Search

Objective: Antibody-dependent enhancement (ADE) affects host-virus dynamics in fundamentally different ways: i) enhancement of initial virus acquisition, and/or ii) increased disease progression/severity. Here we address the question whether anti-HIV-1 antibodies can enhance initial infection. While cell-culture experiments hinted at this possibility, in-vivo proof remained elusive., Design: We used passive immunization in nonhuman primates challenged with simian-human immunodeficiency virus (SHIV), a chimera expressing HIV-1 envelope. We purified IgG from rhesus monkeys with early-stage SHIV infection - before cross-neutralizing anti-HIV-1 antibodies had developed - and screened for maximal complement-mediated antibody-dependent enhancement (C'-ADE) of viral replication with a SHIV strain phylogenetically distinct from that harbored by IgG donor macaques. IgG fractions with maximal C'-ADE but lacking neutralization were combined to yield enhancing anti-SHIV IgG (enSHIVIG)., Results: We serially enrolled naive macaques (Group 1) to determine the minimal and 50% animal infectious doses required to establish persistent infection after intrarectal SHIV challenge. The first animal was inoculated with a 1 : 10 virus-stock dilution; after this animal's viral RNA load was >104copies/ml, the next macaque was challenged with 10x less virus, a process repeated until viremia no longer ensued. Group 2 was pretreated intravenously with enSHIVIG 24 h before SHIV challenge. Overall, Group 2 macaques required 3.4-fold less virus compared to controls (P = 0.002). This finding is consistent with enhanced susceptibility of the passively immunized animals to mucosal SHIV challenge., Conclusion: These passive immunization data give proof of IgG-mediated enhanced virus acquisition after mucosal exposure - a potential concern for antibody-based AIDS vaccine development., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: The prevalence of HIV-associated neurocognitive disorders continues to rise despite the widespread use of antiretroviral therapy. We aimed to define the risk of neurocognitive dysfunction among smokers relative to nonsmokers., Methods: We conducted a retrospective cohort study including HIV-infected adults ages 21 to 65 years. The Mental Alternation Test (MAT) was the primary outcome. The odds of cognitive impairment were compared using random-effects logistic regression to adjust for potential confounders., Results: Of 3033, 1486 (49%) were smokers. The odds ratio for the association between smoking and cognitive impairment was 1.12 (95% confidence interval: 0.85-1.49). Nonsmokers had a higher median MAT score relative to smokers ( P = .01)., Conclusion: There was no evidence that HIV-infected smokers had greater neurocognitive dysfunction relative to HIV-infected nonsmokers. While tobacco use remains an important health risk issue to address in the HIV population, it may not represent a risk factor for neurocognitive impairment.

Youth living with HIV (YLWH) are less likely than older adults to achieve and sustain viral suppression. While treatment guidelines recommend decreased viral load (VL) monitoring in individuals with well-controlled HIV, the appropriateness of this strategy for adolescents is unknown. We conducted a retrospective cohort study to describe longitudinal viral suppression and identify incidence of, and risk factors for, virologic failure among YLWH at a US adolescent HIV clinic from 2002 to 2015. We utilized Cox proportional hazards modeling to compare hazard ratios (HRs) for virologic failure stratified by baseline characteristics. Study participants (n = 365) were predominately African American (87%) and cisgender men and transgender women who have sex with men (80%) and the majority (79%) entered care from 2002 to 2012. Of antiretroviral therapy (ART)-treated participants (n = 201), 88% achieved viral suppression, with 29% subsequently developing virologic failure at a median 12.0 months [interquartile range (IQR) 6.9-22.4] after suppression. The cohort incidence rate of virologic failure was 200 (confidence interval [95% CI]: 151-264) per 1000 person years (PY), with a rate after ≥2 years sustained suppression of 113 (95% CI: 57-227) per 1000 PY. After adjusting for time to ART initiation, initial regimen class, and year of cohort entry, cisgender women had increased hazards of virologic failure (HR 3.2 95% CI: 1.3-7.9, p = 0.01). In conclusion, youth remained at high risk of virologic failure throughout their treatment course, with higher hazards of virologic failure among cisgender women compared with other youth. Maintaining frequent VL monitoring in YLWH may be warranted, even after prolonged viral suppression.

