by
Pauli N. Amornkul;
Etienne Karita;
Anatoli Kamali;
Wasima N. Rida;
Eduard J. Sanders;
Shabir Lakhi;
Matt A. Price;
William Kilembe;
Emmanuel Cormier;
Omu Anzala;
Mary H. Latka;
Linda-Gail Bekker;
Susan Allen;
Jill Gilmour;
Patricia E. Fast
Objective: To describe immunologic, virologic, and clinical HIV disease progression by HIV-1 subtype among Africans with well documented estimated dates of HIV infection (EDIs). Design: Prospective cohort. Methods: Adults and youth with documented HIV-1 infection in the past 12 months were recruited from seroincidence cohorts in East and Southern Africa and followed at 3-6 month intervals. Blood for lymphocyte subset and viral load determination was collected at each visit. Pol was sequenced from the first positive specimen to ascertain subtype. Preantiretroviral therapy disease progression was measured by three time-toevent endpoints: CD4 + cell count 350 cells/ml or less, viral load measurement at least 1*105 copies/ml, and clinical AIDS. Results: From 2006 to 2011, 615 participants were enrolled at nine research centers in Kenya, Rwanda, South Africa, Uganda, and Zambia; 579 (94.1%) had viral subtyping completed. Predominant subtypes were C (256, 44.2%), A (209, 36.1%), and D (84, 14.5%). After adjustment for age, sex, and human leukocyte antigen alleles in Cox regression analyses, subtype C-infected participants progressed faster than subtype A to all three endpoints [CD4 + hazard ratio 1.60, 95% (confidence interval) CI 1.16, 2.20; viral load hazard ratio 1.59, 95% CI 1.12, 2.25; and AIDS hazard ratio 1.60, 95% CI 1.11, 2.31). Subtype D-infected participants reached high viral load more rapidly (hazard ratio 1.61, 95% CI 1.01, 2.57) and progressed nearly twice as fast to AIDS compared to subtype A (hazard ratio 1.93, 95% CI 1.21, 3.09). Conclusion: Subtype-specific differences in HIV disease progression suggest that the local subtype distribution be considered when planning HIV programs and designing and defining clinical endpoints for HIV prevention trials.
by
Matthew Triplette;
Amy Justice;
Engi F. Attia;
Janet Tate;
Sheldon T. Brown;
Matthew Bidwell Goetz;
Joon W. Kim;
Maria C. Rodriguez-Barradas;
Guy W. Soo Hoo;
Cherry Wongtrakool;
Kathleen Akgun;
Kristina Crothers
Objective: Aging people living with HIV (PLWH) face an increased burden of comorbidities, including chronic obstructive pulmonary disease (COPD). The impact of COPD on mortality in HIV remains unclear. We examined associations between markers of COPD and mortality among PLWH and uninfected study participants. Design: Longitudinal analysis of the Examinations of HIV-Associated Lung Emphysema (EXHALE) cohort study. Methods: EXHALE includes 196 PLWH and 165 uninfected smoking-matched study participants who underwent pulmonary function testing and computed tomography (CT) to define COPD and were followed. We determined associations between markers of COPD with mortality using multivariable Cox regression models, adjusted for smoking and the Veterans Aging Cohort Study (VACS) Index, a validated predictor of mortality in HIV. Results: Median follow-up time was 6.9 years; the mortality rate was 2.7/100 person-years among PLWH and 1.7/100 person-years among uninfected study participants (P = 0.11). The VACS Index was associated with mortality in both PLWH and uninfected study participants. In multivariable models, pulmonary function and CT characteristics defining COPD were associated with mortality in PLWH: Those with airflow obstruction (forced expiratory volume in 1 s/ forced vital capacity <0.7) had 3.1 times the risk of death [hazard ratio 3.1 (95% confidence interval 1.4-7.1)], compared with those without; those with emphysema (>10% burden) had 2.4 times the risk of death [hazard ratio 2.4 (95% confidence interval 1.1-5.5)] compared with those with ≤ 10% emphysema. In uninfected subjects, pulmonary variables were not significantly associated with mortality, which may reflect fewer deaths limiting power. Conclusion: Markers of COPD were associated with greater mortality in PWLH, independent of the VACS Index. COPD is likely an important contributor to mortality in contemporary PLWH.
