Maintenance of Viral Suppression in Human Immunodeficiency Virus Controllers Despite Waning T-Cell Responses During Antiretroviral Therapy.
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ABSTRACT:
SUBMITTER: Jilg N
PROVIDER: S-EPMC7896274 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human immunodeficiency virus (HIV)-specific B-cell responses in infected individuals are maintained by active HIV replication. Suppression of viremia by antiretroviral therapy (ART) leads to quantitative and qualitative changes that remain unclear. Accordingly, B-cell responses were investigated in elite controllers (ECs), who maintain undetectable HIV levels without ART, and in individuals whose viremia was suppressed by ART. Despite a higher HIV burden in the ART group, compared with the EC group, frequencies of HIV-specific B cells were higher in the EC group, compared with those in the ART group. However, the initiation of ART in several ECs was associated with reduced frequencies of HIV-specific B cells, suggesting that responses are at least in part sustained by HIV replication. Furthermore, B-cell responses to tetanus toxin but not influenza hemagglutinin in the ART group were lower than those in the EC group. Thus, the superior HIV-specific humoral response in ECs versus ART-treated individuals is likely due to a more intact humoral immune response in ECs and/or distinct responses to residual HIV replication.
| S-EPMC4936645 | biostudies-literature
Project description:Background and aimsLiver injury may persist in patients with HBV receiving antiviral therapy who have ongoing transcription and translation. We sought to assess ongoing HBV transcription by serum HBV RNA, translation by serum hepatitis B core related antigen (HBcrAg), and their associations with hepatic HBsAg and HBcAg staining in patients coinfected with HBV and HIV.MethodsThis is a cross-sectional study of 110 adults coinfected with HBV and HIV who underwent clinical assessment and liver biopsy. Immunohistochemistry (IHC) was performed for HBsAg and HBcAg. Viral biomarkers included quantitative HBsAg, HBV RNA, and HBcrAg.ResultsParticipants' median age was 49 years (male, 93%; Black, 51%; HBeAg+, 65%), with suppressed HBV DNA (79%) and undetectable HIV RNA (77%) on dually active antiretroviral therapy. Overall, HBV RNA and HBcrAg were quantifiable in 81% and 83%, respectively (96% and 100% in HBeAg+, respectively). HBcAg staining was detected in 60% and HBsAg in 79%. Higher HBV RNA was associated with higher HBcAg and HBsAg IHC grades (both p < 0.0001). The HBsAg membranous staining pattern was significantly associated with higher HBV-RNA and HBcrAg levels.ConclusionHBcAg and HBsAg IHC staining persisted despite viral suppression, and IHC grades and staining patterns correlated with markers of transcription (HBV RNA) and translation (HBcrAg). These data indicate that apparent HBV suppression is associated with residual transcription and translation that could contribute to liver pathology. Additional antiviral strategies directed to HBV protein expression may be useful to ameliorate liver injury.
| S-EPMC9800637 | biostudies-literature
Project description:BackgroundDespite low plasma human immunodeficiency virus (HIV) RNA, HIV controllers have evidence of viral replication and elevated inflammation. We assessed the effect of antiretroviral therapy (ART) on HIV suppression, immune activation, and quality of life (QoL).MethodsA5308 was a prospective, open-label study of rilpivirine/emtricitabine/tenofovir disoproxil fumarate in ART-naive HIV controllers (N = 35), defined as having HIV RNA <500 copies/mL for ≥12 months. The primary outcome measured change in %CD38+HLA-DR+ CD8+ T cells. Residual plasma viremia was measured using the integrase single-copy assay. QoL was measured using the EQ-5D questionnaire. Outcomes were evaluated using repeated measures general estimating equations models.ResultsBefore ART, HIV controllers with undetectable residual viremia <0.6 HIV-1 RNA copies/mL had higher CD4+ counts and lower levels of T-cell activation than those with detectable residual viremia. ART use was effective in further increasing the proportion of individuals with undetectable residual viremia (pre-ART vs after 24-48 weeks of ART: 19% vs 94%, P < .001). Significant declines were observed in the %CD38+HLA-DR+CD8+ T cells at 24-48 (-4.0%, P = .001) and 72-96 (-7.2%, P < .001) weeks after ART initiation. ART use resulted in decreases of several cellular markers of immune exhaustion and in a modest but significant improvement in self-reported QoL. There were no significant changes in CD4+ counts or HIV DNA.ConclusionsART in HIV controllers reduces T-cell activation and improves markers of immune exhaustion. These results support the possible clinical benefits of ART in this population.
