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In secondary lymphoid tissues, human immunodeficiency virus (HIV) can replicate in both the follicular and extrafollicular compartments. Yet, virus is concentrated in the follicular compartment in the absence of antiretroviral therapy, in part due to the lack of cytotoxic T lymphocyte (CTL)-mediated activity there. CTLs home to the extrafollicular compartment, where they can suppress virus load to relatively low levels. We use mathematical models to show that this compartmentalization can explain seemingly counter-intuitive observations. First, it can explain the observed constancy of the viral decline slope during antiviral therapy in the peripheral blood, irrespective of the presence of CTL in Simian Immunodeficiency Virus (SIV)-infected macaques, under the assumption that CTL-mediated lysis significantly contributes to virus suppression. Second, it can account for the relatively long times it takes for CTL escape mutants to emerge during chronic infection even if CTL-mediated lysis is responsible for virus suppression. The reason is the heterogeneity in CTL activity and the consequent heterogeneity in selection pressure between the follicular and extrafollicular compartments. Hence, to understand HIV dynamics more thoroughly, this analysis highlights the importance of measuring virus populations separately in the extrafollicular and follicular compartments rather than using virus load in peripheral blood as an observable; this hides the heterogeneity between compartments that might be responsible for the particular patterns seen in the dynamics and evolution of the HIV in vivo.
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Recognizing challenges faced by people living with HIV is vital for improving their HIV treatment outcomes. While individual-level interventions play a crucial role, community factors can shape the impact of individual interventions on treatment outcomes. Understanding neighborhood characteristics' association with HIV treatment outcomes is crucial for optimizing effectiveness. This review aims to summarize the research scope on the association between neighborhood characteristics and HIV treatment outcomes. The databases PubMed, CINAHL (EBSCOhost), Embase (Elsevier), and PsychINFO (EBSCOhost) were searched from the start of each database to Nov 21, 2022. Screening was performed by three independent reviewers. Full-text publications of all study design meeting inclusion criteria were included in the review. There were no language or geographical limitations. Conference proceedings, abstract only, and opinion reports were excluded from the review. The search yielded 7,822 publications, 35 of which met the criteria for inclusion in the review. Studies assessed the relationship between neighborhood-level disadvantage (n = 24), composition and interaction (n = 17), social-economic status (n = 18), deprivation (n = 16), disorder (n = 8), and rural-urban status (n = 7) and HIV treatment outcomes. The relationship between all neighborhood characteristics and HIV treatment outcomes was not consistent across studies. Only 7 studies found deprivation had a negative association with HIV treatment outcomes; 6 found that areas with specific racial/ethnic densities were associated with poor HIV treatment outcomes, and 5 showed that disorder was associated with poor HIV treatment outcomes. Three studies showed that rural residence was associated with improved HIV treatment outcomes. There were inconsistent findings regarding the association between neighborhood characteristics and HIV treatment outcomes. While the impact of neighborhood characteristics on disease outcomes is highly recognized, there is a paucity of standardized definitions and metrics for community characteristics to support a robust assessment of this hypothesis. Comparative studies that define and assess how specific neighborhood indicators independently or jointly affect HIV treatment outcomes are highly needed.