by
James E. Voss;
Matthew S. Macauley;
Kenneth A. Rogers;
Francois Villinger;
Lijie Duan;
Liang Shang;
Elizabeth A. Fink;
Raiees Andrabi;
Arnaud D. Colantonio;
James E. Robinson;
Robert Johnson;
Dennis R. Burton;
Ashley T. Haase
Vaccination with SIV mac239 δnef provides robust protection against subsequent challenge with wild-type simian immunodeficiency virus (SIV), but safety issues have precluded designing an HIV-1 vaccine based on a live-attenuated virus concept. Safe immunogens and adjuvants that could reproduce identified immune correlates of SIV mac239 δnef protection therefore offer an alternative path for development of an HIV vaccine. Here we describe SIV envelope trimeric gp41 (gp41t) immunogens based on a protective correlate of antibodies to gp41t concentrated on the path of virus entry by the neonatal Fc receptor (FcRn) in cervical vaginal epithelium. We developed a gp41t immunogen-monophosphoryl lipid A adjuvant liposomal nanoparticle for intramuscular (i.m.) immunization and a gp41t-Fc immunogen for intranasal immunization for pilot studies in mice, rabbits, and rhesus macaques. Repeated immunizations to mimic persistent antigen exposure in infection elicited gp41t antibodies in rhesus macaques that were detectable in FcRn cervical vaginal epithelium, thus recapitulating one key feature of SIV mac239 δnef vaccinated and protected animals. Although this strategy did not reproduce the system of local production of antibody in SIV mac239 δnef-vaccinated animals, passive immunization experiments supported the concept that sufficiently high levels of antibody can be concentrated by the FcRn at mucosal frontlines, thus setting the stage for assessing protection against vaginal challenge by gp41t immunization.
Objective: Higher incidence of osteopenia and osteoporosis underlie increased rates of fragility fracture in HIV infection. B cells are a major source of osteoprotegerin (OPG), an inhibitor of the key osteoclastogenic cytokine receptor activator of nuclear factor-κB ligand (RANKL). We previously showed that higher B-cell RANKL/OPG ratio contributes to HIV-induced bone loss. T-cell OPG production in humans, however, remains undefined and the contribution of T-cell OPG and RANKL to HIV-induced bone loss has not been explored. Design: We investigated T-cell OPG and RANKL production in ART-naive HIV-infected and uninfected individuals in relation to indices of bone loss in a cross-sectional study.
Methods: T-cell RANKL and OPG production was determined by intracellular staining and flow cytometry, and plasma levels of bone resorption markers were determined by ELISA.
Results: We demonstrate for the first time in-vivo human T-cell OPG production, which was significantly lower in HIV-infected individuals and was coupled with moderately higher T-cell RANKL production, resulting in a significantly higher T-cell RANKL/OPG ratio. T-cell RANKL/OPG ratio correlated significantly with BMD-derived z-scores at the hip, lumbar spine and femur neck in HIV-infected individuals with CD4+ T-cell counts at least 200 cells/μl but not in those with lower counts.