| S-EPMC7146008 | biostudies-literature
Project description:Mechanisms responsible for natural control of human immunodeficiency type 1 (HIV) replication in elite controllers (EC) remain incompletely defined. To determine if EC generate high quality HIV-specific IgA responses, we used Western blotting to compare the specificities and frequencies of IgA to HIV antigens in serum of gender-, age- and race-matched EC and aviremic controllers (HC) and viremic noncontrollers (HN) on highly active antiretroviral therapy (HAART). Concentrations and avidity of IgA to HIV antigens were measured using ELISA or multiplex assays. Measurements for IgG were performed in parallel. EC were found to have stronger p24- and V1V2-specific IgG responses than HN, but there were no IgG differences for EC and HC. In contrast, IgA in EC serum bound more frequently to gp160 and gag proteins than IgA in HC or HN. The avidity of anti-gp41 IgA was also greater in EC, and these subjects had stronger IgA responses to the gp41 heptad repeat region 1 (HR1), a reported target of anti-bacterial RNA polymerase antibodies that cross react with gp41. However, EC did not demonstrate greater IgA responses to E. coli RNA polymerase or to peptides containing the shared LRAI sequence, suggesting that most of their HR1-specific IgA antibodies were not induced by intestinal microbiota. In both EC and HAART recipients, the concentrations of HIV-specific IgG were greater than HIV-specific IgA, but their avidities were comparable, implying that they could compete for antigen. Exceptions were C1 peptides and V1V2 loops. IgG and IgA responses to these antigens were discordant, with IgG reacting to V1V2, and IgA reacting to C1, especially in EC. Interestingly, EC with IgG hypergammaglobulinemia had greater HIV-specific IgA and IgG responses than EC with normal total IgG levels. Heterogeneity in EC antibody responses may therefore be due to a more focused HIV-specific B cell response in some of these individuals. Overall, these data suggest that development of HIV-specific IgA responses and affinity maturation of anti-gp41 IgA antibodies occurs to a greater extent in EC than in subjects on HAART. Future studies will be required to determine if IgA antibodies in EC may contribute in control of viral replication.
| S-EPMC5495342 | biostudies-literature
Project description:BackgroundAs many as 40% of the 1 million children living with HIV (CLHIV) receiving antiretroviral treatment (ART) in resource limited settings have not achieved viral suppression (VS). Kenya has a large burden of pediatric HIV with nearly 140,000 CLHIV. Feasible, scalable, and cost-effective approaches to ensure VS in CLHIV are urgently needed. The goal of this study is to determine the feasibility and impact of point-of-care (POC) viral load (VL) and targeted drug resistance mutation (DRM) testing to improve VS in children on ART in Kenya.MethodsWe are conducting a randomized controlled study to evaluate the use of POC VL and targeted DRM testing among 704 children aged 1-14 years on ART at health facilities in western Kenya. Children are randomized 1:1 to intervention (higher frequency POC VL and targeted DRM testing) vs. control (standard-of-care) arms and followed for 12 months. Our primary outcome is VS (VL < 1000 copies/mL) 12 months after enrollment by study arm. Secondary outcomes include time to VS and the impact of targeted DRM testing on VS. In addition, key informant interviews with patients and providers will generate an understanding of how the POC VL intervention functions. Finally, we will model the cost-effectiveness of POC VL combined with targeted DRM testing.DiscussionThis study will provide critical information on the impact of POC VL and DRM testing on VS among CLHIV on ART in a resource-limited setting and directly address the need to find approaches that maximize VS among children on ART.Trials registrationNCT03820323.