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Etnicidade , Grupos Raciais , Hesitação Vacinal , Vacinas , Humanos , Estados Unidos , Vacinas/efeitos adversosRESUMO
Background: The efficacy of messenger RNA (mRNA)-1273 against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well defined, particularly among young adults. Methods: Adults aged 18-29 years with no known history of SARS-CoV-2 infection or prior vaccination for coronavirus disease 2019 (COVID-19) were recruited from 44 US sites from 24 March to 13 September 2021 and randomized 1:1 to immediate vaccination (receipt of 2 doses of mRNA-1273 vaccine at months 0 and 1) or the standard of care (receipt of COVID-19 vaccine). Randomized participants were followed up for SARS-CoV-2 infection measured by nasal swab testing and symptomatic COVID-19 measured by nasal swab testing plus symptom assessment and assessed for the primary efficacy outcome. A vaccine-declined observational group was also recruited from 16 June to 8 November 2021 and followed up for SARS-CoV-2 infection as specified for the randomized participants. Results: The study enrolled 1149 in the randomized arms and 311 in the vaccine-declined group and collected >122 000 nasal swab samples. Based on randomized participants, the efficacy of 2 doses of mRNA-1273 vaccine against SARS-CoV-2 infection was 52.6% (95% confidence interval, -14.1% to 80.3%), with the majority of infections due to the Delta variant. Vaccine efficacy against symptomatic COVID-19 was 71.0% (95% confidence interval, -9.5% to 92.3%). Precision was limited owing to curtailed study enrollment and off-study vaccination censoring. The incidence of SARS-CoV-2 infection in the vaccine-declined group was 1.8 times higher than in the standard-of-care group. Conclusions: mRNA-1273 vaccination reduced the incidence of SARS-CoV-2 infection from March to September 2021, but vaccination was only one factor influencing risk. Clinical Trials Registration: NCT04811664.
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Early initiation of antiretroviral therapy (ART) alters viral rebound kinetics after analytic treatment interruption (ATI) and may play a role in promoting HIV-1 remission. Autologous neutralizing antibodies (aNAbs) represent a key adaptive immune response in people living with HIV-1. We aimed to investigate the role of aNAbs in shaping post-ATI HIV-1 rebound variants. We performed single-genome amplification of HIV-1 env from pre-ART and post-ATI plasma samples of 12 individuals who initiated ART early after infection. aNAb activity was quantified using pseudoviruses derived from the most common plasma variant, and the serum dilution that inhibited 50% of viral infections was determined. aNAb responses matured while participants were on suppressive ART, because on-ART plasma and purified immunoglobulin G (IgG) demonstrated improved neutralizing activity against pre-ART HIV-1 strains when compared with pre-ART plasma or purified IgG. Post-ATI aNAb responses exerted selective pressure on the rebounding viruses, because the post-ATI HIV-1 strains were more resistant to post-ATI plasma neutralization compared with the pre-ART virus. Several pre-ATI features distinguished post-treatment controllers from noncontrollers, including an infecting HIV-1 sequence that was more similar to consensus HIV-1 subtype B, more restricted proviral diversity, and a stronger aNAb response. Post-treatment control was also associated with the evolution of distinct N-glycosylation profiles in the HIV-1 envelope. In summary, aNAb responses appeared to mature after early initiation of ART and applied selective pressure on rebounding viruses. The combination of aNAb activity with select HIV-1 sequence and reservoir features identified individuals with a greater chance of post-treatment control.
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Anticorpos Neutralizantes , Infecções por HIV , Humanos , Anticorpos Neutralizantes/uso terapêutico , Antirretrovirais/uso terapêutico , Provírus , Imunoglobulina G , Anticorpos Anti-HIV , Carga ViralRESUMO
HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4+ and CD8+ T cell activation, lower CD4+ T cell exhaustion, and more robust Gag-specific CD4+ T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4+ T cell% and CD4+/CD8+ ratio, more functional NK cells, and a lower CD4+ T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.
