Higher CD4 T-cell Counts Research Articles

Clinical importance of cerebrospinal fluid protein levels in HIV-associated cryptococcal meningitis: Insights from a prospective cohort study in Uganda.

Cerebrospinal fluid (CSF) protein levels exhibit high variability in HIV-associated cryptococcal meningitis; however, its clinical implications remain unclear. We analyzed data from 890 adults with HIV-associated cryptococcal meningitis randomized into two clinical trials in Uganda between 2015 and 2021. CSF protein was grouped into < 100mg/dl (72%, n =641) and ≥ 100mg/dl (28%, n =249). We described baseline clinical variables and 18-week mortality by CSF protein groups. Those with CSF protein ≥ 100mg/dl were more likely to present with Glasgow coma scale score<15 (P < .01), self-reported seizures at baseline (P = .02), higher CD4 T-cell count (P < .001), and higher CSF white blood cells (P < .001). Moreover, those with a baseline CSF protein ≥ 100mg/dl also had a lower baseline CSF fungal burden (P < .001) and a higher percentage of sterile CSF cultures at day 14 (P = .02). Individuals with CSF protein ≥ 100mg/dl demonstrated a more pronounced immune response consisting of upregulation of immune effector molecules, pro-inflammatory cytokines, T-helper cell type 1 and 17 cytokines, and immune-exhaustion marker (P < .05). 18-week mortality risk in individuals with a CSF protein < 100mg/dl was 34% higher (unadjusted Hazard Ratio 1.34; 95% Confidence Interval, 1.05-1.70; P = .02) than those with CSF protein ≥ 100mg/dl. In HIV-associated cryptococcal meningitis, individuals with baseline CSF protein ≥ 100mg/dl more frequently presented with neurological symptoms, higher CSF inflammatory cytokines, reduced fungal burden, and lower mortality risk. The findings underscore the prognostic significance of baseline CSF protein levels in predicting disease severity and mortality risk in cryptococcal meningitis.

Trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio in patients with HIV and long-term virological suppression based on Yunnan HIV cohort.

Our objective was to evaluate the trajectory of immunology in patients with HIV with different baseline CD4 T-cell count strata after antiretroviral therapy (ART) under long-term viral suppression. This was a sub-analysis focused on patients with virological suppression for at least 5 years after ART. Data were obtained from the Yunnan HIV cohort in China. Patients were categorized according to prespecified baseline CD4 T-cell counts. The trajectories of CD4 T-cell count, CD8 T-cell count, and CD4/CD8 ratio changing over time were fitted using a B-spline regression model. The Cox proportional hazards regression model was used to assess the association of baseline CD4 T-cell count with the risk of both immunological responder (IR) and CD4/CD8 ratio normalization. A total of 2618 patients with a median follow-up of 7.25 years (interquartile range [IQR] 5.92-8.75) were included. Over a period of 12 years, the mean CD4 T-cell count remained above 500 cells/μL in all groups. The mean CD4/CD8 ratio was solely normalized in patients whose baseline CD4 T-cell counts were above 350 cells/μL. Patients with higher baseline CD4 T-cell counts showed higher risks of both IR and CD4/CD8 ratio normalization than those with the lowest (all p trend <0.001). A higher baseline CD4 T-cell count predicted a shorter time for both IR and CD4/CD8 ratio normalization. Long-term, sustained viral suppression may not be able to fully normalize immunological functions in patients with HIV. A high baseline CD4 T-cell count benefits IR and CD4/CD8 ratio normalization.

SARS-CoV-2 vaccine immunogenicity for people living with HIV: A systematic review and meta-analysis.