The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution. Selective expression of the effector-associated transcription factors T-bet and eomesodermin in cytokine-producing HIV-specific CD8+ T cells differentiated HIV-specific from bulk memory CD8+ T cell effector expansion. As infection progressed expression of perforin was maintained in HIV-specific CD8+ T cells with high levels of T-bet, but not necessarily in the population of T-betLo HIV-specific CD8+ T cells that expand as infection progresses. Together, these data demonstrate that while HIV-specific CD8+ T cells in acute HIV infection initially possess cytolytic potential, progressive transcriptional dysregulation leads to the reduced CD8+ T cell perforin expression characteristic of chronic HIV infection.

Non-AIDS defining malignancies, particularly colorectal cancer (CRC), may be more prevalent among persons living with HIV (PLWH). Further, PLWH may be less likely to receive CRC screening (CRCS). We studied the epidemiology of CRC and CRCS patterns in PLWH and HIV-uninfected persons in a large US Medicaid population. We performed a matched cohort study examining CRC incidence in 2006 and CRCS between 1999 and 2007. Study participants were continuously enrolled in the Medicaid programs of California, Florida, New York, Ohio, and Pennsylvania. All PLWH enrollees were matched to five randomly sampled HIV-uninfected enrollees on 5-year age group, gender, and state. Adjusted odds ratios (AORs) for incident CRC (adjusted for comorbidity index) and the presence of CRCS (adjusted for comorbidity index and years in the data-set) among PLWH compared to HIV-uninfected enrollees were calculated. PLWH were not more likely to be diagnosed with CRC after adjusting for comorbidity index (unadjusted OR: 1.73, 95% confidence interval [CI]: 1.37-2.19; AOR 1.29; 95% CI: 0.98-1.70). While CRCS rates were low overall, PLWH were more likely to have received CRCS in unadjusted analyses (35.8% vs. 33.7%; OR 1.10, 95% CI: 1.07-1.13). This relationship was reversed after adjusting for comorbidity index and years in the data-set (AOR: 0.80, 95% CI: 0.77-0.83). Limitations of the study include a focus on the Medicaid population, an inability to detect fecal occult blood tests (FOBT), and having half of patients between 50 and 55 years of age. In conclusion, PLWH were not more likely to be diagnosed with CRC, but in adjusted analyses, were less likely to have received CRCS. As we showed a low rate of CRCS overall in this Medicaid population, researchers, clinicians, and policy-makers should improve access to and uptake of CRCS among all Medicaid patients, and particularly among PLWH.

Background: Metabolic complications, including type 2 diabetes mellitus and metabolic syndrome, are increasingly recognized among HIV-infected individuals. Low vitamin D levels increase the risk of type 2 diabetes mellitus, and vitamin D supplementation has been shown to decrease the risk of type 2 diabetes mellitus in patients without HIV infection., Objectives: The primary objective was to determine whether vitamin D deficiency (serum 25-hyrdoxyvitamin D <20 ng/ml) was associated with type 2 diabetes mellitus among HIV-infected patients. Our secondary objective was to determine whether vitamin D deficiency was associated with metabolic syndrome in HIV., Methods: We conducted a cross-sectional study among participants enrolled in the prospective Modena (Italy) HIV Metabolic Clinic Cohort. Clinical and laboratory data, including history of type 2 diabetes mellitus, fasting blood glucose, components of metabolic syndrome, and 25-hydroxyvitamin D levels, were obtained for all participants., Results: After adjusting for vitamin D supplementation, sex, age, body mass index, and hepatitis C virus co-infection, vitamin D deficiency was associated with type 2 diabetes mellitus [adjusted odds ratio (OR) 1.85; 95% confidence interval (CI) 1.03-3.32; P = 0.038]. The association between vitamin D deficiency and metabolic syndrome was not significant after adjusting for vitamin D supplementation, sex, age and body mass index (adjusted OR 1.32; 95% CI 1.00-1.75; P = 0.053)., Conclusions: Our study demonstrates an association between vitamin D deficiency and type 2 diabetes mellitus. Clinical trials are needed to better characterize the association between vitamin D deficiency and type 2 diabetes mellitus in HIV infection and to evaluate whether vitamin D is able to prevent or delay the onset of type 2 diabetes mellitus.

Objective: To explore the prevalence and features of HIV-associated neurocognitive disorders (HANDS) in Botswana, a sub-Saharan country at the center of the HIV epidemic., Design and Methods: A cross sectional study of 60 HIV-positive individuals, all receiving highly active antiretroviral therapy (HAART), and 80 demographically matched HIV-seronegative control subjects. We administered a comprehensive neuropsychological test battery and structured psychiatric interview. The lowest 10(th) percentile of results achieved by control subjects was used to define the lower limit of normal performance on cognitive measures. Subjects who scored abnormal on three or more measures were classified as cognitively impaired. To determine the clinical significance of any cognitive impairment, we assessed medication adherence, employment, and independence in activities of daily living (ADL)., Results: HIV+ subjects were impaired for all cognitive-motor ability areas compared with matched, uninfected control subjects. Thirty seven percent of HIV+ patients met criteria for cognitive impairment., Conclusion: These findings indicate that neurocognitive impairment is likely to be an important feature of HIV infection in resource-limited countries; underscoring the need to develop effective treatments for subjects with, or at risk of developing, cognitive impairment.

Pre-existing immunity to human adenovirus serotype 5 (AdHu5) has been shown to suppress the immunogenicity of recombinant Ad5 (rAdHu5) vector-based vaccines for human immunodeficiency virus type 1 (HIV-1) in both preclinical studies and clinical trials. As a potential solution to this problem we developed adenovirus vaccine vectors of chimpanzee origin. In the present study we assessed the immunogenicity of various chimpanzee adenovirus vectors in a prime/boost regimen to HIV-1 envelope and SIV Gag-Pol in rhesus monkeys and their ability to protect against pathogenic viral challenge. Although rAdHu5-primed monkeys had higher magnitude T cell responses than rAdC7 or rAdC68 prior to challenge, the rAdC7-rAdC1/C5 and rAdHu5-rAdC1/C5 immunizations resulted in comparable magnitude recall cellular immune responses and comparable level of control of viremia post-challenge.

Human immunodeficiency virus type 1 transmission selects for virus variants with genetic characteristics distinct from those of donor quasispecies, but the biological factors favoring their transmission or establishment in new hosts are poorly understood. We compared primary target cell tropisms and entry coreceptor utilizations of donor and recipient subtype C Envs obtained near the time of acute infection from Zambian heterosexual transmission pairs. Both donor and recipient Envs demonstrated only modest macrophage tropism, and there was no overall difference between groups in macrophage or CD4 T-cell infection efficiency. Several individual pairs showed donor/recipient differences in primary cell infection, but these were not consistent between pairs. Envs had surprisingly broad uses of GPR15, CXCR6, and APJ, but little or no use of CCR2b, CCR3, CCR8, GPR1, and CXCR4. Donors overall used GPR15 better than did recipients. However, while several individual pairs showed donor/recipient differences for GPR15 and/or other coreceptors, the direction of the differences was inconsistent, and several pairs had unique alternative coreceptor patterns that were conserved across the transmission barrier. CCR5/CCR2b chimeras revealed that recipients as a group were more sensitive than were donors to replacement of the CCR5 extracellular loops with corresponding regions of CCR2b, but significant differences in this direction were not consistent within pairs. These data show that sexual transmission does not select for enhanced macrophage tropism, nor for preferential use of any alternative coreceptor. Recipient Envs are somewhat more constrained than are donors in flexibility of CCR5 use, but this pattern is not universal for all pairs, indicating that it is not an absolute requirement.

Objective: To examine the associations between past intimate partner abuse experienced during adolescence (verbal and physical), recent intimate partner abuse (verbal, physical, and sexual), and HIV risk (as indicated by lack of condom use) for sexually active young adult women in relationships with male partners., Design: Secondary data analysis of waves II and III of the National Longitudinal Study of Adolescent Health (Add Health)., Setting: The Add Health Study is a longitudinal, in-home survey of a nationally representative sample of adolescents., Sample: Analyses involved 2,058 sexually active young adult women., Main Outcome Measures: HIV risk was measured by consistent condom use over the past 12 months., Results: Physical and verbal abuse experienced in adolescence were associated with physical/verbal abuse experienced in young adulthood. Young, sexually active women experiencing no abuse in their relationships were more likely to consistently use condoms in the past 12 months than were their abused counterparts., Conclusion: A causal pathway may exist between prior abuse, current abuse, and HIV risk.