Elite Controllers Research Articles

Piecewise immunosuppressive infection model with viral logistic growth and effector cell-guided therapy

<abstract><p>This work investigated a piecewise immunosuppressive infection model that assessed the effectiveness of implementing this therapeutic regimen once the effector cell count falls below a specific threshold level by introducing a threshold strategy. The sliding mode dynamics, global dynamics, and boundary equilibrium bifurcations of the Filippov system were examined based on the global dynamics of the two subsystems. Our primary findings indicate that the HIV viral loads and effector cell counts can be stabilized within the required predetermined level. This outcome depends on the threshold level, immune intensity, and the initial values of the system. Therefore, properly combining these key factors makes it possible to effectively curb the abnormal increase of virus and keep the effector cells at a reliable level. This approach maximizes the controllable range of the HIV. The proposed switching system incorporating pseudo-equilibrium exhibits three types of equilibriums that could be bistable or tristable. It means there is a possibility of controlling the virus after administering therapy if the immune intensity $ c $ is limited within the range of the post-treatment control threshold and the elite control threshold when $ {R_0} > {R_{{c_1}}} > {R_{{c_2}}} > 1 $.</p></abstract>

The Costs and Benefits of Clan Culture: Elite Control Versus Cooperation in China

The Costs and Benefits of Clan Culture: Elite Control Versus Cooperation in China

The HLA-B*57:01 allele corresponds to a very large MHC haploblock likely explaining its massive effect for HIV-1 elite control.

We have reanalyzed the genomic data of the International Collaboration for the Genomics of HIV (ICGH), centering on HIV-1 Elite Controllers. We performed a genome-wide Association Study comparing 543 HIV Elite Controllers with 3,272 uninfected controls of European descent. Using the latest database for imputation, we analyzed 35,552 Single Nucleotide Polymorphisms (SNPs) within the Major Histocompatibility Complex (MHC) region. Our analysis identified 2,626 SNPs significantly associated (p<5. 10-8) with elite control of HIV-1 infection, including well-established MHC signals such as the rs2395029-G allele which tags HLA-B*57:01. A thorough investigation of SNPs in linkage disequilibrium with rs2395029 revealed an extensive haploblock spanning 1.9 megabases in the MHC region tagging HLA-B*57:01, comprising 379 SNP alleles impacting 72 genes. This haploblock contains damaging variations in proteins like NOTCH4 and DXO and is also associated with a strong differential pattern of expression of multiple MHC genes such as HLA-B, MICB, and ZBTB12. The study was expanded to include two cohorts of seropositive African-American individuals, where a haploblock tagging the HLA-B*57:03 allele was similarly associated with control of viral load. The mRNA expression profile of this haploblock in African Americans closely mirrored that in the European cohort. These findings suggest that additional molecular mechanisms beyond the conventional antigen-presenting role of class I HLA molecules may contribute to the observed influence of HLA-B*57:01/B*57:03 alleles on HIV-1 elite control. Overall, this study has uncovered a large haploblock associated with HLA-B*57 alleles, providing novel insights into their massive effect on HIV-1 elite control.

IL-15-dependent immune crosstalk between natural killer cells and dendritic cells in HIV-1 elite controllers

As the principal effector cell population of the innate immune system, natural killer (NK) cells may make critical contributions to natural, immune-mediated control of HIV-1 replication. Using genome-wide assessments of activating and inhibitory chromatin features, we demonstrate here that cytotoxic NK (cNK) cells from elite controllers (ECs) display elevated activating histone modifications at the interleukin 2 (IL-2)/IL-15 receptor β chain and the BCL2 gene loci. These histone changes translate into increased responsiveness of cNK cells to paracrine IL-15 secretion, which coincides with higher levels of IL-15 transcription by myeloid dendritic cells in ECs. The distinct immune crosstalk between these innate immune cell populations results in improved IL-15-dependent cNK cell survival and cytotoxicity, paired with a metabolic profile biased toward IL-15-mediated glycolytic activities. Together, these results suggest that cNK cells from ECs display a programmed IL-15 response signature and support the emerging role of innate immune pathways in natural, drug-free control of HIV-1.