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Linfócitos T CD8-Positivos , Infecções por HIV , Humanos , Células Matadoras Naturais , Ativação Linfocitária , RNA , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , ViremiaRESUMO
Posttreatment controllers (PTCs) are rare HIV-infected individuals who can limit viral rebound after antiretroviral therapy interruption (ATI), but the mechanisms of this remain unclear. To investigate these mechanisms, we quantified various HIV RNA transcripts (via reverse transcription droplet digital PCR [RT-ddPCR]) and cellular transcriptomes (via RNA-seq) in blood cells from PTCs and noncontrollers (NCs) before and two time points after ATI. HIV transcription initiation did not significantly increase after ATI in PTCs or in NCs, whereas completed HIV transcripts increased at early ATI in both groups and multiply-spliced HIV transcripts increased only in NCs. Compared to NCs, PTCs showed lower levels of HIV DNA, more cell-associated HIV transcripts per total RNA at all times, no increase in multiply-spliced HIV RNA at early or late ATI, and a reduction in the ratio of completed/elongated HIV RNA after early ATI. NCs expressed higher levels of the IL-7 pathway before ATI and expressed higher levels of multiple cytokine, inflammation, HIV transcription, and cell death pathways after ATI. Compared to the baseline, the NCs upregulated interferon and cytokine (especially TNF) pathways during early and late ATI, whereas PTCs upregulated interferon and p53 pathways only at early ATI and downregulated gene translation during early and late ATI. In NCs, viral rebound after ATI is associated with increases in HIV transcriptional completion and splicing, rather than initiation. Differences in HIV and cellular transcription may contribute to posttreatment control, including an early limitation of spliced HIV RNA, a delayed reduction in completed HIV transcripts, and the differential expression of the IL-7, p53, and TNF pathways. IMPORTANCE The findings presented here provide new insights into how HIV and cellular gene expression change after stopping ART in both noncontrollers and posttreatment controllers. Posttreatment control is associated with an early ability to limit increases in multiply-spliced HIV RNA, a delayed (and presumably immune-mediated) ability to reverse an initial rise in processive/completed HIV transcripts, and multiple differences in cellular gene expression pathways. These differences may represent correlates or mechanisms of posttreatment control and may provide insight into the development and/or monitoring of therapeutic strategies that are aimed at a functional HIV cure.
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Infecções por HIV , RNA Viral , Transcriptoma , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/imunologia , HIV-1/genética , Interferons/genética , Interleucina-7/genética , RNA Viral/genética , Transcriptoma/imunologia , Proteína Supressora de Tumor p53/genéticaRESUMO
A major barrier in the use of humanized mice as models of HIV-1 (HIV) infection is the inadequate generation of virus-specific antibody responses. Humanized DRAGA (hDRAGA) mice generate antigen-specific class switched antibodies to several pathogens, but whether they do so in HIV infection and the extent to which their secondary lymphoid tissues (sLT) support germinal center responses is unknown. hDRAGA mice were evaluated for their ability to support HIV replication, generate virus-specific antibody responses, develop splenocyte subsets, and organize sLT architecture. hDRAGA mice supported persistent HIV replication and developed modest levels of gp41-specific human IgM and IgG. Spleens from uninfected and HIV infected hDRAGA mice contained differentiated B and CD4+ T cell subsets including germinal center (GC) B cells and T follicular helper cells (TFH); relative expansions of TFH and CD8+ T cells, but not GC B cells, occurred in HIV-infected hDRAGA mice compared to uninfected animals. Immunofluorescent staining of spleen and mesenteric lymph node sections demonstrated atypical morphology. Most CD4+ and CD8+ T cells resided within CD20hi areas. CD20hi areas lacked canonical germinal centers, as defined by staining for IgD-Ki67+cells. No human follicular dendritic cells (FDC) were detected. Mouse FDC were distributed broadly throughout both CD20hi and CD20lo regions of sLT. HIV RNA particles were detected by in situ hybridization within CD20+ areas and some co-localized with mouse FDC. Viral RNA+ cells were more concentrated within CD20hi compared to CD20lo areas of sLT, but differences were diminished in spleen and eliminated in mesenteric lymph nodes when adjusted for CD4+ cell frequency. Thus, hDRAGA mice recapitulated multiple aspects of HIV pathogenesis including HIV replication, relative expansions in TFH and CD8+ T cells, and modest HIV-specific antibody production. Nevertheless, classical germinal center morphology in sLT was not observed, which may account for the inefficient expansion of GC B cells and generation of low titer human antibody responses to HIV-1 in this model.
