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HIV infection and T-cell responses of PBMC from the case patient. (a) In vitro susceptibility to HIV infection in 2009. 9 CD4+ T-cells of the case patient or healthy donors (HD) were PHA-activated and infected in vitro with 100 ng p24 Gag of HIV YU2b (R5-tropic), HIV NL4-3 (×4-tropic), and HIV KON a primary isolate of the same clade than CRF02_AG isolate. Viral replication was monitored by p24 Gag ELISA during 16 days post-infection (p.i.). (ni = non infected). (b) Ex vivo IFN-γ-ELISpot assay was performed in November 2009 using PBMC and lymph node (LN) cells loaded with 18 HIV-1 pools of 15-mers peptides overlapping by 11 amino acids. Eleven pools covered the three HIV type 1 Gag proteins: three pools for p17 Gag (1-55, 45-99, and 89-143), five pools for p24 Gag (133-187, 177-231, 221-275, 265-319, and 309-363), three pools for the small Gag proteins (Smp Gag) (p2/p7/p1/p6) (353-407, 397-451, and 441512), four pools corresponding to poly-epitopic RT regions (293-352, 157-187, 177-216, and 4-52), and three pools corresponding to poly-epitopic Nef regions (181-206, 65-107, and 97-147). All results are expressed as specific IFN-γ-producing cells after subtracting the number of SFCs observed with cells alone, without stimulation. The IFN-γ producing HIV-specific CD8+ T cells were first investigated in an ELISpot assay detecting in 2009 significant responses to p17Gag (1-55) in PBMC and lymph node cells (110 SFC/10 6 cells) and to p24Gag (265319) in PBMC alone (680 SFC/10 6 cells. (c) PBMC obtained in November 2009 were stimulated with the p17Gag 1 to 55 pool or with the p24 Gag 265 to 319 pool that elicited an IFN-γELISpot production. The percentages of CD3 + CD8+ T cells producing IFN-γ, TNF-α or IL-2 were analyzed by intracellular cytokine staining and flow cytometry. The percentages of activated cells not subjected to peptide stimulation were subtracted. The immune-dominant CMV-derived HLA-B*07-restricted epitope (pp65 417 TPRVTGGGAM 426 ), and staphylococcal enterotoxin B (SEB) were used as positive controls. Cells alone served as negative control.
Source publication
Background:
We describe a homosexual man who strongly controlled HIV-1 for ten years despite lack of protective genetic background.
Methods:
HIV-1 DNA was measured in blood and other tissues. Cell susceptibility was evaluated with various strains. HIV-1-specific (CD4 and CD8 activation markers and immune check points) and NK cells responses were...
Citations
... Multiple laboratories have cultured virus from a subset of these patients (10)(11)(12)(13)(14), and full genome sequence analysis of virus isolated from some controllers has not revealed any large deletions or signature mutations (10). There have also been several transmission pair studies in which transmission of virus between patients with progressive disease and HIV controllers has been documented (15)(16)(17)(18)(19). In cases in which replication-competent virus was isolated from both partners, comparable viral fitness was seen in three out of four of these pairs (15)(16)(17). ...
A small percentage of people living with HIV-1 can control viral replication without antiretroviral therapy (ART). These patients are called elite controllers (ECs) if they are able to maintain viral suppression without initiating ART and posttreatment controllers (PTCs) if they control HIV replication after ART has been discontinued. Both types of controllers may serve as a model of a functional cure for HIV-1 but the mechanisms responsible for viral control have not been fully elucidated. In this review, we highlight key lessons that have been learned so far in the study of ECs and PTCs and their implications for HIV cure research.
... The definitive cure of HIV relies then on the need to restore a functional immune response. This hypothesis is supported by the existence of elite HIV controllers' exhibiting a sustained low number of HIV copies in the blood (<50 HIV RNA copies/ml) in the absence of any antiretroviral therapy (ART) [12][13][14][15]. In these individuals, the central and effector memory CD4 þ T cell populations are persevered [5,7,16], as well as the CD8 þ T cells, which have a higher clonal turnover, superior functional avidity and better cytotoxic activities [17][18][19]. ...
Purpose of review:
Cell-based immunotherapies have made enormous progress over the last decade with the approval of several anti-CD19-chimeric antigen receptor (CAR)-T cell therapies for haemato-oncological diseases. CARs are synthetic receptors comprising an antigen-specific extracellular domain fused to a hinge, transmembrane and intracellular signalling domains. The success obtained with CD19 CAR-T cells rekindled interest in using CAR-T cells to treat HIV seropositive patients. The purpose of this review is to discuss historical and recent developments of anti-HIV CARs.