Agroforestry Distribution and Contributions in Ancient Hawaiian Agriculture

AbstractAgriculture is one of the most fundamental ways in which human societies interact with the environment. The form and function of agriculture have important socio-political implications in terms of yields, labor requirements, variability and resilience, and elite control. Hawai‘i has been used as a model system for the discussion of coupled human and natural systems, and how the uneven distribution of agricultural opportunities has manifested in the political ecology. However, consideration of agriculture has emphasized forms with physical infrastructure documented through archaeology and have not included arboricultural forms that were extensive among Pacific Islands. We leverage existing, independent data sets to build and validate spatial models of two intensities of arboriculture across the Hawaiian archipelago: Agroforestry and Novel Forest. Model validation demonstrates good accuracy that includes both expected and unexpected sources of errors. Results of the models demonstrate that arboricultural techniques accounted for ~70% of the agricultural potential by area and ~40% of the agricultural potential by yield. Unlike existing agricultural forms modeled, such as flooded wetland terrace cultivation and rainfed field production, which have strong distributional patterns based on the age of the islands, arboricultural potential is well distributed across all the islands. The extent, distribution, and characteristics of arboricultural methods provide important augmentation of the current narrative of production dynamics and distribution, and the political ecology, of pre-contact Hawai‘i.

Long-term non-progression and risk factors for disease progression among children living with HIV in Botswana and Uganda: A retrospective cohort study

ObjectivesWe utilize a large retrospective study cohort derived from electronic medical records to estimate the prevalence of long-term non-progression (LTNP) and determine the factors associated with progression among children infected with HIV in Botswana and Uganda. MethodsElectronic medical records from large tertiary HIV clinical centers in Botswana and Uganda were queried to identify LTNP children 0-18 years enrolled between June 2003 and May 2014 and extract demographic and nutritional parameters. Multivariate subdistribution hazard analyses were used to examine demographic factors and nutritional status in progression in the pre-antiretroviral therapy era. ResultsBetween the two countries, 14,246 antiretroviral therapy-naïve children infected with HIV were enrolled into clinical care. The overall proportion of LTNP was 6.3% (9.5% in Botswana vs 5.9% in Uganda). The median progression-free survival for the cohort was 6.3 years, although this was lower in Botswana than in Uganda (6.6 vs 8.8 years; P <0.001). At baseline, the adjusted subdistribution hazard ratio (aHRsd) of progression was increased among underweight children (aHRsd 1.42; 95% confidence interval [CI]: 1.32-1.53), enrolled after 2010 (aHRsd 1.32; 95% CI 1.22-1.42), and those from Botswana (aHRsd 2; 95% CI 1.91-2.10). ConclusionsIn our study, the prevalence of pediatric LTNP was lower than that observed among adult populations, but progression-free survival was higher than expected. Underweight, year of enrollment into care, and country of origin are independent predictors of progression among children.

Association of Viral Control and Maternal Antibody Titers in Congenital Zika Virus Infection

Abstract Background Exposure to Zika virus (ZIKV) in utero can result in a wide spectrum of outcomes, ranging from asymptomatic to severe neurological defects or fetal demise. The presence of virus in the fetus or in the mother’s blood for a prolonged period of time may lead to worse outcomes, which means that limiting the duration of fetal exposure to virus may improve outcomes. One factor that may be related to control of maternal viremia and presence of virus in the fetus is the maternal IgG antibody response. We utilized a rhesus macaque model of prenatal ZIKV to quantify the viral RNA present in the maternal blood and maternal-fetal interface (MFI) tissues and determine the association of viral RNA loads with maternal IgG antibody titers over time. Methods Dams were infected with either African lineage ZIKV-DAKAR (n=9) or Asian lineage ZIKV-PRVABC59 (PR, n=10) isolate in the first trimester, then all fetal and MFI tissues were removed either 7 or 14 days post-infection (dpi) and viral RNA loads were measured. Maternal plasma was tested for viral RNA and IgG throughout pregnancy. Results A greater proportion of animals infected with the DAKAR isolate had viral RNA present in the MFI tissues compared with the animals infected with the PR isolate, at both 7 and 14 dpi. DAKAR animals also tested positive for ZIKV-specific IgG at 14 dpi or earlier, while IgG was typically negative at 14 dpi for PR animals. Viral RNA was detected in the fetal and MFI tissues in a higher proportion of dams that still had ZIKV RNA positive plasma at 14 dpi had viral RNA. We found no difference in IgG antibody titers between dams that were ZIKV positive or negative at 14 dpi. Conclusions The presence of ZIKV in the MFI tissues and earlier detection of ZIKV-specific maternal IgG responses were both associated with the DAKAR isolate, suggesting that it may be a more virulent isolate. A higher proportion of dams that had virus in their plasma at 14 dpi also had virus present in the fetal and MFI tissues, but there was no difference in long term IgG response within either isolate between animals that tested positive or negative at 14 dpi. This suggests that the dam clearing viral RNAfrom their plasma by 14 dpi may impact whether or not the virus infects the MFI tissues, but that maternal IgG response likely does not play a role in this difference.

