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Despite scientific evidence originating from two patients published to date that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure human immunodeficiency virus type 1 (HIV-1), the knowledge of immunological and virological correlates of cure is limited. Here we characterize a case of long-term HIV-1 remission of a 53-year-old male who was carefully monitored for more than 9 years after allogeneic CCR5Δ32/Δ32 HSCT performed for acute myeloid leukemia. Despite sporadic traces of HIV-1 DNA detected by droplet digital PCR and in situ hybridization assays in peripheral T cell subsets and tissue-derived samples, repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice did not reveal replication-competent virus. Low levels of immune activation and waning HIV-1-specific humoral and cellular immune responses indicated a lack of ongoing antigen production. Four years after analytical treatment interruption, the absence of a viral rebound and the lack of immunological correlates of HIV-1 antigen persistence are strong evidence for HIV-1 cure after CCR5Δ32/Δ32 HSCT. The recipient of an allogeneic stem cell transplant from a CCR5Δ32/Δ32 donor shows evidence of HIV type 1 cure, including the absence of a viral rebound over 4 years after stopping antiretroviral treatment.

Achieving durable viral remission without antiretroviral therapy (ART) remains a central challenge in HIV-1 cure research. Using a pathogenic SIV model in male cynomolgus macaques, we investigated mucosal and systemic immune features associated with post-treatment control (PTC). Chronic SIV infection disrupts intestinal macrophage homeostasis, skewing the compartment toward a CX3CR1 low inflammatory phenotype marked by increased expression of costimulatory and homing markers. This polarization is associated with mucosal CD4 + T cell depletion, elevated neutrophil activation, and systemic cytokine induction. Non-controllers exhibit a similar inflammatory profile. In contrast, PTCs maintain CX3CR1 high macrophages, preserve regulatory CD4 + T cells, and exhibit attenuated mucosal and systemic immune activation, resembling uninfected animals. CX3CR1 high macrophage abundance inversely correlates with viral burden, T cell activation, and pro-inflammatory cytokines, suggesting a potential role in post-treatment control. These findings identify CX3CR1-expressing intestinal macrophages as a potential biomarker of mucosal immune regulation and highlight their relevance as targets in HIV cure strategies. A better understanding of post-treatment control after therapy cessation can help design therapeutic strategies for people living with HIV. Here the authors show in a SIV macaque model that intestinal CX3CR1 + macrophages are preserved in SIV post-treatment controllers, while their loss is associated with increased CD4 + T cell activation and viral persistence, linking mucosal immune balance to long-term viral remission.

Introduction: The unchanged global HIV incidence may be related to ignoring acute HIV infection (AHI). This scoping review examines diagnostic, clinical, and public health implications of identifying and treating persons with AHI. Methods: We searched PubMed, in addition to hand‐review of key journals identifying research pertaining to AHI detection and treatment. We focused on the relative contribution of AHI to transmission and the diagnostic, clinical, and public health implications. We prioritized research from low‐ and middle‐income countries (LMICs) published in the last fifteen years. Results and Discussion: Extensive AHI research and limited routine AHI detection and treatment have begun in LMIC. Diagnostic challenges include ease‐of‐use, suitability for application and distribution in LMIC, and throughput for high‐volume testing. Risk score algorithms have been used in LMIC to screen for AHI among individuals with behavioural and clinical characteristics more often associated with AHI. However, algorithms have not been implemented outside research settings. From a clinical perspective, there are substantial immunological and virological benefits to identifying and treating persons with AHI – evading the irreversible damage to host immune systems and seeding of viral reservoirs that occurs during untreated acute infection. The therapeutic benefits require rapid initiation of antiretrovirals, a logistical challenge in the absence of point‐of‐care testing. From a public health perspective, AHI diagnosis and treatment is critical to: decrease transmission via viral load reduction and behavioural interventions; improve pre‐exposure prophylaxis outcomes by avoiding treatment initiation for HIV‐seronegative persons with AHI; and, enhance partner services via notification for persons recently exposed or likely transmitting. Conclusions: There are undeniable clinical and public health benefits to AHI detection and treatment, but also substantial diagnostic and logistical barriers to implementation and scale‐up. Effective early ART initiation may be critical for HIV eradication efforts, but widespread use in LMIC requires simple and accurate diagnostic tools. Implementation research is critical to facilitate sustainable integration of AHI detection and treatment into existing health systems and will be essential for prospective evaluation of testing algorithms, point‐of‐care diagnostics, and efficacious and effective first‐line regimens.

Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.

Mechanisms underlying durable control of HIV after antiretroviral therapy interruption remain poorly understood. Here we provide a comprehensive longitudinal analysis in a non-human primate model of post-treatment control using SIVmac251-infected male cynomolgus macaques (pVISCONTI study). Controllers exhibit lower levels of SIV DNA, intact proviruses, transcriptional activity, and viral evolution compared to non-controllers in blood and tissues long after therapy interruption. Before interruption, controllers already have fewer intact proviruses in lymph nodes, and this difference persists in blood shortly after interruption, prior to viral rebound. Intact provirus levels in lymph nodes before interruption negatively correlate with CD8⁺ T-cell capacity to suppress SIV and reflect rebound magnitude. The study demonstrates that markers of post-treatment control are detectable in lymph nodes before therapy interruption and in blood shortly after, and suggests that host immune responses may shape intact provirus profiles during treatment. Using a non-human primate model, the authors show that SIV post-treatment control is associated with fewer intact proviruses in lymph nodes before treatment interruption, linked to stronger SIV-suppressive activity of CD8 T cells.