Recent findings:
Since the first description of CD4+-based CARs in the early 90s, new generations of anti-HIV CARs were developed. They target the hetero-trimeric glycoprotein gp120/gp41 and consist of either a CD4+ extracellular domain or a VH/VL segment derived from broadly neutralizing antibodies. Recent efforts were employed in multiplexing CAR specificities, intracellular signalling domains and T cells resistance to HIV.
Summary:
Several new-anti HIV CAR-T cells were successfully tested in preclinical mice models and are now waiting to be evaluated in clinical trials. One of the key parameters to successfully using CAR-T cells in HIV treatment will depend on their capacity to control the HIV reservoir without causing off-targeting activities.
... Therefore, spontaneous LTNPs or ECs who are also MSM could provide a natural model of HIVhost immunity interactions. However, despite intensive studies comparing "dichotomized" infectors (Bendenoun et al., 2018), the mechanisms of "natural" protective mechanisms have not been clarified (Gurdasani et al., 2014). When considering the scenario, mucosal immunity as the first barrier (Miller et al., 1989;Xu et al., 2013) is the primary step in HIV infection, even in cases where infection occurs by the intravenous route (Bolton et al., 2012;Sutton et al., 2016). ...
Human immunodeficiency virus (HIV) infection is characterized by a dynamic process and highly variable progression. Although extensive comparisons have been reported between the minority of non-progressors (NPGs) and the majority of progressors (PGs), the underlying mechanism is still unclear. One reason for this is that the initial onset of infection is very difficult to track, particularly when men who have sex with men (MSM) are predominantly responsible for the transmission of human HIV. To find potential early protection strategies against later progression during chronic mucosal exposure, 10 Chinese-origin rhesus macaques (ChRhs) that underwent repetitive simian immunodeficiency virus (SIV) intrarectal exposure were longitudinally tracked. The results of the periodic detection of peripheral blood mononuclear cells (PBMCs) and colorectal mucosal lamina propria mononuclear cells (LPMCs) with immunoglobulins in rectal fluid were compared between non-progressive and progressive subgroups, which were classified based on their circulating viral loads. As a result, four NPGs and six PGs were observed after disease onset for 2 months. Upon comparing the mucosal and systemic immune responses, the PBMC response did not differ between the two subgroups. Regarding LPMCs, the increased activation of B1a/B1 cells among B cells and a peak in IgM in rectal fluid was observed approximately 10 days after the first exposure, followed by consistently low viremia in the four non-progressive ChRhs. In the six progressive ChRhs, neither B cell activation nor a peak in IgM was observed, while a robust elevation in IgG was observed, followed by consistently high viremia post exposure. Based on the PBMC-LPMC disparity between the subgroups of monkeys, we hypothesize that early B1 activation in LPMCs that result in an IgM peak might attenuate the entry and acquisition of SIV in the mucosa, resulting in very low dissemination into blood. Our models have suggested that the use of early surveillance both systemically and in the mucosa to comprehensively determine virus–host interactions would be informative for mucosal vaccine development.
... Vice versa, the presence of "unfavorable" does not preclude individuals from becoming ECs (Bendenoun et al., 2018;Emu et al., 2008). ...
Acquired Immunodeficiency Syndrome (AIDS) is an immunodeficiency caused by infection with Human Immunodeficiency Virus (HIV). Since its first documentation in 1981, the AIDS pandemic has claimed the lives of 32 million people worldwide. The introduction of antiretroviral therapy drugs (ART) and combined therapy in 1995 has transformed HIV infections from a “death-sentence” into a manageable and often non-fatal chronic condition. Still, no cure is available. While without ART most HIV-infected individuals (>99%) progress to AIDS, a subset of infected individuals (
... As a consequence of this multifactorial response and the different contribution of the distinct factors to the infection control, the group of LTNP EC is not homogenous. There are reports of LTNP EC that control viral replication without known host markers [41], or without protective HLA alleles [42]. Also, our group demonstrated that a combination of non-replicating viruses and a strong antiviral immune response explained the non-progressor phenotype in a super-infected HIV individual [43]. ...
