNs) from natural hosts versus HIV-1/SIVmac infections. Schematic representation of a LN after HIV or SIV infection in pathogenic models (human, macaques, top) and natural hosts [African green monkey (AGM), sooty mangabey, bottom]. (Top) HIV-1 and SIVmac infection in, respectively, humans and macaques result in the formation of hyperplastic germinal centers in LNs with massive B cell proliferation. TFH cells also expand during HIV-1 and SIVmac infections. Inflammation is uncontrolled and leads to collagen deposition and fibrosis. The follicular dendritic cell (FDC) network is disrupted on the long term. HIV-1 and SIVmac replicates in combined antiretroviral therapy (cART)-naïve individuals and animals in both T and B cell zones, but the viral burden is highest in the B cell zones (follicles). In the follicles, virus replication is concentrated within follicular helper T cells (TFH). Virus is also trapped by FDC and remains infectious. On cART, virus persists mostly in TFH cells in the follicles, where it is often outreach of conventional CD8+ T cells and of optimal drug concentrations, as well as in CTLA4+CD4+ T cells within the T zone. The latter cells have a capacity for long survival. NK cells and conventional HIV/SIV-specific CD8+T cells are often expressing immune checkpoint inhibitors. The presence of CXRC5+CD8+T lymphocytes has been described, but their role needs to be further studied. (Bottom) In natural hosts, virus replication is strongly controlled during the chronic phase of infection. Most follicles are exempt of virus. Conventional SIV-specific CD8+ T cell responses are weak. NK cells play a major role in the control of viral replication in AGM LNs. Both the IFN-α and NK cell responses appear earlier than in SIVmac-infected macaques. NK cells accumulate in follicles in SIVagm-infected AGMs, which might be a direct consequence of a high production of IL-15 in the follicles. NK cell migration into B cell follicles in response to SIVagm infection is associated with the acquisition of CXCR5. CXCR5+ NK cells express high levels of Fcγ receptors and of CD107a, which raises the question if they have the capacity to control SIVagm replication through antibody-dependent and/or -independent cellular cytotoxicity.

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