Conclusion: Our data suggest that T cells may be a physiologically relevant source of OPG and T-cell RANKL/OPG imbalance is associated with HIV-induced bone loss in CD4+ T-cell-sufficient patients. Both B and T lymphocytes may thus contribute to HIV-induced bone loss.
by
T.B. Depp;
K.A. McGinnis;
K. Kraemer;
K.M. Akguen;
E.J. Edelman;
D.A. Fiellin;
A.A. Butt;
S. Crystal;
A.J. Gordon;
M. Freiberg;
C.L. Gibert;
David Rimland;
K.J. Bryant;
K. Crothers
Objective: To determine the association between HIV infection and other risk factors for acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Design: Longitudinal, national Veterans Aging Cohort Study including 43 618 HIV-infected and 86 492 uninfected veterans. Methods: AECOPD was defined as an inpatient or outpatient COPD ICD-9 diagnosis accompanied by steroid and/or antibiotic prescription within 5 days. We calculated incidence rate ratios (IRR) and 95% confidence intervals (CI) for first AECOPD over 2 years and used Poisson regression models to adjust for risk factors. Results: Over 234 099 person-years of follow-up, 1428 HIV-infected and 2104 uninfected patients had at least one AECOPD. HIV-infected patients had an increased rate of AECOPD compared with uninfected (18.8 vs. 13.3 per 1000 person-years, P < 0.001). In adjusted models, AECOPD risk was greater in HIV-infected individuals overall (IRR 1.54; 95% CI 1.44-1.65), particularly in those with more severe immune suppression when stratified by CD4 cell count (cells/ml) compared with uninfected (HIV-infected CD4+ < 200: IRR 2.30, 95% CI 2.10-2.53, HIV-infected CD4+ ≥ 200-349: IRR 1.32, 95% CI 1.15-1.51, HIV-infected CD4+≥350: IRR 0.99, 95% CI 0.88-1.10). HIV infection also modified the association between current smoking and alcohol-related diagnoses with risk for AECOPD such that interaction terms for HIV and current smoking or HIV and alcohol-related diagnoses were each significantly associated with AECOPD. Conclusion: HIV infection, especially with lower CD4+ cell count, is an independent risk factor for AECOPD. Enhanced susceptibility to harm from current smoking or unhealthy alcohol use in HIV-infected patients may also contribute to the greater rate of AECOPD.
by
Brian Moldt;
Khoa Le;
Diane G. Carnathan;
James B Whitney;
Niccole Schultz;
Mark G. Lewis;
Erica Borducchi;
Kaitlin Smith;
Joseph J. Mackel;
Shelby L. Sweat;
Andrew P. Hodges;
Adam Godzik;
Paul W. H. I. Parren;
Guido Silvestri;
Dan H. Barouch;
Dennis R. Burton
Objective: Passive administration of broadly neutralizing antibodies has been shown to protect against both vaginal and rectal challenge in the simian/human immunodeficiency virus (SHIV)/macaque model of HIV transmission. However, the relative efficacy of antibody against the two modes of exposure is unknown and, given differences in the composition and immunology of the two tissue compartments, this is an important gap in knowledge. To investigate the significance of the challenge route for antibody-mediated protection, we performed a comparative protection study in macaques using the highly potent human monoclonal antibody, PGT126. Design: Animals were administered PGT126 at three different doses before challenged either vaginally or rectally with a single dose of SHIV SF163P3. Methods: Viral loads, PGT126 serum concentrations, and serum neutralizing titers were monitored. Results: In vaginally challenged animals, sterilizing immunity was achieved in all animals administered 10 mg/kg, in two of five animals administered 2 mg/kg and in one of five animals administered 0.4 mg/kg PGT126. Comparable protection was observed for the corresponding groups challenged rectally as sterilizing immunity was achieved in three of four animals administered 10 mg/kg, in two of four animals administered 2 mg/kg and in none of four animals administered 0.4 mg/kg PGT126. Serological analysis showed similar serum concentrations of PGT126 and serum neutralization titers in animals administered the same antibody dose. Conclusion: Our data suggest that broadly neutralizing antibody-mediated protection is not strongly dependent on the mucosal route of challenge, which indicates that a vaccine aimed to induce a neutralizing antibody response would have broadly similar efficacy against both primary transmission routes for HIV.