Natural killer (NK) cells play a critical understudied role during HIV infection in tissues. In a natural host of SIV, the African green monkey (AGM), NK cells mediate a strong control of SIVagm infection in secondary lymphoid tissues. We demonstrate that SIVagm infection induces the expansion of terminally differentiated NKG2a low NK cells in secondary lymphoid organs displaying an adaptive transcriptional profile and increased MHC-E-restricted cytotoxicity in response to SIV Env peptides while expressing little IFN-γ. Such NK cell differentiation was lacking in SIVmac-infected macaques. Adaptive NK cells displayed no increased NKG2C expression. This study reveals a previously unknown profile of NK cell adaptation to a viral infection, thus accelerating strategies toward NK-cell directed therapies and viral control in tissues. NK cells control SIV infection in secondary lymphoid tissues in the natural host that typically doesn’t progress toward disease. Here the authors show that this control is associated with terminal NK cell differentiation and improved MHC-E-dependent activity lacking in pathogenic SIV infection.

HIV remission can be achieved in some people, called post-treatment HIV controllers, after antiretroviral treatment discontinuation. Treatment initiation close to the time of infection was suggested to favor post-treatment control, but the circumstances and mechanisms leading to this outcome remain unclear. Here we evaluate the impact of early (week 4) vs. late (week 24 post-infection) treatment initiation in SIVmac 251 -infected male cynomolgus macaques receiving 2 years of therapy before analytical treatment interruption. We show that early treatment strongly promotes post-treatment control, which is not related to a lower frequency of infected cells at treatment interruption. Rather, early treatment favors the development of long-term memory CD8 + T cells with enhanced proliferative and SIV suppressive capacity that are able to mediate a robust secondary-like response upon viral rebound. Our model allows us to formally demonstrate a link between treatment initiation during primary infection and the promotion of post-treatment control and provides results that may guide the development of new immunotherapies for HIV remission. HIV remission has been seen in people living with HIV after the cessation of antiretroviral therapy and is termed post treatment control. Here Passaes and colleagues present an SIV model that shows early initiation of antiretroviral therapy after SIV infection is linked to improved post treatment control upon cessation of antiviral therapy and associates with the expansion of an enhanced memory pool of CD8 + T cells‘.

Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1+ less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.

Some rare HIV-1-infected individuals, referred to as HIV controllers (HIC), have persistently undetectable plasma viral load in the absence of therapy. This control of HIV-1 replication has been associated with a strong, multifunctional specific CD8⁺ T cell response. However, no direct link between this immune response and the control of viremia has so far been provided. We investigated parameters of specific CD8⁺ T cell response and in vitro susceptibility to HIV-1 infection in 11 HIC. We found high frequencies of HIV-specific CD8⁺ T cells. Interestingly, these cells expressed the activation marker HLA-DR but not CD38. This unique phenotype differentiates HIV-specific CD8⁺ T cells from HIC and noncontroller subjects and likely reflects a high potential to expand upon exposure to antigen and a capacity to exert effector functions. Accordingly, although CD4⁺ T cells from HIC were fully susceptible to HIV-1 superinfection, their CD8⁺ T cells effectively suppressed HIV-1 infection. Remarkably, this potent anti-HIV activity was observed without prior stimulation of CD8⁺ T cells. This activity was not mediated by secreted inhibitory factors but was due to the elimination of infected CD4⁺ T cells and was observed only with autologous CD4⁺ T cells, indicating an HLA-restricted cytotoxic mechanism. This constitutive antiviral capacity of CD8⁺ T cells could account for the control of viral replication in HIC.

HIV-1 post-treatment controllers are rare individuals controlling HIV-1 infection for years after antiretroviral therapy interruption. Identification of immune correlates of control in post-treatment controllers could aid in designing effective HIV-1 vaccine and remission strategies. Here, we perform comprehensive immunoprofiling of the humoral response to HIV-1 in long-term post-treatment controllers. Global multivariate analyses combining clinico-virological and humoral immune data reveal distinct profiles in post-treatment controllers experiencing transient viremic episodes off therapy compared to those stably aviremic. Virally-exposed post-treatment controllers display stronger HIV-1 humoral responses, and develop more frequently Env-specific memory B cells and cross-neutralizing antibodies. Both are linked to short viremic exposures, which are also accompanied by an increase in blood atypical memory B cells and activated subsets of circulating follicular helper T cells. Still, most humoral immune variables only correlate with Th2-like circulating follicular helper T cells. Thus, post-treatment controllers form a heterogeneous group with two distinct viral behaviours and associated immune signatures. Post-treatment controllers stably aviremic present “silent” humoral profiles, while those virally-exposed develop functionally robust HIV-specific B-cell and antibody responses, which may participate in controlling infection. A rare sub-population of people living with HIV-1 experience long-lasting viral remission after interrupting antiretroviral therapy and are considered post-treatment controllers. Here the authors characterise the humoral immune response to HIV-1 in a cohort of post-treatment controllers.