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Infecções por HIV , HIV-1 , Camundongos , Animais , Linfócitos T CD8-Positivos , Centro Germinativo , Anticorpos Anti-HIVRESUMO
Follicular helper CD4+ T cells (TFH) are highly permissive to HIV and major foci of virus expression in both untreated and treated infection. Follicular regulatory CD4+ T cells (TFR) limit TFH numbers and function in vitro and in vivo. We evaluated the hypothesis that TFR suppress HIV replication in TFH using a well-established model of ex vivo HIV infection that employs tonsil cells from HIV uninfected individuals spinoculated with CXCR4- and CCR5-tropic HIV-GFP reporter viruses. Both CXCR4 and CCR5-tropic HIV replication were reduced in TFH cultured with TFR as compared to controls. Blocking antibodies to CD39, CTLA-4, IL-10, and TGF-beta failed to reverse suppression of HIV replication by TFR, and there were no sex differences in TFR suppressive activity. TFR reduced viability of TFH and even more so reduced HIV infected TFH as assessed by total and integrated HIV DNA. Exogenous IL-2 enhanced TFH viability and particularly numbers of GFP+ TFH in a concentration dependent manner. TFR reduced productively infected TFH at low and moderate IL-2 concentrations, and this was associated with decreases in extracellular IL-2. Both IL-2 expressing cells and larger numbers of FoxP3+CD4+ cells were detected in follicles and germinal centers of lymph nodes of people living with HIV. TFR may deplete TFH in vivo through restriction of IL-2 and thereby contribute to decay of HIV expressing cells in B cell follicles during HIV infection.
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Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Células T Auxiliares Foliculares , Linfócitos T Reguladores , Interleucina-2RESUMO
Coccidioidomycosis is a fungal infection endemic to the Southwestern United States which is associated with high morbidity and mortality in immunocompromised hosts. Serology is the main diagnostic tool, although less sensitive among immunocompromised hosts. (1â3)-ß-D-glucan (BDG) is a non-specific fungal diagnostic test that may identify suspected coccidioidomycosis and other invasive fungal infections. We retrospectively investigated the utility of BDG between 2017 and 2021 in immunocompromised hosts with positive Coccidioides spp. cultures at our institutions. During the study period, there were 368 patients with positive cultures for Coccidioides spp.; among those, 28 patients were immunocompromised hosts, had both Coccidioides serology and BDG results available, and met other inclusion and exclusion criteria. Half of the patients had positive Coccidioides serology, and 57% had a positive BDG ≥ 80 pg/mL. Twenty-three (82%) had at least one positive test during their hospitalization. Among immunocompromised hosts with suspicion for coccidioidomycosis, the combination of Coccidioides serology and BDG can be useful in the initial work up and the timely administration of appropriate antifungal therapy. However, both tests failed to diagnose many cases, underscoring the need for better diagnostic techniques for identifying coccidioidomycosis in this population.
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BACKGROUND: Biological sex and the estrogen receptor alpha (ESR1) modulate human immunodeficiency virus (HIV) activity. Few women have enrolled in clinical trials of latency reversal agents (LRAs); their effectiveness in women is unknown. We hypothesized that ESR1 antagonism would augment induction of HIV expression by the LRA vorinostat. METHODS: AIDS Clinical Trials Group A5366 enrolled 31 virologically suppressed, postmenopausal women on antiretroviral therapy. Participants were randomized 2:1 to receive tamoxifen (arm A, TAMOX/VOR) or observation (arm B, VOR) for 5 weeks followed by 2 doses of vorinostat. Primary end points were safety and the difference between arms in HIV RNA induction after vorinostat. Secondary analyses included histone 4 acetylation, HIV DNA, and plasma viremia by single copy assay (SCA). RESULTS: No significant adverse events were attributed to study treatments. Tamoxifen did not enhance vorinostat-induced HIV transcription (between-arm ratio, 0.8; 95% confidence interval [CI], .2-2.4). Vorinostat-induced HIV transcription was higher in participants with increases in H4Ac (fold increase, 2.78; 95% CI, 1.34-5.79) vs those 9 who did not (fold increase, 1.04; 95% CI, .25-4.29). HIV DNA and SCA plasma viremia did not substantially change. CONCLUSIONS: Tamoxifen did not augment vorinostat-induced HIV RNA expression in postmenopausal women. The modest latency reversal activity of vorinostat, postmenopausal status, and low level of HIV RNA expression near the limits of quantification limited assessment of the impact of tamoxifen. This study is the first HIV cure trial done exclusively in women and establishes both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV. CLINICAL TRIALS REGISTRATION: NCT03382834.