by
Robert A. Rasmussen;
Nagadenahalli B. Siddappa;
Samir K. Lakhashe;
Jennifer Watkins;
Francois Villinger;
Chris Ibegbu;
Ruth H. Florese;
Marjorie Robert-Guroff;
David C. Montefiori;
Donald N. Forthal;
David O'Connor;
Ruth M. Ruprecht
OBJECTIVE:: To characterize the correlates of protection from systemic infection in a vaccinated rhesus macaque, RAt-9, which had been challenged sequentially with two related clade C simian/human immunodeficiency viruses (SHIV-Cs) yet remained aviremic for more than 5 years despite indirect evidence of cryptic infection.
DESIGN:: To measure long-term anti-SHIV-C immunity, host genetics and gene-expression patterns for protective correlates. METHODS:: Long-term immune reactivity was evaluated and identification of virus in RAt-9 was attempted by RT-PCR analysis of concentrated plasma and blood transfer to CD8 cell-depleted infant macaques. Full MHC genotyping of RAt-9, TRIM5α and KIR3DL allelic expression analysis of PBMC, and microarray gene expression analysis were performed.
RESULTS:: All attempts to detect/isolate virus, including blood transfer to CD8 cell-depleted infant rhesus macaques, were negative, and the animal maintained normal levels of memory CD4 T cells in both peripheral blood and gut tissues. However, RAt-9 maintained high levels of anti-SHIV-C humoral and cellular immunity, including reactivity to nonvaccine neoantigens (Nef and Rev), up to 63 months postinitial challenge, suggesting chronic sub-threshold infection. RAt-9 expressed the Mamu A*001 allele negative for B*008 and B*017, had a B13 serotype, and had increased expression of killer-cell immunoglobulin-like receptors (KIRs) previously linked to favorable outcomes of lentiviral infection. Elements of the gene expression profiling coincided with genotyping results. RAt-9 also displayed CD8 cell noncytotoxic antiviral response (CNAR) activity. CONCLUSION:: Monkey RAt-9 is the first example of a virus-exposed, persistently aviremic animal that has maintained long-term, high-level cellular and humoral antiviral immunity in the absence of an identifiable cryptic reservoir.
Objective: Antiretroviral therapy (ART) paradoxically intensifies bone loss in the setting of HIV-infection. Although the extent of bone loss varies, it occurs with virtually all ART types, suggesting a common pathway that may be aligned with HIV disease reversal. Using an animal model of immunodeficiency we recently demonstrated that immune activation associated with CD4+ T cell reconstitution induces increased production of the osteoclastogenic cytokines RANKL and TNFα by immune cells, driving enhanced bone resorption and loss in bone mineral density.
Design: To confirm these findings in humans, we investigated the early kinetics of CD4+ T cell recovery in relation to biomarkers of bone turnover and osteoclastogenic regulators in a prospective 24-week cohort study.
Methods: Clinical data and blood sampling for HIV-RNA PCR, CD 4+ T cell counts, bone turnover biomarkers, and osteoclastogenic regulators were obtained from ART-naïve HIV-infected subjects initiating standard doses of lopinavir/ritonavir plus tenofovir disoproxil fumarate/emtricitabine at baseline and at weeks 2, 8, 12, and 24 post ART.
Results: C-terminal telopeptide of collagen (CTx) a sensitive biomarker of bone resorption rose by 200% above baseline at week 12, remaining elevated through week 24 (α<0.01), and was associated with significant increases in plasma levels of osteoclastogenic regulators (RANKL and TNFα). Importantly, the magnitude of CD4+ T cell recovery correlated significantly with CTx (Rs=0.387, α=0.01).