| S-EPMC7644580 | biostudies-literature
Project description:BackgroundSynaptic injury is a pathological hallmark of neurological impairment in people living with human immunodeficiency virus (HIV, PLWH), a common complication despite viral suppression with antiretroviral therapy (ART). Measurement of synaptic density in living humans may allow better understanding of HIV neuropathogenesis and provide a dynamic biomarker for therapeutic studies. We applied novel synaptic vesical protein 2A (SV2A) positron emission tomographic (PET) imaging to investigate synaptic density in the frontostriatalthalamic region in PLWH and HIV-uninfected participants.MethodsIn this cross-sectional pilot study,13 older male PLWH on ART underwent magnetic resonance imaging (MRI) and PET scanning with the SV2A ligand [11C]UCB-J with partial volume correction and had neurocognitive assessments. SV2A binding potential (BPND) in the frontostriatalthalamic circuit was compared to 13 age-matched HIV-uninfected participants and assessed with respect to neurocognitive performance in PLWH.ResultsPLWH had 14% lower frontostriatalthalamic SV2A synaptic density compared to HIV-uninfected (PLWH: mean [SD], 3.93 [0.80]; HIV-uninfected: 4.59 [0.43]; P = .02, effect size 1.02). Differences were observed in widespread additional regions in exploratory analyses. Higher frontostriatalthalamic SV2A BPND associated with better grooved pegboard performance, a measure of motor coordination, in PLWH (r = 0.61, P = .03).ConclusionsIn a pilot study, SV2A PET imaging reveals reduced synaptic density in older male PLWH on ART compared to HIV-uninfected in the frontostriatalthalamic circuit and other cortical areas. Larger studies controlling for factors in addition to age are needed to determine whether differences are attributable to HIV or comorbidities in PLWH. SV2A imaging is a promising biomarker for studies of neuropathogenesis and therapeutic interventions in HIV.
| S-EPMC8528400 | biostudies-literature
Project description:Rare human immunodeficiency virus 1-infected individuals, termed elite suppressors (ES), maintain plasma virus levels of <50 copies/ml and normal CD4 counts without therapy. The major histocompatibility complex class I allele group human histocompatibility leukocyte antigen (HLA)-B*57 is overrepresented in this population. Mutations in HLA-B*57-restricted epitopes have been observed in ES, but their significance has remained unclear. Here we investigate the extent and impact of cytotoxic T lymphocyte (CTL) escape mutations in HLA-B*57+ ES. We provide the first direct evidence that most ES experience chronic low level viremia. Sequencing revealed a striking discordance between the genotypes of plasma virus and archived provirus in resting CD4+ T cells. Mutations in HLA-B*57-restricted Gag epitopes were present in all viruses from plasma but were rare in proviruses, suggesting powerful selective pressure acting at these epitopes. Surprisingly, strong CD8+ T cell interferon-gamma responses were detected against some mutant epitopes found in plasma virus, suggesting the development of de novo responses to viral variants. In some individuals, relative CD8+ T cell interleukin-2 responses showed better correlation with the selection observed in vivo. Thus, analysis of low level viremia reveals an unexpectedly high level of CTL escape mutations reflecting selective pressure acting at HLA-B*57-restricted epitopes in ES. Continued viral suppression probably reflects CTL responses against unmutated epitopes and residual or de novo responses against epitopes with escape mutations.