Following the success of HIV-1 antiviral treatment that maintains undetectable levels of viral replication and lack of clinical progression, the design of an HIV-1 cure for patients became the next objective. The success of the treated individuals together with the identification of subjects that spontaneously control the clinical progression for long periods, such as long-term non-progressors (LTNPs) and particularly LTNP Elite Controllers (LTNP EC) have shed hope for the feasibility of a potential cure. Although a successful cure has not been attained yet, these patients have provided critical information on the mechanisms involved in the clinical control such as host genetic factors, as well as strong immune responses against the virus. Less attention has been paid to virological factors, particularly the association of the genetic variability and the control of viral infection. Considering all these studies, it has become clear that a combination of several host, immune and viral factors is needed to attain control of the viral replication control and the non-progressor clinical phenotype. Because this control can be reached through different combinations of factors, this group of individuals is not homogenous. As HIV-1 cure has been shown to be extremely difficult to achieve, a more feasible objective is the functional cure of the viral infection. After the analysis of multiple studies on the mechanisms of control in LTNP EC, we found subjects with various host protective factors and prolonged viral control. These subjects present a complete lack of evolution after more than 20-30 years of infection, stable levels of CD4+ cells (>400-500 cells/μl), a strong immune response, and no signs of clinical progression. We propose that individuals with these characteristics could have attained a functional cure of the HIV-1 infection.
... Despite the enormous advances in the last 15 years showing that the presence of protective genetic factors, as protective HLA alleles and the associated cytotoxic T-lymphocytes (CTL) response, are capital for the spontaneous control of HIV-infection (Pereyra et al., 2010), the detailed nature of the mechanisms associated with this phenomenon are not completely clear. In the study by Bendenoun et al. (2018) in EBioMedicine, the authors describe the case report of the spontaneous control of HIV-1 for ten years in a homosexual man after transmission by his unique couple, who was not able to naturally control the virus. Similar reports had been previously published (Bailey et al., 2008;Buckheit III et al., 2012) but in this case, in contrast to previous works, both individuals had no protective HLA-alleles. ...
... These features associated to persistent control of HIV-infection are very similar to those found in the extreme phenotypes of elite HIV-controllers found in a French cohort (Canouï et al., 2017) with the exception that these individuals had weak HIV-specific CD8+ T-cell response measured by the ability to suppress HIV-1 infection of autologous CD4+ T cells ex vivo. The results by Bendenoun et al. (2018) are also in accordance with the low reservoir and high polyfunctional HIV-specific T-cell response measured by intracellular cytokine staining recently found in a similar phenotype of individuals that persistently controlled the virus compared to patients that transiently controlled HIV-1 (Pernas et al., 2017). As discussed by the authors the individual of the case report may be one of these examples of extreme phenotype with persistent long-term elite control of HIVinfection. ...
... Despite that the host factors seem to be essential in the persistent control of the virus in this case report (Bendenoun et al., 2018), the fact that both individuals were heterozygous for CCR5 Δ 32, does not clarify if this "bottleneck" could render a lower virus fitness that enabled the spontaneous virus control. It remains also unknown at what date during the follow up occurred the transmission. ...
The interaction of HIV-1, human leukocyte antigen (HLA), and elite controllers (EC) compose a still intricate triad. Elite controllers maintain a very low viral load and a normal CD4 count, even without antiretrovirals. There is a lot of diversity in HIV subtypes and HLA alleles. The most common subtype in each country varies depending on its localization and epidemiological history. As we know EC appears to maintain an effective CD8 response against HIV. In this phenomenon, some alleles of HLAs are associated with a slow progression of HIV infection, others with a rapid progression. This relationship also depends on the virus subtype. Epitopes of Gag protein-restricted by HLA-B*57 generated a considerable immune response in EC. However, some mutations allow HIV to escape the CD8 response, while others do not. HLA protective alleles, like HLA-B*27, HLA-B*57 and HLA-B*58:01, that are common in Caucasians infected with HIV-1 Clade B, do not show the same protection in sub-Saharan Africans infected by HIV-1 Clade C. Endogenous pathway of antigen processing and presentation is used to present intracellular synthesized cellular peptides as well as viral protein fragments via the MHC class I molecule to the cytotoxic T-lymphocytes (CTLs). Some epitopes are immunodominant, which means that they drive the immune reaction to some virus. Mutation on an anchor residue of epitope necessary for binding on MHC class I is used by HIV to escape the immune system. Mutations flanking an epitope may lead to T cell lack of recognition and CTL escape. Studying how immunodominance at epitopes drives the EC in a geographically dependent way with genetics and immunological elements orchestrating it may help future research on vaccines or immunotherapy for HIV.
There is a rare group of HIV-1-infected individuals who show permanent control of clinical progression for over 10 years, maintain CD4 ⁺ cells >500 μl and have undetectable viral loads; they are designated long-term non-progressors elite controllers (LTNPs ECs). Multiple studies have demonstrated the necessary contribution of at least two of host, immune and viral factors to the LTNP phenotype. This group of individuals is not homogenous because of the different involvement of these factors. We will review the role of each of these and their combinations to the LTNP EC phenotype. LTNP EC individuals offer an opportunity for the investigation into the mechanisms for the spontaneous control of HIV infection.