Conclusions: Our data suggest that ART-induced bone loss occurs early, is aligned with early events of immune reconstitution, and these immune changes provide a unifying mechanism to explain the skeletal decline common to all ART.
by
Margaret T. May;
Michael J. Gill;
Linda Wittkop;
Marina Klein;
Caroline Sabin;
P. Richard Harrigan;
David Dunn;
Jorg Janne Vehreschild;
Rafael Rubio;
Amanda Mocroft;
Matthias Cavassini;
Peter Reiss;
Antonella D'Arminio Monforte;
Robert Zangerle;
Suzanne M. Ingle;
Teresa Hill;
Sophie Jose;
Jonathan A.C. Sterne;
Jodie L. Guest
OBJECTIVES: To estimate prognosis by viral subtype in HIV-1-infected individuals from start of antiretroviral therapy (ART) and after viral failure. DESIGN: Collaborative analysis of data from eight European and three Canadian cohorts. METHODS: Adults (N>20 000) who started triple ART between 1996 and 2012 and had data on viral subtype were followed for mortality. We estimated crude and adjusted (for age, sex, regimen, CD4 cell count, and AIDS at baseline, period of starting ART, stratified by cohort, region of origin and risk group) mortality hazard ratios (MHR) by subtype. We estimated MHR subsequent to viral failure defined as two HIV-RNA measurements greater than 500 copies/ml after achieving viral suppression. RESULTS: The most prevalent subtypes were B (15 419; 74%), C (2091; 10%), CRF02AG (1057; 5%), A (873; 4%), CRF01AE (506; 2.4%), G (359; 1.7%), and D (232; 1.1%). Subtypes were strongly patterned by region of origin and risk group. During 104 649 person-years of observation, 1172/20 784 patients died. Compared with subtype B, mortality was higher for subtype A, but similar for all other subtypes. MHR for A versus B were 1.13 (95% confidence interval 0.85,1.50) when stratified by cohort, increased to 1.78 (1.27,2.51) on stratification by region and risk, and attenuated to 1.59 (1.14,2.23) on adjustment for covariates. MHR for A versus B was 2.65 (1.64,4.28) and 0.95 (0.57,1.57) for patients who started ART with CD4 cell count below, or more than, 100 cells/μl, respectively. There was no difference in mortality between subtypes A, B and C after viral failure. CONCLUSION: Patients with subtype A had worse prognosis, an observation which may be confounded by socio-demographic factors.
OBJECTIVE:: Antiretroviral therapy (ART) has been implicated in bone loss in HIV. The role of inflammation and vitamin D is unclear and better investigated in ART-naive individuals. DESIGN AND METHODS:: This is a 48-week, prospective cohort study to compare baseline and change in hip and spine bone mineral density (BMD) measured by dual-energy X-ray absorptiometry in HIV-infected, ART-naive adults and healthy controls matched by age, sex, and race. We also studied associations between bone loss and inflammation markers and plasma 25-hydroxyvitamin D [25(OH)D] using logistic regression. RESULTS:: Forty-seven HIV-infected adults and 41 controls were included. Baseline 25(OH)D, BMD at total hip, trochanter, and spine, and prevalence of osteopenia and osteoporosis were similar between groups. In the HIV-infected group, total hip and trochanter, but not spine, BMD decreased over 48 weeks [hip-0.005 (-0.026-0.008) g/cm, P=0.02 within group; trochanter-0.013 (-0.03-0.003), P<0.01]. BMD did not change at any site within controls. The HIV-infected group was more likely to have bone loss at the trochanter (P=0.03). This risk persisted after adjustment for age, sex, race, BMI, smoking, and hepatitis C (odds ratio 4, 95% confidence interval 1.2-15.8). In the HIV-infected group, higher interleukin-6 concentrations (P=0.04) and Caucasian race (P<0.01) were independently associated with progression to osteopenia or osteoporosis, but not 25(OH)D levels. CONCLUSION:: BMD at the total hip and trochanter sites decreased in the HIV-infected, ART-naive adults, but not controls, over this 48-week study. Higher serum interleukin-6 concentrations were associated with progression to osteopenia or osteoporosis status in the HIV-infected group.