Previous publications on the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in people living with HIV (PLWH) have reported inconsistent results. Additionally, a meta-analysis investigating the immunogenicity in PLWH after the third SARS-CoV-2 vaccine dose is lacking. In this article we aim to provide a systematic review and a meta-analysis studying the immunogenicity of SARS-CoV-2 vaccines in PLWH and to identify potential drivers for antibody response in PLWH. We used three databases (PubMed, Embase and Web of Science) to conduct our review. Studies with information on numbers of PLWH producing immunoglobulin G (IgG) antibodies or neutralizing antibodies were included. The meta-analysis included 59 studies and illustrated a pooled serological response of 87.09% in the 10 343 PLWH after they received a SARS-CoV-2 vaccine. High CD4 T-cell counts and low viral load indicated that the study populations had HIV that was well treated, despite varying in location. The pooled effect increased to 91.62% for 8053 PLWH when excluding studies that used inactivated vaccines (BBIBP-CorV and CoronaVac). For the third vaccine dose, the pooled effect was 92.35% for 1974 PLWH. Additionally, weighted linear regression models demonstrated weak relationships between CD4 T-cell count, percentages of people with undetectable HIV load, and age compared with the percentages of PLWH producing a serological response. However, more research is needed to determine the effect of those factors on SARS-CoV-2 vaccine immunogenicity in PLWH. SARS-CoV-2 vaccines show a favourable effect on immunogenicity in PLWH. However, the results are not ideal. This meta-analysis suggests that a third SARS-CoV-2 vaccine dose and good HIV treatment procedures are vital to induce a good immunogenicity in PLWH.

COVID-19 hospitalization outcomes in adults by HIV status; a nation-wide register-based study.

To assess the outcome of patients hospitalized with COVID-19 by HIV status and risk factors for severe COVID-19 in people living with HIV (PWH), we performed a nationwide cohort study using register data. All people aged ≥18 years hospitalized with a primary COVID-19 diagnosis (U07.1 or U07.2) in Sweden between February 2020 and October 2021 were included. The primary outcome was severe COVID-19 [intensive care unit (ICU) admission or 90-day mortality]. Secondary outcomes were days in hospital and ICU, complications in hospital, and risk factors for severe COVID-19 in PWH. Regression analyses were performed to assess severe COVID-19 by HIV status and risk factors. Data from 64 815 hospitalized patients were collected, of whom 121 were PWH (0.18%). PWH were younger (p < 0.001), and larger proportions were men (p = 0.014) and migrants (p < 0.001). Almost all PWH had undetectable HIV-RNA (93%) and high CD4 T-cell counts (median = 560 cells/μL, interquartile range: 376-780). In an unadjusted model, PWH had statistically significant lower odds of severe COVID-19 compared with patients without HIV [odds ratio (OR) = 0.6, 95% confidence interval (CI): 0.34-0.94], but there was no significant difference after adjusting for age and comorbidity (adjusted OR = 0.7, 95% CI: 0.43-1.26). A statistically significant lower proportion of PWH (8%, 95% CI: 5-15%) died within 90 days compared with those without HIV (16%, 95% CI: 15-16%, p = 0.024). There was no statistically significant difference in days in hospital and complications during the hospital stay between PWH and patients without HIV. In this nationwide study including well-treated PWH, HIV was not a risk factor in hospitalized patients for developing severe COVID-19.

Correlation between CD4 T-Cell Counts and Seroconversion among COVID-19 Vaccinated Patients with HIV: A Meta-Analysis.

To evaluate the potential factors for predicting seroconversion due to the coronavirus disease 2019 (COVID-19) vaccine in people living with HIV (PLWH). We searched the PubMed, Embase and Cochrane databases for eligible studies published from inception to 13th September 2022 on the predictors of serologic response to the COVID-19 vaccine among PLWH. This meta-analysis was registered with PROSPERO (CRD42022359603). A total of 23 studies comprising 4428 PLWH were included in the meta-analysis. Pooled data demonstrated that seroconversion was about 4.6 times in patients with high CD4 T-cell counts (odds ratio (OR) = 4.64, 95% CI 2.63 to 8.19) compared with those with low CD4 T-cell counts. Seroconversion was about 17.5 times in patients receiving mRNA COVID-19 vaccines (OR = 17.48, 95% CI 6.16 to 49.55) compared with those receiving other types of COVID-19 vaccines. There were no differences in seroconversion among patients with different ages, gender, HIV viral load, comorbidities, days after complete vaccination, and mRNA type. Subgroup analyses further validated our findings about the predictive value of CD4 T-cell counts for seroconversion due to COVID-19 vaccines in PLWH (OR range, 2.30 to 9.59). The CD4 T-cell counts were associated with seroconversion in COVID-19 vaccinated PLWH. Precautions should be emphasized in these patients with low CD4 T-cell counts, even after a complete course of vaccination.

Factors associated with reduced function and quality of life among adult people with HIV with depression and substance use in the Asia-Pacific region.