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Síndrome da Imunodeficiência Adquirida , Infecções por HIV , HIV-1 , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Linfócitos T CD4-Positivos , DNA/uso terapêutico , Receptor alfa de Estrogênio/metabolismo , Feminino , HIV-1/genética , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histonas/metabolismo , Histonas/uso terapêutico , Humanos , RNA/metabolismo , RNA/uso terapêutico , Tamoxifeno/efeitos adversos , Tamoxifeno/metabolismo , Viremia/tratamento farmacológico , Latência Viral , Vorinostat/metabolismo , Vorinostat/farmacologia , Vorinostat/uso terapêuticoRESUMO
During chronic human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection prior to AIDS progression, the vast majority of viral replication is concentrated within B cell follicles of secondary lymphoid tissues. We investigated whether infusion of T cells expressing an SIV-specific chimeric antigen receptor (CAR) and the follicular homing receptor, CXCR5, could successfully kill viral-RNA+ cells in targeted lymphoid follicles in SIV-infected rhesus macaques. In this study, CD4 and CD8 T cells from rhesus macaques were genetically modified to express antiviral CAR and CXCR5 moieties (generating CAR/CXCR5-T cells) and autologously infused into a chronically infected animal. At 2 days post-treatment, the CAR/CXCR5-T cells were located primarily in spleen and lymph nodes both inside and outside of lymphoid follicles. Few CAR/CXCR5-T cells were detected in the ileum, rectum, and lung, and no cells were detected in the bone marrow, liver, or brain. Within follicles, CAR/CXCR5-T cells were found in direct contact with SIV-viral RNA+ cells. We next infused CAR/CXCR5-T cells into ART-suppressed SIV-infected rhesus macaques, in which the animals were released from ART at the time of infusion. These CAR/CXCR5-T cells replicated in vivo within both the extrafollicular and follicular regions of lymph nodes and accumulated within lymphoid follicles. CAR/CXR5-T cell concentrations in follicles peaked during the first week post-infusion but declined to undetectable levels after 2 to 4 weeks. Overall, CAR/CXCR5-T cell-treated animals maintained lower viral loads and follicular viral RNA levels than untreated control animals, and no outstanding adverse reactions were noted. These findings indicate that CAR/CXCR5-T cell treatment is safe and holds promise as a future treatment for the durable remission of HIV.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptores CXCR5/imunologia , Receptores de Antígenos Quiméricos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/terapia , Vírus da Imunodeficiência Símia/imunologia , Animais , Linfócitos B/imunologia , Centro Germinativo/imunologia , Humanos , Imunoterapia , Linfonodos/imunologia , Macaca mulatta , RNA Viral , Receptores CXCR5/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Carga ViralRESUMO
HIV-specific chimeric antigen receptor (CAR) T cells that target lymphoid follicles have the potential to functionally cure HIV infection. CD8+ T cells, NK cells, or peripheral blood mononuclear cells (PBMC) may be modified to express HIV-specific CARs as well as follicular homing molecules such as CXCR5 to target the virally infected T follicular helper cells that concentrate within B cell follicles during HIV infection. This chapter outlines methods utilizing a simian immunodeficiency virus (SIV) rhesus macaque model of HIV to produce transduced T cells from primary PBMCs. Methods are presented for production of an SIV-specific CAR/CXCR5-encoding retrovirus used to transduce primary rhesus macaque PBMCs. Procedures to evaluate the functionality of the expanded CAR/CXCR5 T cells in vitro and ex vivo are also presented. An in vitro migration assay determines the ability of the T cells expressing CAR/CXCR5 to migrate to the CXCR5 ligand CXCL13, while an ex vivo migration assay allows measurement of the transduced T cell migration into the B cell follicle. Antiviral activity of the CAR/CXCR5 transduced T cells is determined using a viral suppression assay. These methods can be used to produce T cells for immunotherapy in SIV-infected rhesus macaques and to evaluate the functionality of the cells prior to infusion. Similar procedures can be used to produce HIV-specific CAR/CXCR5 T cells.