| S-EPMC2121215 | biostudies-literature
Project description:Human immunodeficiency virus (HIV)-infected individuals exhibit residual inflammation regardless of virologic suppression. We evaluated whether suboptimal adherence to combination antiretroviral therapy (cART) is associated with greater residual inflammation than optimal adherence, despite virologic suppression.?Longitudinal self-reported cART adherence data and serum concentrations of 24 biomarkers of inflammation and immune activation were measured at the same study visit in HIV RNA-suppressed (<50 copies/mL) HIV-infected men in the Multicenter AIDS Cohort Study from 1998 to 2009. Associations between dichotomized 6-month (<100% vs 100%) and categorized 4-day (<85%, 85%-99%, and 100%) cART adherence with biomarker concentrations were evaluated.?A total of 912 men provided 2816 person-visits with documented plasma HIV RNA suppression. In adjusted models, person-visits at which <100% cART 6-month adherence was reported had higher concentrations of interleukin 2, 6, and 10, interferon ?, tumor necrosis factor ?, and C-reactive protein than person-visits at which 100% cART adherence (P < .05) was reported. These same differences were observed in person-visits reporting <85% versus 100% 4-day cART adherence, but not in visits reporting 85%-99% versus 100% cART adherence. After adjustment for multiple comparisons, tumor necrosis factor ? remained significantly higher (11% increase; P < .001) in person-visits at which <100% adherence was reported.?Higher concentrations of inflammatory biomarkers were observed among HIV RNA-suppressed men who reported <100% cART adherence than among more adherent men. Residual HIV replication (ie, below the limit of detection), more likely among men with suboptimal adherence, is a plausible mechanism. Whether improving cART adherence could affect residual inflammation and associated morbidity and mortality rates should be investigated.
| S-EPMC5146724 | biostudies-literature
Project description:BackgroundIt is unclear whether human immunodeficiency virus (HIV) infection results in permanent loss of T-cell memory or if it affects preexisting antibodies to childhood vaccinations or infections.MethodsWe conducted a matched cohort study involving 50 pairs of HIV-infected and HIV-uninfected women. Total memory T-cell responses were measured after anti-CD3 or vaccinia virus (VV) stimulation to measure T cells elicited after childhood smallpox vaccination. VV-specific antibodies were measured by means of enzyme-linked immunosorbent assay (ELISA).ResultsThere was no difference between HIV-infected and HIV-uninfected study participants in terms of CD4+ T-cell responses after anti-CD3 stimulation (P = .19) although HIV-infected participants had significantly higher CD8+ T-cell responses (P = .03). In contrast, there was a significant loss in VV-specific CD4+ T-cell memory among HIV-infected participants (P = .04) whereas antiviral CD8+ T-cell memory remained intact (P > .99). VV-specific antibodies were maintained indefinitely among HIV-uninfected participants (half-life, infinity; 95% confidence interval, 309 years to infinity) but declined rapidly among HIV-infected participants (half-life; 39 years; 24-108 years; P = .001).ConclusionsDespite antiretroviral therapy-associated improvement in CD4+ T-cell counts (nadir, <200/μL; >350/μL after antiretroviral therapy), antigen-specific CD4+ T-cell memory to vaccinations or infections that occurred before HIV infection did not recover after immune reconstitution, and a previously unrealized decline in preexisting antibody responses was observed.
| S-EPMC7323495 | biostudies-literature
Project description:The impact of antiretroviral therapy (ART) on the genetics of simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) populations has been incompletely characterized. We analyzed SIV genetic variation before, during, and after ART in a macaque model. Six pigtail macaques were infected with an SIV/HIV chimeric virus, RT-SHIV(mne), in which SIV reverse transcriptase (RT) was replaced by HIV-1 RT. Three animals received a short course of efavirenz (EFV) monotherapy before combination ART was started. All macaques received 20 weeks of tenofovir, emtricitabine, and EFV. Plasma virus populations were analyzed by single-genome sequencing. Population diversity was measured by average pairwise difference, and changes in viral genetics were assessed by phylogenetic and panmixia analyses. After 20 weeks of ART, viral diversity was not different from pretherapy viral diversity despite more than 10,000-fold declines in viremia, indicating that, within this range, there is no relationship between diversity and plasma viremia. In two animals with consistent SIV RNA suppression to <15 copies/ml during ART, there was no evidence of viral evolution. In contrast, in the four macaques with viremias >15 copies/ml during therapy, there was divergence between pre- and during-ART virus populations. Drug resistance mutations emerged in two of these four animals, resulting in virologic failure in the animal with the highest level of pretherapy viremia. Taken together, these findings indicate that viral diversity does not decrease with suppressive ART, that ongoing replication occurs with viremias >15 copies/ml, and that in this macaque model of ART drug resistance likely emerges as a result of incomplete suppression and preexisting drug resistance mutations.
| S-EPMC3019993 | biostudies-literature