Depression and substance use (SU) disorders are prevalent among people with HIV (PWH) and impact health outcomes despite successful antiretroviral therapy (ART). We explored quality of life, functional ability and associated factors among PWH screened positive for depression and/or SU. This cross-sectional study recruited adult PWH during routine follow-up at five HIV clinical sites in the Asia-Pacific region. Participants were screened for depression using Patient Health Questionnaire-9 and SU using Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). Quality of life (QoL) was assessed with WHOQOL-HIV BREF and functional ability with World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Factors associated with mean QoL and disability scores were analysed using linear regression. Of 864 PWH enrolled, 753 screened positive for depression or SU. The median (interquartile range, IQR) age was 38 (31-47) years and 97% were on ART. Overall mean WHOQOL-HIV BREF and WHODAS scores indicated greater impairment with increasing depressive symptom severity and SU risk. In multivariate analysis, PWH reporting previous trauma/stress (difference = 2.7, 95% confidence interval [CI] 1.5-3.9, P < 0.001) and past mental health diagnosis (difference = 5.0, 95% CI 2.9-7.1, P < 0.001) were associated with greater disability and poorer QoL scores across multiple domains ( P < 0.01 for all). Higher CD4 T-cell counts was also associated with better QoL scores and functional ability. PWH with depression/SU experienced poorer QoL and function despite routine engagement in HIV care. Efforts to integrate mental health services and interventions addressing disability into HIV management should be prioritized in the region.

796. HIV transmission clusters among people who inject drugs in North Carolina, 2010 to 2021

Abstract Background The marked increase in injecting drug use (IDU) in the past decade presents concern for increased HIV transmission among people who inject drugs (PWID) and explosive outbreaks. Among statewide HIV molecular surveillance, we assessed demographic, clinical, and reported behavioral risk factors associated with HIV clusters involving PWID in North Carolina (NC). Methods Persons ≥ 13 years old with HIV-infection residing in NC with ≥ 1 partial pol sequence collected between April 2010 and December 2021 were included in the study. We used an automated cluster analysis pipeline to detect genetic clusters (nextHIV2), defined as ≥ 2 sequences with a pairwise genetic distance &amp;lt; 1.5%. Logistic regression was used to estimate the risk and adjusted odds ratios of the relationship between the demographic factors that were likely associated with HIV clustering. Graphics were generated using the R packages ggplot2 and igraph. Results Among 19,641 persons with a sequence, 1,611 were PWID. Of these, 347 (21.5%) PWID were members of 248 clusters involving a total of 2,083 persons (size ranged 2–104). Sixty-four clusters (25%) had ≥2 PWID, whereas 2 (1%) included at least 5 PWID. The most commonly injected drug among cluster members was methamphetamine (19%). Overall, in a univariate analysis, younger age, dual risks of male-to-male sex and IDU, having sex under the influence of drugs, recent IDU (past 12 months), acute HIV infection, higher viral loads and higher CD4 T-cell count at the time of HIV diagnosis were significantly associated with clustering PWID individuals (all P&amp;lt; 0.001). In multivariate analyses, only recent IDU and higher CD4 T-cell count at the time of HIV diagnosis were significantly associated with clustering (P&amp;lt; 0.01). In addition, the proportion of PWID in clusters increased from 11.2% in 2010–2013 to 28.5% in 2018–2021 (P&amp;lt; 0.001). Nodes are colored by their reported PWID in darkred and reported non-PWID in blue. Conclusion We detected an increase in HIV genetic clusters among PWID in NC in recent years. Our results support the use of routine local molecular HIV surveillance to identify high priority clusters and offer prevention interventions for specific risk groups to prioritize limited public health resources. Disclosures Joseph J. Eron, MD, GSK: Advisor/Consultant|Merck: Advisor/Consultant.

Clinical Outcomes and Inflammatory Markers by HIV Serostatus and Viral Suppression in a Large Cohort of Patients Hospitalized With COVID-19.

