Spontaneous HIV expression during suppressive ART is associated with the magnitude and function of HIV-specific CD4+ and CD8+ T cells.

Spontaneous transcription and translation of HIV can persist during suppressive antiretroviral therapy (ART). The quantity, phenotype, and biological relevance of this spontaneously "active" reservoir remain unclear. Using multiplexed single-cell RNAflow-fluorescence in situ hybridization (FISH), we detect active HIV transcription in 14/18 people with HIV on suppressive ART, with a median of 28/million CD4 <sup>+</sup> T cells. While these cells predominantly exhibit abortive transcription, p24-expressing cells are evident in 39% of participants. Phenotypically diverse, active reservoirs are enriched in central memory T cells and CCR6- and activation-marker-expressing cells. The magnitude of the active reservoir positively correlates with total HIV-specific CD4 <sup>+</sup> and CD8 <sup>+</sup> T cell responses and with multiple HIV-specific T cell clusters identified by unsupervised analysis. These associations are particularly strong with p24-expressing active reservoir cells. Single-cell vDNA sequencing shows that active reservoirs are largely dominated by defective proviruses. Our data suggest that these reservoirs maintain HIV-specific CD4 <sup>+</sup> and CD8 <sup>+</sup> T responses during suppressive ART

Multiple Remissions of Extracavitary Primary Effusion Lymphoma Treated With a Single Cycle of Liposomal Doxorubicin in a Patient Infected With HIV

Primary effusion lymphoma (PEL) is a rare human herpesvirus 8 (HHV8)–related large B cell lymphoma with plasmablastic, immunoblastic, or anaplastic features that often carries a poor prognosis. This lymphoma occurs mainly in patients with hiv infection, most often with Epstein–Barr virus (EBV) co-infection, and usually presents as body cavity effusions or, less commonly, as extracavitary lesions without effusion (EC-PEL). Chemotherapeutic treatment options are limited and require concurrent antiretroviral therapy (ART). Here, we report the case of an adult patient with HIV infection and chronic hepatitis E virus (HEV) co-infection who had low CD4 T cell recovery after years of ART. The patient then developed a cutaneous EC-PEL which rapidly regressed after 1 cycle of liposomal doxorubicin (LD) for his Kaposi sarcoma (KS) before treatment with chop chemotherapy. He had previously received numerous cycles of LD for cutaneous ks over 2 years. Because of the patient’s low CD4 T cell count, HEV co-infection, and earlier unexpected remission of EC-PEL before CHOP, the patient opted for a single trial of LD before other options. Surprisingly, he experienced a complete remission lasting 18 months. Subsequently, his EC-PEL relapsed twice at 31 and at 41 months after the initial diagnosis. Upon recurrence, a similar single cycle of LD was given, which again induced remission. The patient today is in complete remission after a total of 4 LD infusions over 54 months. This patient represents a unique case of HIV-with-HHV8–related, EBV-negative EC-PEL with chronic HEV coinfection, in which rapid remission was achieved after a single cycle of LD, suggesting an antiviral response in addition to the chemotherapeutic effect

Clinical outcome after lipectomy in the management of patients with human immunodeficiency virus-associated dorsocervical fat accumulation: An observational cohort study

Lipo-accumulation of the dorsocervical fat pad ("buffalo hump") is a complication observed in people living with human immunodeficiency virus (HIV). We described the clinical outcome of people living with HIV with "buffalo hump" treated by excisional lipectomy.From April 2013 to March 2018, medical records of people living with HIV, who received care in our hospital have been evaluated. Among them, patients with dorsocervical fat accumulation treated by excisional lipectomy have been retrospectively assessed.Nine patients with "buffalo hump" among 2886 people living with HIV (3.1‰, 9/2886) were included. Eight were women with a mean age of 47.9 ± 8.0 years old (range, 36-60). Most of them have been infected by blood transfusion (77%, 7/9) and the mean duration of HIV infection was 14.1 ± 5.5 years (range, 6-22). The mean duration for antiretroviral therapy was 8.8 ± 2.1 years (range, 6-11). The mean pre-ART CD4+ T cell count was 91.3 ± 76.5 cells/μL (range, 4-233) and 477.4 ± 271.8 cells/μL (range, 114-926) at the time of surgery. All 9 patients underwent excisional lipectomy of their hypertrophied dorsocervical fat pad. The mean size of the excised specimens was 14 × 11 × 6 cm. The median follow-up time was 24 months (range, 2-60), all 9 patients reported satisfaction with their results, with no recurrence has been observed.Corrective surgery used to treat localized fat accumulations in people living with HIV with "buffalo hump" showed a favorable effect and can therefore be considered when necessary. Whereas drugs such as integrase inhibitors may avoid lipo-accumulation related syndrome and should be given to people living with HIV in China

PD-1 blockade potentiates HIV latency reversal ex vivo in CD4⁺ T cells from ART-suppressed individuals.