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Vírus da Imunodeficiência Símia , Linfócitos T , Animais , Linfócitos T CD8-Positivos , Infecções por HIV , Leucócitos Mononucleares , Macaca mulatta , Receptores CXCR5/genéticaRESUMO
Clinical trials including an analytical treatment interruption (ATI) are vital for evaluating the efficacy of novel strategies for HIV remissions. We briefly describe an interactive tool for predicting viral rebound timing in ATI trials and the impact of posttreatment controller (PTC) definitions on PTC frequency estimates. A 4-week viral load threshold of 1000âcps/ml provides both high specificity and sensitivity for PTC detection. PTC frequency varies greatly based on the definition of a PTC.
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Infecções por HIV , Infecções por HIV/tratamento farmacológico , Humanos , Testes Sorológicos , Carga ViralRESUMO
The major obstacle to a cure for HIV infection is the persistence of replication-competent viral reservoirs during antiretroviral therapy. HIV-specific chimeric antigen receptor (CAR) T cells have been developed to target latently infected CD4+ T cells that express virus either spontaneously or after intentional latency reversal. Whether HIV-specific CAR-T cells can recognize and eliminate the follicular dendritic cell (FDC) reservoir of HIV-bound immune complexes (ICs) is unknown. We created HIV-specific CAR-T cells using human peripheral blood mononuclear cells (PBMCs) and a CAR construct that enables the expression of CD4 (domains 1 and 2) and the carbohydrate recognition domain of mannose binding lectin (MBL) to target native HIV Env (CD4-MBL CAR). We assessed CAR-T cell cytotoxicity using a carboxyfluorescein succinimidyl ester (CFSE) release assay and evaluated CAR-T cell activation through interferon gamma (IFN-γ) production and CD107a membrane accumulation by flow cytometry. CD4-MBL CAR-T cells displayed potent lytic and functional responses to Env-expressing cell lines and HIV-infected CD4+ T cells but were ineffective at targeting FDC bearing HIV-ICs. CD4-MBL CAR-T cells were unresponsive to cell-free HIV or concentrated, immobilized HIV-ICs in cell-free experiments. Blocking intercellular adhesion molecule-1 (ICAM-1) inhibited the cytolytic response of CD4-MBL CAR-T cells to Env-expressing cell lines and HIV-infected CD4+ T cells, suggesting that factors such as adhesion molecules are necessary for the stabilization of the CAR-Env interaction to elicit a cytotoxic response. Thus, CD4-MBL CAR-T cells are unable to eliminate the FDC-associated HIV reservoir, and alternative strategies to eradicate this reservoir must be sought.IMPORTANCE Efforts to cure HIV infection have focused primarily on the elimination of latently infected CD4+ T cells. Few studies have addressed the unique reservoir of infectious HIV that exists on follicular dendritic cells (FDCs), persists in vivo during antiretroviral therapy, and likely contributes to viral rebound upon cessation of antiretroviral therapy. We assessed the efficacy of a novel HIV-specific chimeric antigen receptor (CAR) T cell to target both HIV-infected CD4+ T cells and the FDC reservoir in vitro Although CAR-T cells eliminated CD4+ T cells that express HIV, they did not respond to or eliminate FDC bound to HIV. These findings reveal a fundamental limitation to CAR-T cell therapy to eradicate HIV.