Limited data exist about clinical outcomes and levels of inflammatory and immune markers among people hospitalized with COVID-19 by HIV serostatus and by HIV viral suppression. Large tertiary care health system in the Bronx, NY, USA. We conducted a retrospective cohort study of 4613 SARS-CoV-2 PCR-positive patients admitted between March 10, 2020, and May 11, 2020. We examined in-hospital intubation, acute kidney injury (AKI), hospitalization length, and in-hospital mortality by HIV serostatus, and by HIV-viral suppression and CD4 counts among people living with HIV (PLWH) using adjusted competing risks regression. We also compared immune and inflammatory marker levels by HIV serostatus and viral suppression. Most patients were either non-Hispanic Black (36%) or Hispanic (37%); 100/4613 (2.2%) were PLWH, among whom 15 had detectable HIV viral load. PLWH compared to patients without HIV had increased intubation rates (adjusted hazard ratio 1.73 [95% CI: 1.12 to 2.67], P = 0.01). Both groups had similar rates of AKI, length of hospitalization, and death. No (0%) virally unsuppressed PLWH were intubated or died, versus 21/81 (26%, P = 0.04) and 22/81 (27%, P = 0.02) of virally suppressed PLWH, respectively. Among PLWH, higher CD4 T-cell counts were associated with increased intubation rates. C-reactive protein, IL-6, neutrophil counts, and ferritin levels were similar between virally suppressed PLWH and patients without HIV, but significantly lower for unsuppressed PLWH (all P < 0.05). PLWH had increased risk of intubation but similarly frequent rates of AKI and in-hospital death as those without HIV. Findings of no intubations or deaths among PLWH with unsuppressed HIV viral load warrant further investigation.

Escalating and sustained immunovirological dissociation among antiretroviral drug-experienced perinatally human immunodeficiency virus-1-infected children and adolescents living in the Central African Republic: A STROBE-compliant study.

Sub-Saharan Africa has the vast majority (∼90%) of new pediatric acquired immunodeficiency syndrome cases worldwide. Biologically monitoring HIV-infected pediatric populations remains challenging. The differential interest of human immunodeficiency virus (HIV)-1 RNA loads and CD4 T-cell counts is debated for the treatment of pediatric acquired immunodeficiency syndrome patients.Long-term antiretroviral treatment (ART) outcomes regarding immunological and virological surrogate markers were longitudinally evaluated between 2009 and 2014 (over 57 months) in 245 perinatally HIV-1-infected children and adolescents born from HIV-infected mothers, treated at inclusion for at least 6 months by the World Health Organization-recommended ART in Bangui, Central African Republic.Patients were monitored over time biologically for CD4 T-cell counts, HIV-1 RNA loads, and drug resistance mutation genotyping.Children lost to follow-up totaled 6%. Four categories of immunovirological responses to ART were observed. At baseline, therapeutic success with sustained immunological and virological responses was observed in 80 (32.6%) children; immunological and virologic nonresponses occurred in 32 (13.0%) children; finally, the majority (133; 54.2%) of the remaining children showed discordant immunovirological responses. Among them, 33 (13.4%) children showed rapid virological responses to ART with an undetectable viral load, whereas immunological responses remained absent after 6 months of treatment and increased progressively over time in most of the cases, suggesting slow immunorestoration. Notably, nearly half of the children (40.8% at baseline and 48.2% at follow-up) harbored discordant immunovirological responses with a paradoxically high CD4 T-cell count and HIV-1 RNA load, which are always associated with high levels of drug resistance mutations. The latter category showed a significant increase over time, with a growth rate of 1.23% per year of follow-up.Our STROBE-compliant study demonstrates the high heterogeneity of biological responses under ART in children with frequent passage from 1 category to another over time. Close biological evaluation with access to routine plasma HIV-1 RNA load monitoring is crucial for adapting the complex outcomes of ART in HIV-infected children born from infected mothers.

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in HIV-infected adults in the era of highly active antiretroviral therapy: analysis stratified by CD4 T-cell count

ABSTRACTHIV-infected patients are 30- to 100-fold more susceptible to invasive pneumococcal diseases than are healthy adults. Pneumococcal vaccination may be the best way to decrease the large pneumococcal disease burden, but the optimal timing of vaccination is still unclear. In this study, HIV-infected subjects aged ≥18 years were recruited and divided into 2 age-matched groups: group 1 (subjects with CD4 T-cell count ≥350 cells/µL) and group 2 (CD4 T-cell count <350 cells/µL). Multiplex opsonophagocytic killing assay was used to compare immunogenicity after immunization with 13-valent pneumococcal conjugate vaccine (PCV13). Among 70 subjects, 67 (group 1, N = 34; group 2, N = 33) were available for the assessment of immunogenicity and safety. With respect to the post-vaccination geometric mean titer (GMT) ratios, the non-inferiority criteria were not met. Post-vaccination GMTs were significantly lower in group 2 compared to group 1 for all 4 pneumococcal serotypes (5, 6B, 18C, and 19A) tested. PCV13 was safe and well tolerated in HIV-infected patients irrespective of immune status. In conclusion, PCV13 showed significantly inferior immunogenicity among HIV-infected patients with CD4 T-cell count <350 cells/µL compared to those with a higher CD4 T-cell count.

Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children.

Pediatric slow progressors (PSP) are rare ART-naïve, HIV-infected children who maintain high CD4 T-cell counts and low immune activation despite persistently high viral loads. Using a well-defined cohort of PSP, we investigated the role of regulatory T-cells (TREG) and of IL-7 homeostatic signaling in maintaining normal-for-age CD4 counts in these individuals. Compared to children with progressive disease, PSP had greater absolute numbers of TREG, skewed toward functionally suppressive phenotypes. As with immune activation, overall T-cell proliferation was lower in PSP, but was uniquely higher in central memory TREG (CM TREG), indicating active engagement of this subset. Furthermore, PSP secreted higher levels of the immunosuppressive cytokine IL-10 than children who progressed. The frequency of suppressive TREG, CM TREG proliferation, and IL-10 production were all lower in PSP who go on to progress at a later time-point, supporting the importance of an active TREG response in preventing disease progression. In addition, we find that IL-7 homeostatic signaling is enhanced in PSP, both through preserved surface IL-7receptor (CD127) expression on central memory T-cells and increased plasma levels of soluble IL-7receptor, which enhances the bioactivity of IL-7. Combined analysis, using a LASSO modeling approach, indicates that both TREG activity and homeostatic T-cell signaling make independent contributions to the preservation of CD4 T-cells in HIV-infected children. Together, these data demonstrate that maintenance of normal-for-age CD4 counts in PSP is an active process, which requires both suppression of immune activation through functional TREG, and enhanced T-cell homeostatic signaling.

Which HIV-infected adults with high CD4 T-cell counts benefit most from immediate initiation of antiretroviral therapy? A post-hoc subgroup analysis of the START trial

Immediate initiation of antiretroviral therapy (ART) in asymptomatic adults with CD4 counts higher than 500 cells per μL, as recommended, might not always be possible in resource-limited settings. We aimed to identify subgroups of individuals who would benefit most from immediate treatment. The START trial was a randomised controlled trial in asymptomatic, HIV-positive adults previously untreated with ART. Participants with CD4 counts higher than 500 cells per μL were randomly assigned to receive immediate ART or to defer ART until CD4 counts were lower than 350 cells per μL. The primary endpoint of the study was serious AIDS-defining illnesses or death from AIDS and serious non-AIDS illnesses or non-AIDS-related death. In this post-hoc analysis, we estimated event rates and absolute risk reduction with immediate versus deferred ART, overall and by subgroup. Subgroups were prespecified in the study protocol or formed post hoc on the basis of baseline characteristics associated with morbidity and mortality in people with HIV. For continuous characteristics, approximate terciles were chosen as subgroup cutoff points, unless different cutoffs were clinically meaningful (eg, age ≥50 years). We estimated the number needed to treat immediately with ART for 1 year to prevent one primary event. Heterogeneity in the absolute risk reduction between subgroups was assessed with bootstrap tests. The START trial is registered with ClinicalTrials.gov, number NCT00867048. Between April 15, 2009, and Dec 23, 2013, we enrolled 4684 participants from 35 countries across five continents, of whom 2325 were assigned to immediate ART and 2359 were assigned to deferred ART. The primary endpoint occurred in 42 participants in the immediate ART group (0·58 events per 100 person-years) and 100 participants in the deferred ART group (1·37 events per 100 person-years). The absolute risk reduction was 0·80 (95% CI 0·48-1·13) per 100 person-years with immediate treatment, and the number needed to treat immediately to prevent one event was 126 (95% CI 89-208). Significant heterogeneity in absolute risk reduction with immediate ART was found across subgroups according to age (p=0·0022), CD4 to CD8 ratio (p=0·0007), and plasma HIV RNA viral load (p=0·033) at baseline. The highest absolute risk reductions and the lowest numbers needed to treat were found in participants aged 50 years or older, those with CD4 to CD8 ratios of less than 0·5, and those with plasma HIV RNA viral loads of 50 000 copies per mL or higher. Asymptomatic, ART-naive adults with CD4 counts higher than 500 cells per μL who are older, have a low CD4 to CD8 ratio, or a high plasma HIV RNA viral load benefit most from immediate initiation of ART and should be prioritised for treatment. US National Institute of Allergy and Infectious Diseases.