HIV persists in latently infected CD4 <sup>+</sup> T cells during antiretroviral therapy (ART). Immune checkpoint molecules, including PD-1, are preferentially expressed at the surface of persistently infected cells. However, whether PD-1 plays a functional role in HIV latency and reservoir persistence remains unknown. Using CD4 <sup>+</sup> T cells from HIV-infected individuals, we show that the engagement of PD-1 inhibits viral production at the transcriptional level and abrogates T-cell receptor (TCR)-induced HIV reactivation in latently infected cells. Conversely, PD-1 blockade with the monoclonal antibody pembrolizumab enhances HIV production in combination with the latency reversing agent bryostatin without increasing T cell activation. Our results suggest that the administration of immune checkpoint blockers to HIV-infected individuals on ART may facilitate latency disruption

Effect of IL-7 Therapy on Phospho-Ribosomal Protein S6 and TRAF1 Expression in HIV-Specific CD8 T Cells in Patients Receiving Antiretroviral Therapy.

Copyright © 2018 by The American Association of Immunologists, Inc. IL-7 therapy has been evaluated in patients who do not regain normal CD4 T cell counts after virologically successful antiretroviral therapy. IL-7 increases total circulating CD4 and CD8 T cell counts; however, its effect on HIV-specific CD8 T cells has not been fully examined. TRAF1, a prosurvival signaling adaptor required for 4-1BB-mediated costimulation, is lost from chronically stimulated virus-specific CD8 T cells with progression of HIV infection in humans and during chronic lymphocytic choriomeningitis infection in mice. Previous results showed that IL-7 can restore TRAF1 expression in virus-specific CD8 T cells in mice, rendering them sensitive to anti-4-1BB agonist therapy. In this article, we show that IL-7 therapy in humans increases the number of circulating HIV-specific CD8 T cells. For a subset of patients, we also observed an increased frequency of TRAF1+HIV-specific CD8 T cells 10 wk after completion of IL-7 treatment. IL-7 treatment increased levels of phospho-ribosomal protein S6 in HIV-specific CD8 T cells, suggesting increased activation of the metabolic checkpoint kinase mTORC1. Thus, IL-7 therapy in antiretroviral therapy-treated patients induces sustained changes in the number and phenotype of HIV-specific T cells

Loss of the signaling adaptor TRAF1 causes CD8⁺ T cell dysregulation during human and murine chronic infection.

The signaling adaptor TNFR-associated factor 1 (TRAF1) is specifically lost from virus-specific CD8 T cells during the chronic phase of infection with HIV in humans or lymphocytic choriomeningitis virus (LCMV) clone 13 in mice. In contrast, TRAF1 is maintained at higher levels in virus-specific T cells of HIV controllers or after acute LCMV infection. TRAF1 expression negatively correlates with programmed death 1 expression and HIV load and knockdown of TRAF1 in CD8 T cells from viral controllers results in decreased HIV suppression ex vivo. Consistent with the desensitization of the TRAF1-binding co-stimulatory receptor 4-1BB, 4-1BBL-deficient mice have defects in viral control early, but not late, in chronic infection. TGFβ induces the posttranslational loss of TRAF1, whereas IL-7 restores TRAF1 levels. A combination treatment with IL-7 and agonist anti-4-1BB antibody at 3 wk after LCMV clone 13 infection expands T cells and reduces viral load in a TRAF1-dependent manner. Moreover, transfer of TRAF1(+) but not TRAF1(-) memory T cells at the chronic stage of infection reduces viral load. These findings identify TRAF1 as a potential biomarker of HIV-specific CD8 T cell fitness during the chronic phase of disease and a target for therapy

Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.

Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART