Probes for HIV

Humanized mice have become an important workhorse model for HIV research. Advances that enabled development of a human immune system in immune deficient mouse strains have aided new basic research in HIV pathogenesis and immune dysfunction. The small animal features facilitate development of clinical interventions that are difficult to study in clinical cohorts, and avoid the high cost and regulatory burdens of using non-human primates. The model also overcomes the host restriction of HIV for human immune cells which limits discovery and translational research related to important co-infections of people living with HIV. In this review we emphasize recent advances in modeling bacterial and viral co-infections in the setting of HIV in humanized mice, especially neurological disease, and Mycobacterium tuberculosis and HIV co-infections. Applications of current and future co-infection models to address important clinical and research questions are further discussed.

Spontaneous control of HIV infection has been repeatedly linked to antiviral CD8+ T cells but is not always permanent. To address mechanisms of durable and aborted control of viremia, we evaluated immunologic and virologic parameters longitudinally among 34 HIV-infected subjects with differential outcomes. Despite sustained recognition of autologous virus, HIV-specific proliferative and cytolytic T cell effector functions became selectively and intrinsically impaired prior to aborted control. Longitudinal transcriptomic profiling of functionally impaired HIV-specific CD8+ T cells revealed altered expression of genes related to activation, cytokine-mediated signaling, and cell cycle regulation, including increased expression of the antiproliferative transcription factor KLF2 but not of genes associated with canonical exhaustion. Lymphoid HIV-specific CD8+ T cells also exhibited poor functionality during aborted control relative to durable control. Our results identify selective functional impairment of HIV-specific CD8+ T cells as prognostic of impending aborted HIV control, with implications for clinical monitoring and immunotherapeutic strategies.

Background The increase in syphilis rates worldwide, particularly in people living with HIV (PLWH), as well as the challenging diagnosis that secondary syphilis represents, make essential the accurate recognition of its manifestations, particularly in easy-access sites like the oral mucosa. Objective To describe the clinicopathologic spectrum of oral secondary syphilis (OSS) in PLWH. Methods A cross-sectional and descriptive study that included PLWH with OSS from 3 HIV referral centers in Mexico City (2004-2020). Demographic and clinical data were obtained. A comprehensive oral examination was done. OSS was diagnosed following established criteria. Histopathologic/cytological procedures were performed to rule out specific oral lesions. In all patients, Venereal Disease Research Laboratory tests were assessed and, if possible, a confirmatory fluorescent treponemal antibody test or biopsy was performed. Statistical analysis was performed using SPSS v25. Results Forty-seven PLWH with OSS (97.8% male, median age: 32 years, 63.8% with acquired immunodeficiency syndrome) were included. Thirty-five were receiving combination antiretroviral therapy (74.5%; median of 1146 [Q1-Q3: 337.5-1971] days) with a median CD4+ count of 385 (Q1-Q3: 223-664) cells/mm3 and a Log10 HIV viral load of 4.1 (Q1-Q3: 3.7-5.3) copies/mL. Forty had a complete clinical-serological diagnosis (85.1%; 17 had histopathologic confirmation) and 7 had a clinical-histopathologic diagnosis. Twenty-nine individuals presented 1 lesion (61.7%), and mucous patch was the most common type mainly on oropharyngeal mucosa, followed by ulcers and macular lesions. Ten patients presented maculopapular dermatosis (21.3%). Conclusions In PLWH, oral lesions, particularly mucous patch and/or ulcers on the oral and oropharyngeal mucosa, must alert specialists to consider a diagnosis of syphilis and perform a comprehensive panel of confirmatory tests.

An impediment to curing HIV-1 infection is the persistence of latently infected cells in ART-treated people living with HIV (PLWH). A key strategy for curing HIV-1 infection is to activate transcription and translation of latent virus using latency reversing agents (LRAs) and eliminate cells harboring reactivated virus via viral cytopathic effect or immune clearance. In this review, we provide an overview of available LRAs and their use in clinical trials. Furthermore, we describe recent data suggesting that CD8+ T cells promote HIV-1 latency in the context of ART, even in the presence of LRAs, which might at least partially explain the clinical inefficiency of previous "shock and kill" trials. Here, we propose a novel cure strategy called "unlock, shock, disarm, and kill". The general premise of this strategy is to shut down the pro-latency function(s) of CD8+ T cells, use LRAs to reverse HIV-1 latency, counteract anti-apoptotic molecules, and engage natural killer (NK) cells to mediate the killing of cells harboring reactivated latent HIV-1.