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Células Dendríticas Foliculares/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Receptores de Antígenos Quiméricos/imunologia , Anticorpos Monoclonais , Anticorpos Antivirais , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Células Dendríticas , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/virologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Leucócitos Mononucleares/virologia , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos/genética , Latência Viral/fisiologiaRESUMO
BACKGROUND: Evidence regarding the safety of using proviral HIV-1 DNA genotype (DNA GT) to guide antiretroviral therapy (ART) is limited. We hypothesized that HIV RNA would not increase following ART adjustment guided by DNA GT in a university HIV clinic. METHODS: Data were obtained from electronic medical records of adult persons living with HIV-1 (PWH) who underwent DNA GT testing and changed ART between October 2014 and November 2017. Logistic regression was used to evaluate the effect of ART switch on HIV RNA over time. RESULTS: Eighty-three PWH had DNA GT performed, 66 (80%) switched ART, and 59 had postswitch follow-up. Data were analyzed pre-/postswitch for these 59 PWH (median age, 54 years; 71% LWH ≥10 years; 46% ≥2 previous regimens; 36% recent low-level viremia; 34% unknown medication history). On DNA GT, 58% had ≥1-class ART resistance, 34% ≥2-class, and 10% 3-class. Median follow-up (range) was 337 (34-647) days. There was no change in probability of HIV RNA ≥50 copies/mL over time (Pâ >â .05). At baseline, 76% had HIV RNA <50 vs 88% at last postswitch follow-up (Pâ =â .092). Protease inhibitor use decreased from 58% to 24% (Pâ <â .001). Average daily pills and dosing frequency decreased from 3.48 to 2.05 (Pâ <â .001) and 1.39 to 1.09 (Pâ <â .001), respectively; ART cost did not change. CONCLUSIONS: DNA GT facilitated changes in ART in a treatment-experienced population without increases in HIV RNA. Decreased pill burden occurred without increased ART cost. Further studies to identify optimal use of DNA GT are needed.
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Epidemias , Infecções por HIV/prevenção & controle , Medicina Interna , Papel do Médico , Fármacos Anti-HIV/uso terapêutico , Erradicação de Doenças , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Programas de Rastreamento/métodos , Profilaxia Pré-Exposição/métodos , Estados Unidos/epidemiologiaRESUMO
Chimeric antigen receptor (CAR)-T cells show great promise in treating cancers and viral infections. However, most protocols developed to expand T cells require relatively long periods of time in culture, potentially leading to progression toward populations of terminally differentiated effector memory cells. Here, we describe in detail a 9-day protocol for CAR gene transduction and expansion of primary rhesus macaque peripheral blood mononuclear cells (PBMCs). Cells produced and expanded with this method show high levels of viability, high levels of co-expression of two transduced genes, retention of the central memory phenotype, and sufficient quantity for immunotherapeutic infusion of 1-2 × 108 cells/kg in a 10 kg rhesus macaque. This 9-day protocol may be broadly used for CAR-T cell and other T cell immunotherapy approaches to decrease culture time and increase maintenance of central memory populations.
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OBJECTIVE: Adults with HIV have greater sleep difficulties and are more likely to smoke cigarettes. We tested whether current smoking plays a role in sleep difficulties experienced by young adults with HIV. DESIGN: Cross-sectional. SETTING: Data were from the 2011-2014 waves of the National College Health Assessment, an annual survey conducted by the American College Health Association. PARTICIPANTS: 108,159 (including Nâ¯=â¯224 HIV positive) college students provided data for this study. MEASUREMENTS: Health conditions (including HIV positive status) were self-reported. Participants were also asked whether "sleep difficulties" were "traumatic or difficult for you to handle" over the past 12 months. Smoking was self-reported (smokers reported smoking on at least 20 of the last 30 days). Logistic regression models were adjusted for age, sex, survey year, current alcohol use or current marijuana use, diagnosis and/or treatment of anxiety or depression in last year. RESULTS: HIV positive students were more likely to be smokers (ORâ¯=â¯2.0, SEâ¯=â¯0.43, 95% CI [1.31, 3.05], Pâ¯=â¯.001) and were more likely to experience sleep difficulties (ORâ¯=â¯2.02, SEâ¯=â¯0.29, 95% CI [1.52, 2.68], Pâ¯<â¯.0001). While a significant HIV-x-smoking interaction was not found, when models were stratified by smoking, the relationship between HIV status and sleep difficulties was seen among non-smokers (ORâ¯=â¯1.97), and this relationship was stronger among smokers (ORâ¯=â¯2.64). CONCLUSIONS: Among college students, HIV positive status is associated with increased sleep difficulties. These problems are worse among smokers. Sleep interventions are warranted in this vulnerable group, and could potentially enhance smoking cessation efforts.