Viral and host mediators of non-suppressible HIV-1 viremia

Non-suppressible HIV-1 viremia (NSV) is defined as persistent low-level viremia on antiretroviral therapy (ART) without evidence of ART non-adherence or significant drug resistance. Unraveling the mechanisms behind NSV would broaden our understanding of HIV-1 persistence. Here we analyzed plasma virus sequences in eight ART-treated individuals with NSV (88% male) and show that they are composed of large clones without evidence of viral evolution over time in those with longitudinal samples. We defined proviruses that match plasma HIV-1 RNA sequences as ‘producer proviruses’, and those that did not as ‘non-producer proviruses’. Non-suppressible viremia arose from expanded clones of producer proviruses that were significantly larger than the genome-intact proviral reservoir of ART-suppressed individuals. Integration sites of producer proviruses were enriched in proximity to the activating H3K36me3 epigenetic mark. CD4+ T cells from participants with NSV demonstrated upregulation of anti-apoptotic genes and downregulation of pro-apoptotic and type I/II interferon-related pathways. Furthermore, participants with NSV showed significantly lower HIV-specific CD8+ T cell responses compared with untreated viremic controllers with similar viral loads. We identified potential critical host and viral mediators of NSV that may represent targets to disrupt HIV-1 persistence.

Genotypic and Phenotypic Characterization of Replication-Competent HIV-2 Isolated from Controllers and Progressors.

Although some individuals with HIV-2 develop severe immunodeficiency and AIDS-related complications, most may never progress to AIDS. Replication-competent HIV-2 isolated from asymptomatic long-term non-progressors (controllers) have lower replication rates than viruses from individuals who progress to AIDS (progressors). To investigate potential retroviral factors that correlate with disease progression in HIV-2, we sequenced the near full-length genomes of replication-competent viruses previously outgrown from controllers and progressors and used phylogeny to seek genotypic correlates of disease progression. We validated the integrity of all open reading frames and used cell-based assays to study the retroviral transcriptional activity of the long terminal repeats (LTRs) and Tat proteins of HIV-2 from controllers and progressors. Overall, we did not identify genotypic defects that may contribute to HIV-2 non-progression. Tat-induced, LTR-mediated transcription was comparable between viruses from controllers and progressors. Our results were obtained from a small number of participants and should be interpreted accordingly. Overall, they suggest that progression may be determined before or during integration of HIV-2.

A follow-up study: 6-year cART-free virologic control of rhesus macaques after PD-1-based DNA vaccination against pathogenic SHIVSF162P3CN challenge.

An effective vaccine for combination antiretroviral therapy (cART)-free virologic control of HIV-1 by enhancing antigen-specific effector-memory CD8+ T lymphocytes could be useful in controlling the AIDS pandemic. Previously, we demonstrated that a programmed death-1 (PD-1)-based DNA vaccine, pRhPD1-p27, was effective in inducing Gag-p27-specific effector-memory CD8+ T cells for viremia suppression in rhesus macaques infected with pathogenic SHIVSF162P3CN for 2 years. In this follow-up study, we report on two pRhPD1-p27-vaccinated and SHIVSF162P3CN-infected macaques that have remained alive to date with undetectable viremia levels and low proviral loads over 6 years in the absence of cART, achieving a state of sustained virologic control. Polyfunctional effector-memory Gag-p27-specific T cells were maintained in these macaques. Moreover, several T cell epitopes found at 6 years post-viral challenge were identical to those induced during the vaccination phase, indicating sustained vaccine-induced memory T cell responses. The viral challenge resulted in de novo Nef-specific T cell responses, which were also maintained. These Gag-p27- and Nef-specific T cell responses were stronger than those in some SHIVSF162P3CN-infected macaques that showed viremia control after experimental therapy using a tandem bispecific neutralizing antibody. Our findings indicate that the PD-1-based DNA vaccine strategy holds promise as a clinical immunotherapy for long-term HIV-1 suppression.IMPORTANCEEfficient strategies for HIV-1 cART-free virologic control are critical for ending the AIDS pandemic. The essential role of effector-memory CD8+ T cells in controlling viremia and eliminating virus-infected cells has made them a promising target for vaccine development. It has been previously reported that PD-1-based DNA vaccination was effective in inducing polyfunctional effector-memory CD8+ T cells for AIDS virus control for 2 years in rhesus monkeys. This follow-up study extends the findings and shows that a viremia-free period of over 6 years was detected in two monkeys immunized with PD-1-based DNA vaccine against pathogenic SHIVSF162P3CN infection in the absence of antiretroviral therapy. Long-term vaccine-induced memory T cell responses were detected. Our results warrant the clinical trials of PD-1-based DNA vaccines for achieving HIV-1 cART-free virologic control used either alone or in combination with other biomedical interventions.