A high rate of HIV‐1 acquisition post immigration among migrants in Sweden determined by a CD4 T‐cell decline trajectory model

There is a lack of knowledge about the extent to which migrants become HIV-1 infected after arrival in European countries. The objective of this study was to assess the extent to which migrants to Sweden become HIV-1 infected post immigration using a CD4 T-cell decline trajectory model. All migrants (n = 2268) who were ≥ 15 years old, were diagnosed with HIV-1 infection in the period 1983-2013, had a known year of arrival in Sweden, did not have primary HIV infection and were not infected via mother-to-child transmission were included in the study. The CD4 T-cell decline trajectory model was applied and estimates of HIV acquisition were compared to the clinical reports. Phylogenetic analysis was performed in a subset of patients to explore whether this would favour the model or the doctor's estimate. The model estimated 19% of individuals to have been infected after arrival in Sweden, whereas the physician's estimate was 12%. In 79% of cases the estimates agreed. Discordance was predominantly seen when the doctor estimated HIV acquisition to have occurred before arrival in Sweden, while the model estimated it to have occurred after arrival in Sweden, and this type of discordance was seen in 10% of all patients. The probability of a discordance was greater for older patients, those with a high first CD4 T-cell count and those infected via heterosexual transmission. The phylogenetic analysis showed a higher concordance with the CD4 model than with the clinical reports (36 vs. 13%, respectively). The model indicated that a substantially higher proportion of migrants are infected after arrival in Sweden than estimated using clinical routine reports. It is therefore important to further emphasize primary preventive measures among migrants who have established themselves in their new country.

Human papillomavirus 16 (HPV16) and HPV52 E6-specific immunity in HIV-infected adults on combination antiretroviral therapy.

Human papillomavirus (HPV)-associated cancers disproportionately affect those infected with HIV despite effective combination antiretroviral therapy (cART). The primary aim of this study was to quantify HPV16 and HPV52 E6-specific interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) T-cell responses, a correlate of protective immunity, in the first year following cART initiation and subsequently in those patients with suboptimal (sIR) and optimal (oIR) immune reconstitution. Ninety-four HIV-infected patients were recruited to the study; a longitudinal cohort of patients recruited just prior to commencing cART and followed up for 48 weeks (n = 27), and a cross-sectional cohort (n = 67) consisting of patients with sIR (CD4 T-cell count < 350 cells/μL) and oIR (CD4 T-cell count > 500 cells/μL) after a minimum of 2 years on cART. Controls (n = 29) consisted of HIV-negative individuals. IFN-γ ELISPOT responses against HPV16 and HPV52 E6 were correlated to clinical characteristics, anal and oral HPV carriage, T-cell maturational subsets, markers of activation, senescence and T-regulatory cells. HPV16 and HPV52 E6-specific T-cell responses were detected in only one of 27 patients (3.7%) during the initial phase of immune recovery. After at least 2 years of cART, those who achieved oIR had significantly higher E6-specific responses (9 of 34; 26.5%) compared with those with sIR (2 of 32; 6.3%) (P = 0.029). Apart from higher CD4 T-cell counts and lower CD4 T-cell activation, no other immunological correlates were associated with the detection of HPV16 and HPV52 E6-specific responses. HPV16 and HPV52 E6-specific IFN-γ T-cell responses, a correlate of protective immunity, were detected more frequently among HIV-infected patients who achieved optimal immune recovery on cART (26.5%) compared with those with suboptimal recovery (6.3%).

Cytokine and Chemokine Signature in Elite Versus Viremic Controllers Infected with HIV.

