ART duration and immunometabolic state determine efficacy of DC-based treatment restoring functional HIV- specific CD8+ T cells in Chronic PLWH.

Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated in detail. Here, we studied the association of ART duration with memory subsets, exhaustion and metabolic profiles of CD8+ T cells from PLWH and improvement of polyfunctional and effector HIV-1 specific responses after stimulation with Gag-adjuvant-primed DC. HIV-1-specific CD8+ T cell responses from a larger proportion PLWH on ART for more than 10 years (LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro. In contrast, CD8+ T cells from PLWH on ART for less than a decade (ST-ARTp) were less responsive to DC treatment and functional improvement was limited in this group. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolytic induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+PD1- cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells. Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines.

Valganciclovir as Add-On Therapy Modifies the Frequency of NK and NKT Cell Subpopulations in Disseminated Kaposi Sarcoma Patients

Human herpesvirus-8 infection (HHV-8) is the causative agent of Kaposi sarcoma (KS) and is highly prevalent among people living with HIV (KS/HIV). It has been reported that valganciclovir (VGC) reduces HHV-8 replication in KS/HIV patients. However, currently it is unclear if VGC modifies the frequency and induces changes in markers of immune regulation of immune cells necessary to eliminate HHV8-infected cells, such as Natural Killer (NK) and NK T cells (NKT). This study evaluated the effect of VGC used as antiviral HHV8 therapy in KS patients on the frequency of NK and NKT subpopulations based on the CD27 and CD57 expression, and the immunosenescence markers, PD-1 and KLRG1. Twenty KS/HIV patients were followed-up at baseline (W0), 4 (W4), and 12 weeks (W12) of the study protocol. Among them, 10 patients received a conventional treatment scheme (CT), solely antiretroviral therapy (ART), and 10 patients received a modified treatment regime (MT), including VGC plus ART. In both groups, bleomycin/vincristine was administrated according to the treating physician’s decision. The soluble levels of IL-15, PD-L1, PD-L2, and E-cadherin were quantified across the follow-up. Our results showed that the higher IL-15 levels and lower NK frequencies cells in KS/HIV patients reach almost normal values with both treatments regimes at W12. CD27+ NK and NKT cell frequencies increased since W4 on KS/HIV patients with MT. Furthermore, PD-1 expression decreased while KLRG1 increased on NK and NKT subpopulations at W12, and it is accompanied by increased PD-L1 plasma level since W4. Our study highlights the disruption of NK and NKT subpopulations in patients with KS/HIV and explores VGC treatment’s contribution to immune reconstitution during the first weeks of treatment.

People with HIV Have Higher Risk of COVID-19 Diagnosis but Similar Outcomes than the General Population

Background We investigated the effect of HIV on COVID-19 outcomes with attention to selection bias due to differential testing and to comorbidity burden. Methods Retrospective cohort analysis using four hierarchical outcomes: positive SARS-CoV-2 test, COVID-19 hospitalization, intensive care unit (ICU) admission, and hospital mortality. The effect of HIV status was assessed using traditional covariate-adjusted, inverse probability weighted (IPW) analysis based on covariate distributions for testing bias (testing IPWs), HIV infection status (HIV IPWs), and combined models. Among PWH, we evaluated whether CD4 count and HIV plasma viral load (pVL) discriminated between those who did or did not develop study outcomes using receiver operating characteristic analysis. Results Between March and November 2020, 63,319 people were receiving primary care services at UCSD, of whom 4,017 were people living with HIV (PWH). PWH had 2.1 times the odds of a positive SARS-CoV-2 test compared to those without HIV after weighting for potential testing bias, comorbidity burden, and HIV-IPW (95% CI 1.6-2.8). Relative to persons without HIV, PWH did not have an increased rate of COVID-19 hospitalization after controlling for comorbidities and testing bias [adjusted incidence rate ratio (aIRR): 0.5, 95% CI: 0.1-1.4]. PWH had neither a different rate of ICU admission (aIRR:1.08, 95% CI; 0.31-3.80) nor in-hospital death (aIRR:0.92, 95% CI; 0.08-10.94) in any examined model. Neither CD4 count nor pVL predicted any of the hierarchical outcomes among PWH. Conclusions PWH have a higher risk of COVID-19 diagnosis but similar outcomes compared to those without HIV.

Patient-reported outcomes among people living with HIV on single- versus multi-tablet regimens: Data from a real-life setting

Background The use of single-tablet regimens (STRs) in HIV treatment is ubiquitous. However, reintroducing the (generic) components as multi-tablet regimens (MTRs) could be an interesting cost-reducing strategy. It is essential to involve patient-reported outcome measures (PROs) to examine the effects of such an approach. Hence, this study compared PROs of people living with HIV taking an STR versus a MTR in a real world setting. Materials and methods This longitudinal study included 188 people living with HIV. 132 remained on a MTR and 56 switched to an STR. At baseline, months 1-3-6-12-18 and 24, participants filled in questionnaires on health-related quality of life (HRQoL), depressive symptoms, HIV symptoms, neurocognitive complaints (NCC), treatment satisfaction and adherence. Generalized linear mixed models and generalized estimation equations mixed models were built. Results Clinical parameters and PROs of the two groups were comparable at baseline. Neurocognitive complaints and treatment satisfaction did differ over time among the groups. In the STR-group, the odds of having NCC increased monthly by 4,1% as compared to the MTR-group (p = 0.035). Moreover, people taking an STR were more satisfied with their treatment after 6 months: the median change score was high: 24 (IQR 7,5–29). Further, treatment satisfaction showed a contrary evolution in the groups: the estimated state score of the STR-group increased by 3,3 while it decreased by 0,2 in the MTR-group (p = 0.003). No differences over time between the groups were observed with regard to HRQoL, HIV symptoms, depressive symptoms and adherence. Conclusions Neurocognitive complaints were more frequently reported among people on an STR versus MTR. This finding contrasts with the higher treatment satisfaction in the STR-group over time. The long-term effects of both PROs should guide the decision-making on STRs vs. (generic) MTRs.