Antiviral capacity of the early CD8 T-cell response is predictive of natural control of SIV infection: Learning in vivo dynamics using ex vivo data.

While most individuals suffer progressive disease following HIV infection, a small fraction spontaneously controls the infection. Although CD8 T-cells have been implicated in this natural control, their mechanistic roles are yet to be established. Here, we combined mathematical modeling and analysis of previously published data from 16 SIV-infected macaques, of which 12 were natural controllers, to elucidate the role of CD8 T-cells in natural control.

Identification of macaque dendritic cell precursors in blood and tissue reveals their dysregulation in early SIV infection.

Distinct dendritic cell (DC) subsets play important roles in shaping immune responses. Circulating DC precursors (pre-DCs) are more susceptible to HIV infection in vitro, which may explain the inefficiency of immune responses against HIV. However, the interplay between HIV and pre-DC is not defined in vivo.

CXCR3 and CXCR5 are highly expressed in HIV-1-specific CD8 central memory T cells from infected patients.

New ways of characterizing CD8 memory T cell responses in chronic infections are based on the measurement of chemokine receptor expression (CXCR3, CXCR5, and CX3CR1). We applied these novel phenotyping strategies to chronic HIV infection by comparing healthy donors (HDs), HIV-infected patients receiving antiretroviral therapy (ART), and spontaneous HIV controllers (HICs). In all groups, the memory cells exhibited high proportion of CXCR3 cells.

Optimal Maturation of the SIV-Specific CD8 T Cell Response after Primary Infection Is Associated with Natural Control of SIV: ANRS SIC Study.

Highly efficient CD8 T cells are associated with natural HIV control, but it has remained unclear how these cells are generated and maintained. We have used a macaque model of spontaneous SIVmac251 control to monitor the development of efficient CD8 T cell responses. Our results show that SIV-specific CD8 T cells emerge during primary infection in all animals.

Metabolic plasticity of HIV-specific CD8 T cells is associated with enhanced antiviral potential and natural control of HIV-1 infection.

Spontaneous control of human immunodeficiency virus (HIV) is generally associated with an enhanced capacity of CD8 T cells to eliminate infected CD4 T cells, but the molecular characteristics of these highly functional CD8 T cells are largely unknown. In the present study, using single-cell analysis, it was shown that HIV-specific, central memory CD8 T cells from spontaneous HIV controllers (HICs) and antiretrovirally treated non-controllers have opposing transcriptomic profiles. Genes linked to effector functions and survival are upregulated in cells from HICs.

Mass Cytometry Analysis Reveals Complex Cell-State Modifications of Blood Myeloid Cells During HIV Infection.

Dendritic cells (DC), which are involved in orchestrating early immune responses against pathogens, are dysregulated in their function by HIV infection. This dysregulation likely contributes to tip the balance toward viral persistence. Different DC subpopulations, including classical (cDCs) and plasmacytoid (pDCs) dendritic cells, are subjected to concomitant inflammatory and immunoregulatory events during HIV infection, which hampers the precise characterization of their regulation through classical approaches.

Cynomolgus macaque IL37 polymorphism and control of SIV infection.

The association between gene polymorphisms and plasma virus load at the set point (SP-PVL) was investigated in Mauritian macaques inoculated with SIV. Among 44 macaques inoculated with 50 AID50, six individuals were selected: three with SP-PVL among the highest and three with SP-PVL among the lowest. The exons of 390 candidate genes of these six animals were sequenced.

The Frequencies of Immunosuppressive Cells in Adipose Tissue Differ in Human, Non-human Primate, and Mouse Models.

Although the metabolic properties of white adipose tissue have been extensively characterized, the tissue's immune properties are now attracting renewed interest. Early experiments in a mouse model suggested that white adipose tissue contains a high density of regulatory T cells (Tregs), and so it was assumed that all adipose tissue has an immunosuppressive profile-even though the investigation was limited to visceral body fat in relatively old male mice. This observation was also corroborated by high frequencies of other cell subsets with immunoregulatory properties, such as anti-inflammatory M2 macrophages, and regulatory B cells.

Mass Cytometry Analysis Reveals the Landscape and Dynamics of CD32a CD4 T Cells From Early HIV Infection to Effective cART.

CD32a has been proposed as a specific marker of latently HIV-infected CD4 T cells. However, CD32a was recently found to be expressed on CD4 T cells of healthy donors, leading to controversy on the relevance of this marker in HIV persistence. Here, we used mass cytometry to characterize the landscape and variation in the abundance of CD32a CD4 T cells during HIV infection.

Correction: Stage-specific IFN-induced and IFN gene expression reveal convergence of type I and type II IFN and highlight their role in both acute and chronic stage of pathogenic SIV infection.

[This corrects the article DOI: 10.1371/journal.pone.

Stage-specific IFN-induced and IFN gene expression reveal convergence of type I and type II IFN and highlight their role in both acute and chronic stage of pathogenic SIV infection.

Interferons (IFNs) play a major role in controlling viral infections including HIV/SIV infections. Persistent up-regulation of interferon stimulated genes (ISGs) is associated with chronic immune activation and progression in SIV/HIV infections, but the respective contribution of different IFNs is unclear. We analyzed the expression of IFN genes and ISGs in tissues of SIV infected macaques to understand the respective roles of type I and type II IFNs.

Early SIV and HIV infection promotes the LILRB2/MHC-I inhibitory axis in cDCs.

Classical dendritic cells (cDCs) play a pivotal role in the early events that tip the immune response toward persistence or viral control. In vitro studies indicate that HIV infection induces the dysregulation of cDCs through binding of the LILRB2 inhibitory receptor to its MHC-I ligands and the strength of this interaction was proposed to drive disease progression. However, the dynamics of the LILRB2/MHC-I inhibitory axis in cDCs during early immune responses against HIV are yet unknown.

High proportion of PD-1-expressing CD4 T cells in adipose tissue constitutes an immunomodulatory microenvironment that may support HIV persistence.

We and others have demonstrated that adipose tissue is a reservoir for HIV. Evaluation of the mechanisms responsible for viral persistence may lead to ways of reducing these reservoirs. Here, we evaluated the immune characteristics of adipose tissue in HIV-infected patients receiving antiretroviral therapy (ART) and in non-HIV-infected patients.

Elevated Basal Pre-infection CXCL10 in Plasma and in the Small Intestine after Infection Are Associated with More Rapid HIV/SIV Disease Onset.

Elevated blood CXCL10/IP-10 levels during primary HIV-1 infection (PHI) were described as an independent marker of rapid disease onset, more robust than peak viremia or CD4 cell nadir. IP-10 enhances the recruitment of CXCR3+ cells, which include major HIV-target cells, raising the question if it promotes the establishment of viral reservoirs. We analyzed data from four cohorts of HIV+ patients, allowing us to study IP-10 levels before infection (Amsterdam cohort), as well as during controlled and uncontrolled viremia (ANRS cohorts).

Adipose Tissue Is a Neglected Viral Reservoir and an Inflammatory Site during Chronic HIV and SIV Infection.

Two of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV).

Long-term control of simian immunodeficiency virus (SIV) in cynomolgus macaques not associated with efficient SIV-specific CD8+ T-cell responses.

Unlabelled: The spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8(+) T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8(+) T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. To address this question, we transiently depleted CD8(+) T cells from five SIV-infected cynomolgus macaques with long-term viral control and weak CD8(+) T-cell responses.

Plasmacytoid dendritic cell dynamics tune interferon-alfa production in SIV-infected cynomolgus macaques.

IFN-I production is a characteristic of HIV/SIV primary infections. However, acute IFN-I plasma concentrations rapidly decline thereafter. Plasmacytoid dendritic cells (pDC) are key players in this production but primary infection is associated with decreased responsiveness of pDC to TLR 7 and 9 triggering.

Influence of the MHC genotype on the progression of experimental SIV infection in the Mauritian cynomolgus macaque.

Experimental infection of Mauritian cynomolgus macaques by simian immunodeficiency virus is a representative model of HIV infection, currently in favour for evaluating the efficacy of new preventive or curative treatments. Extensive studies of major histocompatibility complex (MHC) polymorphism by microsatellites revealed seven haplotypes (H1-H7). We present statistical evidence of the influence of MHC polymorphism on the set-point plasma viral load (PVL).

Suppressive activity of regulatory T cells correlates with high CD4(+) T-cell counts and low T-cell activation during chronic simian immunodeficiency virus infection.

Objective: HIV/simian immunodeficiency virus (SIV) infection is characterized by progressive CD4(+) T-cell depletion and immune exhaustion. CD25(+)FoxP3(+) regulatory T cells were evidenced in HIV/SIV infection and disease. They could be positive by suppressing immune activation during chronic infection and/or damper T-cell immunity.

Dynamics of viral replication in blood and lymphoid tissues during SIVmac251 infection of macaques.

Background: Extensive studies of primary infection are crucial to our understanding of the course of HIV disease. In SIV-infected macaques, a model closely mimicking HIV pathogenesis, we used a combination of three markers -- viral RNA, 2LTR circles and viral DNA -- to evaluate viral replication and dissemination simultaneously in blood, secondary lymphoid tissues, and the gut during primary and chronic infections. Subsequent viral compartmentalization in the main target cells of the virus in peripheral blood during the chronic phase of infection was evaluated by cell sorting and viral quantification with the three markers studied.

Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I interferon, and immune suppression.

Plasmacytoid dendritic cells (pDCs) are antigen-presenting cells that develop into type-I interferon (IFN-I)-producing cells in response to pathogens. Their role in human immunodeficiency virus (HIV) pathogenesis needs to be understood. We analyzed their dynamics in relation to innate and adaptive immunity very early during the acute phase of simian immunodeficiency virus (SIV) infection in 18 macaques.

Effect of SIVmac infection on plasmacytoid and CD1c+ myeloid dendritic cells in cynomolgus macaques.

Dendritic cells (DCs) are known to be essential for the induction and regulation of immune responses. Non-human primates are essential in biomedical research and contribute to our understanding of the involvement of DCs in human infectious diseases. However, no direct single-platform method for quantifying DC precursors has yet been optimized in macaques to give accurate absolute blood counts of these rare-event cell populations in the blood.

CCR5 or CXCR4 use influences the relationship between CD4 cell depletion, NKp44L expression and NK cytotoxicity in SHIV-infected macaques.

Objective: HIV-1 infection is characterized by a progressive decline of CD4 cell count, the underlying mechanisms of which are still debated. We recently found that during HIV-1 infection, CD4 T cells overexpress a ligand of the NK activating receptor NKp44 (NKp44L) and are sensitized to NK cytolytic activity. The expression of NKp44L is triggered by a highly conserved motif of gp41 (3S) and is inhibited by anti-3S antibodies.

Improved protection against simian immunodeficiency virus mucosal challenge in macaques primed with a DNA vaccine and boosted with the recombinant modified vaccinia virus Ankara and recombinant Semliki Forest virus.

Using the experimental infection of cynomolgus macaques with simian immunodeficiency virus (SIV) as a model of human immunodeficiency virus infection in humans, we studied the immunogenicity and protective efficacy of a vaccine strategy combining DNA, the modified recombinant vaccinia virus strain Ankara (MVA) and Semliki Forest virus (SFV) expressing gag, pol, env, tat, rev and nef from SIV. Although this immunization strategy induced moderate immune responses, the control of pathogenic SIVmac251 infection following mucosal challenge was clearly improved by vaccination. The viral load in vaccinated animals was reduced by 2 logs during the acute phase of infection and, in five of the six macaques, viral load fell below the detection limit at set point.

Early divergence in lymphoid tissue apoptosis between pathogenic and nonpathogenic simian immunodeficiency virus infections of nonhuman primates.

The events that contribute to the progression to AIDS during the acute phase of a primate lentiviral infection are still poorly understood. In this study, we used pathogenic and nonpathogenic simian models of simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) and African green monkeys (AGMs), respectively, to investigate the relationship between apoptosis in lymph nodes and the extent of viral replication, immune activation, and disease outcome. Here, we show that, in SIVmac251-infected RMs, a marked increased in lymphocyte apoptosis is evident during primary infection at the level of lymph nodes.