HIV long-term nonprogressors (LTNPs) maintaining high CD4(+) T-cell counts without antiretroviral therapy (ART) are divided into elite controllers (ECs) with undetectable and viremic controllers (VCs) with low viral loads. Little is known about the long-term changes of T-cell subsets and inflammation patterns in ECs versus VCs. The aim of the study was to explore the long-term evolution of CD4(+) T-cell levels in LTNPs and to analyze cytokine profiles in ECs versus VCs. Nineteen ECs and 15 VCs were enrolled from the natural virus controller cohort (NaViC). T-cell counts were monitored over years, the mean annual change was calculated, and plasma concentrations of 25 cytokines were evaluated using a multiplex bead array. While absolute numbers of T cells did not differ between ECs and VCs over time, we observed a significant decrease of CD4(+) T-cell percentages in VCs, but not in ECs (median [interquartile range]: ECs: 37% [28-41] vs. VCs: 29% [25-34]; p = .02). ECs had lower levels of macrophage inflammatory protein-1β (MIP-1β, p = .003), interferon γ-induced protein-10 (IP-10, p = .03), and monokine induced by interferon-γ (MIG, p = .02). CD4(+) T-cell percentages inversely correlated with MIP 1-β (r = -0.42, p = .017) and IP-10 (r = -0.77, p < .0001). A subtle decline of CD4(+) T-cell percentages could be observed in VCs, but not in ECs, which was associated with higher plasma levels of proinflammatory cytokines. Hence, even low levels of HIV replication might go along with a progressive decline in CD4(+) T-cell counts in LTNPs.

Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection

An effective human immunodeficiency virus type 1 (HIV-1) vaccine is the best solution for halting the acquired immune deficiency syndrome epidemic. Here, we describe the design and preclinical immunogenicity of T-cell vaccine expressing novel immunogens tHIVconsvX, vectored by DNA, simian (chimpanzee) adenovirus, and poxvirus modified vaccinia virus Ankara (MVA), a combination highly immunogenic in humans. The tHIVconsvX immunogens combine the three leading strategies for elicitation of effective CD8(+) T cells: use of regions of HIV-1 proteins functionally conserved across all M group viruses (to make HIV-1 escape costly on viral fitness), inclusion of bivalent complementary mosaic immunogens (to maximize global epitope matching and breadth of responses, and block common escape paths), and inclusion of epitopes known to be associated with low viral load in infected untreated people (to induce field-proven protective responses). tHIVconsvX was highly immunogenic in two strains of mice. Furthermore, the magnitude and breadth of CD8(+) T-cell responses to tHIVconsvX-derived peptides in treatment-naive HIV-1(+) patients significantly correlated with high CD4(+) T-cell count and low viral load. Overall, the tHIVconsvX design, combining the mosaic and conserved-region approaches, provides an indisputably better coverage of global HIV-1 variants than previous T-cell vaccines. These immunogens delivered in a highly immunogenic framework of adenovirus prime and MVA boost are ready for clinical development.

Proposed clinical case definition for cytomegalovirus-immune recovery retinitis.

Cytomegalovirus (CMV) retinitis has been extensively described in patients with advanced or late human immunodeficiency virus (HIV) disease under ineffective treatment of opportunistic infection and antiretroviral therapy (ART) failure. However, there is limited information about patients who develop active cytomegalovirus retinitis as an immune reconstitution inflammatory syndrome (IRIS) after successful initiation of ART. Therefore, a case definition of cytomegalovirus-immune recovery retinitis (CMV-IRR) is proposed here. We reviewed medical records of 116 HIV-infected patients with CMV retinitis attending our institution during January 2003-June 2012. We retrospectively studied HIV-infected patients who had CMV retinitis on ART initiation or during the subsequent 6 months. Clinical and immunological characteristics of patients with active CMV retinitis were described. Of the 75 patients under successful ART included in the study, 20 had improvement of CMV retinitis. The remaining 55 patients experienced CMV-IRR; 35 of those developed CMV-IRR after ART initiation (unmasking CMV-IRR) and 20 experienced paradoxical clinical worsening of retinitis (paradoxical CMV-IRR). Nineteen patients with CMV-IRR had a CD4 count of ≥50 cells/µL. Six patients with CMV-IRR subsequently developed immune recovery uveitis. There is no case definition for CMV-IRR, although this condition is likely to occur after successful initiation of ART, even in patients with high CD4 T-cell counts. By consequence, we propose the case definitions for paradoxical and unmasking CMV-IRR. We recommend close follow-up of HIV-infected patients following ART initiation.