Impact Of Arabic Language Academies And Their Foundations On Community Service/ أثر مجامع اللغة العربية ومؤسساتها في خدمة المجتمع

This research is a descriptive approach that studies the impact of linguistic academies and institutions concerned with the Arabic language on both the local and the Arab communities. The boundaries of the study are the linguistic academies in Saudi Arabia, Egypt, Iraq, Jordan, Algeria, Syria, and other linguistic institutions; it aims to monitor the goals of the academies and institutions and to show their relationship with society, in addition, to highlight the areas of cooperation between them, to present the areas in which community can be served, and to identify the core obstacles facing these academies and institutions in their linguistic mission. Therefore, the research answers an important question: Is there an impact of Arabic linguistic academies and institutions on the local and Arab community? The sample of study adopted by the research was all the Arab academies, the most prominent of which are the Iraqi, Syrian, Jordanian, Egyptian, Saudi, and Algerian Arabic language academies, by tracking their websites and printed books and collecting the topics they published, and have a direct relationship with the local and Arab community. The most important goals of these academies are to preserve the integrity of the Arabic language, to take care of new terms and Arabize them, to establish linguistic issues, to monitor the reality of the Arabic language, and to make linguistic dictionaries. One of the aspects of the relationship between the academies and the community is through carrying out linguistic projects, communicating with it, and holding courses and competitions for it. The research clarified the most significant obstacles that affect this relationship, the most important of which are low financial resources, the rarity of linguistic experts, and media weakness. The research concludes with the need to break the elite control of linguistic academies and institutions and to expand the integration of human potentials that serve the Arabic language so that there are multiple windows of influence and the need to involve segments of society in linguistic thinking, its problems, ways to solve it and to pay attention to computational, psychological, social, political linguistics, by offering courses, programs, and diplomas that assist national plans for human development.

HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing.

Despite remarkable progress, a cure for HIV-1 infection remains elusive. Rebound competent latent and transcriptionally active reservoir cells persevere despite antiretroviral therapy and rekindle infection due to inefficient proviral silencing. We propose a novel "block-lock-stop" approach, entailing long term durable silencing of viral expression towards an irreversible transcriptionally inactive latent provirus to achieve long term antiretroviral free control of the virus. A graded transformation of remnant HIV-1 in PLWH from persistent into silent to permanently defective proviruses is proposed, emulating and accelerating the natural path that human endogenous retroviruses (HERVs) take over millions of years. This hypothesis was based on research into delineating the mechanisms of HIV-1 latency, lessons from latency reversing agents and advances of Tat inhibitors, as well as expertise in the biology of HERVs. Insights from elite controllers and the availability of advanced genome engineering technologies for the direct excision of remnant virus set the stage for a rapid path to an HIV-1 cure.

Host immunity associated with spontaneous suppression of viremia in therapy-naïve young rhesus macaques following neonatal SHIV infection.

Despite the advent of highly active anti-retroviral therapy, people are still dying from HIV-related causes, many of whom are children, and a protective vaccine or cure is needed to end the HIV pandemic. Understanding the nature and activation states of immune cell subsets during infection will provide insights into the immunologic milieu associated with viremia suppression that can be harnessed via therapeutic strategies to achieve a functional cure, but these are understudied in pediatric subjects. We evaluated humoral and adaptive host immunity associated with suppression of viremia in rhesus macaques infected soon after birth with a pathogenic SHIV. The results from our study provide insights into the immune cell subsets and functions associated with viremia control in young macaques that may translate to pediatric subjects for the design of future anti-viral strategies in HIV-1-infected infants and children and contribute to an understudied area of HIV-1 pathogenesis in pediatric subjects.