Association of single-nucleotide polymorphisms in TLR7 (Gln11Leu) and TLR9 (1635A/G) with a higher CD4T cell count during HIV infection

BackgroundToll-like receptors (TLRs) are essential elements of the innate immune response to different infections including HIV-1 infection. The single-nucleotide polymorphisms (SNPs) in TLRs have been associated with CD4T cell count and HIV disease progression. The TLR7 (Gln11Leu) SNP was shown to be associated with a rapid decline of CD4T cell count. A relation between TLR9 (1635A/G) SNP and CD4T cells count in HIV-infected patients is suggested, although the outcome associated with this SNP is still controversial. ObjectivesTo determine the relation of the TLR7 (Gln11Leu) and TLR9 (1635A/G) SNPs with the damage to the immune system during HIV infection as reflected by the average CD4T cell count. MethodsA total of 63 HIV-infected patients and 100 healthy individuals (controls) were enrolled in this study. The above named SNPs were analyzed after amplification of the regions that potentially contain the SNPs by polymerase chain reaction (PCR) and sequencing of the PCR products. The frequency of these SNPs and their relation with the CD4T cell count were investigated. ResultsThe TLR7 (AA) genotype ‘Gln’ had a trend toward being associated with a CD4T cell count >400cells/μl after controlling viremia via HAART. Additionally, the TLR9 1635 (GG) genotype was associated with a low average CD4T cell count and the TLR9 1635 (AG) genotype was significantly related to a higher average CD4T cell count during the viremic period in HIV-infected patients. ConclusionThe results of this longitudinal study supports the presence of an association between the TLR9 (1635A/G) genotype and the CD4T cell count, which helps clarifying the controversial results regarding this association. It also suggests that the CD4T cell count during the viremic period might be linked to the combination of both TLR7 (Gln11Leu) and TLR9 (1635A/G) genotypes. These results may help predicting the damage to the immune system, and thus impacting the planning for novel anti-HIV strategies.

Lower adiponectin is associated with subclinical cardiovascular disease among HIV-infected men

To examine whether altered levels of adipokines, adipose-derived peptides associated with myocardial infarction in the general population, may contribute to subclinical coronary atherosclerosis in HIV-infected persons. Nested cohort study. We studied HIV-infected (HIV+) and HIV-uninfected (HIV-) men in the Multicenter AIDS Cohort Study with noncontrast computed tomography (CT) to measure coronary artery calcium and regional adiposity; 75% additionally underwent coronary CT angiography to measure plaque composition and stenosis. Adiponectin and leptin levels were assessed. Multiple regression models were used to assess associations between adipokine levels and HIV disease parameters, regional adiposity, and plaque adjusted for age, race, HIV serostatus, and cardiovascular disease (CVD) risk factors. Significant findings were limited to adiponectin. HIV-positive men (n=493) had lower adiponectin levels than HIV-negative men (n=250) after adjusting for CVD risk factors (P<0.0001), which became nonsignificant after adjustment for abdominal visceral and thigh subcutaneous adipose tissue. Among HIV-positive men, lower adiponectin levels were associated with higher CD4 T-cell counts (P=0.004), longer duration of antiretroviral therapy (P=0.006), and undetectable HIV RNA levels (P=0.04) after adjusting for age, race, and CVD risk factors; only CD4 cell count remained significant after further adjustment for adipose tissue. In both groups, lower adiponectin levels were associated with increased odds of coronary stenosis more than 50% (P<0.007). Lower adiponectin levels were associated with increased extent of plaque in HIV-positive and of mixed plaque in HIV-negative men. Adiponectin levels were lower in HIV-infected men and related to the severity of subclinical atherosclerosis, independent of traditional CVD risk factors.

Can early therapy reduce inflammation?

Serious non-AIDS events or noninfectious complications of HIV infection far outnumber AIDS events in the current combination antiretroviral therapy (ART) era and are attributed to chronic inflammation. Thus, a better understanding of why inflammation persists on ART will assist in developing better therapeutic strategies, including optimal timing of ART initiation. Markers of inflammation and coagulation, such as D-dimer, interleukin-6, C-reactive protein, soluble CD14, and soluble CD163, predict end-organ disease and mortality, whereas markers of T-cell activation appear more predictive of CD4 T-cell decline, AIDS events, or response to therapy. Initiating ART at high CD4 T-cell counts can result in less inflammation as supported by studies in acute and early HIV infection, but antiretroviral drugs may differentially affect inflammatory pathways. Decreasing inflammation in HIV-uninfected individuals may decrease morbidity, but long-term outcomes studies in HIV-infected individuals are lacking. Circulating biomarkers of inflammation are among the strongest predictors of non-AIDS outcomes in treated HIV infection. With additional investigation, they may serve in the future as specific end-organ disease surrogate endpoints and may help identify those patients at highest risk of non-AIDS events who may benefit from either early ART and/or potential adjuvant anti-inflammatory therapies.