Immune Responses in Controllers of HIV Infection.

Elite controllers are a heterogeneous group of people living with HIV who control viral replication without antiretroviral therapy. There is substantial evidence that at least some elite controllers are infected with replication-competent virus, thus they may serve as a model of a functional cure of HIV. The mechanisms responsible for virologic control have been actively studied. The most objective data support CD8+ T cell-based mechanisms of control, but other immune responses, mediated by antibodies and natural killer cells, may also play a role in controlling viral replication. In this article, we review the evidence for different mechanisms of immune control in these remarkable individuals. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

HIV infection is associated with upregulated circulating levels of the inflammaging miR-21-5p.

HIV infection produces a chronic inflammation which leads to early aging of people living with HIV. Even though antiretroviral treatments (ART) have significantly increased HIV patient survival, an underlying chronic inflammation persists leading to HIV-related comorbidities. In this context, changes in microRNAs (miRNAs) expression may contribute to this inflammatory response. This study aims to detect differential expression of circulating miRNAs in treatment-naïve HIV-infected individuals compared to uninfected controls and evaluation of altered miRNAs after one year of ART. Serum from patients and controls was collected at baseline and after 48-weeks on ART in HIV-treated patients. Circulating miRNAs were analysed using next generation sequencing. A total of 32 HIV patients and 10 controls were recruited. Of HIV+individuals, 7 were long-term non-progressors (elite controllers), a group of HIV-infected individuals that spontaneously control the infection. Higher circulating levels of miR-21-5p, and lower levels of miR-6503-3p and miR-3135b were detected in HIV+progressors. After one year of ART, these miRNAs remain altered. Moreover, miR-21-5p and miR-6503-3p were also altered in elite controllers compared to control group. In silico analyses showed that miR-21-5p target pathways are related to inflammation mechanisms and immune system. miR-21-5p circulating levels are involved in inflammation and oxidative stress mechanisms in HIV patients even after one year of ART or in elite controllers.

Generating and measuring effective vaccine-elicited HIV-specific CD8 + T cell responses.

There is growing consensus that eliciting CD8 + T cells in addition to antibodies may be required for an effective HIV vaccine for both prevention and cure. Here, we review key qualities of vaccine-elicited CD8 + T cells as well as major CD8 + T cell-based delivery platforms used in recent HIV vaccine clinical trials. Much progress has been made in improving HIV immunogen design and delivery platforms to optimize CD8 + T cell responses. With regards to viral vectors, recent trials have tested newer chimp and human adenovirus vectors as well as a CMV vector. DNA vaccine immunogenicity has been increased by delivering the vaccines by electroporation and together with adjuvants as well as administering them as part of a heterologous regimen. In preclinical models, self-amplifying RNA vaccines can generate durable tissue-based CD8 + T cells. While it may be beneficial for HIV vaccines to recapitulate the functional and phenotypic features of HIV-specific CD8 + T cells isolated from elite controllers, most of these features are not routinely measured in HIV vaccine clinical trials. Identifying a vaccine capable of generating durable T cell responses that target mutationally vulnerable epitopes and that can rapidly intercept infecting or rebounding virus remains a challenge for HIV. Comprehensive assessment of HIV vaccine-elicited CD8 + T cells, as well as comparisons between different vaccine platforms, will be critical to advance our understanding of how to design better CD8 + T cell-based vaccines for HIV.

Immunogenicity and Efficacy of Vaccination in People Living with Human Immunodeficiency Virus.

People living with HIV (PLWH) remain at high risk of mortality and morbidity from vaccine-preventable diseases, even though antiretroviral therapy (ART) has restored life expectancy and general well-being. When, which, and how many doses of vaccine should be administered over the lifetime of PLWH are questions that have become clinically relevant. Immune responses to most vaccines are known to be impaired in PLWH. Effective control of viremia with ART and restored CD4+ T-cell count are correlated with an improvement in responsiveness to routine vaccines. However, the presence of immune alterations, comorbidities and co-infections may alter it. In this article, we provide a comprehensive review of the literature on immune responses to different vaccines in the setting of HIV infection, emphasizing the potential effect of HIV-related factors and presence of comorbidities in modulating such responses. A better understanding of these issues will help guide vaccination and prevention strategies for PLWH.

The role of vaccination route with an adenovirus-vectored vaccine in protection, viral control, and transmission in the SARS-CoV-2/K18-hACE2 mouse infection model.

Vaccination is the most effective mechanism to prevent severe COVID-19. However, breakthrough infections and subsequent transmission of SARS-CoV-2 remain a significant problem. Intranasal vaccination has the potential to be more effective in preventing disease and limiting transmission between individuals as it induces potent responses at mucosal sites. Utilizing a replication-deficient adenovirus serotype 5-vectored vaccine expressing the SARS-CoV-2 RBD (AdCOVID) in homozygous and heterozygous transgenic K18-hACE2, we investigated the impact of the route of administration on vaccine immunogenicity, SARS-CoV-2 transmission, and survival. Mice vaccinated with AdCOVID via the intramuscular or intranasal route and subsequently challenged with SARS-CoV-2 showed that animals vaccinated intranasally had improved cellular and mucosal antibody responses. Additionally, intranasally vaccinated animals had significantly better viremic control, and protection from lethal infection compared to intramuscularly vaccinated animals. Notably, in a novel transmission model, intranasal vaccination reduced viral transmission to naïve co-housed mice compared to intramuscular vaccination. Our data provide convincing evidence for the use of intranasal vaccination in protecting against SARS-CoV-2 infection and transmission.

Interactions between plant-beneficial microorganisms in a consortium: Streptomyces microflavus and Trichoderma harzianum.

The construction of microbial consortia is challenging due to many variables to be controlled, including the cross-compatibility of the selected strains and their additive or synergistic effects on plants. In this work, we investigated the interactions in vitro, in planta, and at the molecular level of two elite biological control agents (BCAs), that is Streptomyces microflavus strain AtB-42 and Trichoderma harzianum strain M10, to understand their attitude to cooperate in a consortium. In vitro, we observed a strong cross-antagonism between AtB-42 and M10 in agar plates due to diffusible metabolites and volatile organic compounds. In liquid co-cultures, M10 hindered the growth of AtB-42 very likely because of secondary metabolites and strong competition for the nutrients. The interaction in the co-culture induced extensive transcriptional reprogramming in both strains, especially in the pathways related to ribosomes, protein synthesis, and oxidoreductase activity, suggesting that each strain recognized the counterpart and activated its defence responses. The metabolome of both strains was also significantly affected. In contrast, in the soil, M10 growth was partially contrasted by AtB-42. The roots of tomato seedlings inoculated with the consortium appeared smaller than the control and single-strain-inoculated plants, indicating that plants diverted some energy from the development to defence activation, as evidenced by the leaf transcriptome. The consortium induced a stronger transcriptional change compared to the single inoculants, as demonstrated by a higher number of differentially expressed genes. Although the cross-antagonism observed in vitro, the two strains exerted a synergistic effect on tomato seedlings by inducing resistance responses stronger than the single inoculants. Our observations pose a question on the usefulness of the sole in vitro assays for selecting BCAs to construct a consortium. In vivo experiments should be preferred, and transcriptomics may greatly help to elucidate the activity of the BCAs beyond the phenotypic effects on the plant.

The TLR7/IRF-5 axis sensitizes memory CD4+ T cells to Fas-mediated apoptosis during HIV-1 infection.

HIV-1 infection is characterized by inflammation and a progressive decline in CD4+ T cell count. Despite treatment with antiretroviral therapy (ART), the majority of people living with HIV (PLWH) maintain residual levels of inflammation, a low degree of immune activation, and higher sensitivity to cell death in their memory CD4+ T cell compartment. To date, the mechanisms responsible for this high sensitivity remain elusive. We have identified the transcription factor IRF-5 to be involved in impairing the maintenance of murine CD4+ T cells during chronic infection. Here, we investigate whether IRF-5 also contributes to memory CD4+ T cell loss during HIV-1 infection. We show that TLR7 and IRF-5 were upregulated in memory CD4+ T cells from PLWH, when compared with naturally protected elite controllers and HIVfree participants. TLR7 was upstream of IRF-5, promoting Caspase 8 expression in CD4+ T cells from ART HIV-1+ but not from HIVfree donors. Interestingly, the TLR7/IRF-5 axis acted synergistically with the Fas/FasL pathway, suggesting that TLR7 and IRF-5 expression in ART HIV-1+ memory CD4+ T cells represents an imprint that predisposes cells to Fas-mediated apoptosis. This predisposition could be blocked using IRF-5 inhibitory peptides, suggesting IRF-5 blockade as a possible therapy to prevent memory CD4+ T cell loss in PLWH.