Publications by authors named "Merlin L Robb"

286 Publications

Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine.

N Engl J Med 2021 Sep 29. Epub 2021 Sep 29.

From the University of Rochester School of Medicine and Dentistry (A.R.F., M.C.K.) and Rochester Regional Health (A.R.F.), Rochester, and Vagelos College of Physicians and Surgeons, New York Presbyterian Columbia University Irving Medical Center, Department of Medicine, Division of Infectious Diseases (M.E.S.) and the New York University Vaccine Center (M.J.M.), New York - all in New York; Biometrics (I.H.) and Infectious Diseases (J.A.G.), Late-Stage Development, Respiratory and Immunology (R.P.M.), Biopharmaceuticals Research and Development (M.N.P.), AstraZeneca, Cambridge, United Kingdom; Biometrics (S.S., K.S.) and Infectious Diseases, Late-Stage Development, Respiratory and Immunology (J.M., T. Takas, T.V., A.G.-L.), Translational Medicine, Microbial Sciences, Biopharmaceuticals Research and Development (E.J.K.), and Clinical Development, Early Global Development, Oncology Research and Development (N.M.), AstraZeneca, Gaithersburg, the Walter Reed Army Institute of Research, Silver Spring (M.L.R.), the University of Maryland School of Medicine (K.M.N.) and the Johns Hopkins Bloomberg School of Public Health (A.D.), Baltimore, the Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense, Edgewood (J.C.), and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda (T. Tong, M.B.I., M.C.N.) - all in Maryland; the University of Washington (L.C., W.H.) and the Fred Hutchinson Cancer Research Center (L.C., W.H., J.H., H.E.J.), Seattle; HealthPartners Institute, St. Paul, MN (C.M.); Orlando Immunology Center, Orlando (E.D.), and JEM Headlands Research, Lake Worth Beach (L.B.) - both in Florida; Hassman Research Institute, Berlin, NJ (M.H.); the University of California San Diego, La Jolla (S.J.L.), the Lundquist Institute at Harbor-UCLA Medical Center, Torrance (E.S.D.), and the San Francisco Department of Public Health, San Francisco (S.B.) - all in California; Children's Mercy Kansas City, Kansas City, MO (B.A.P.); Tekton Research, Austin (P.P.), and Centex Studies, McAllen (J.S.) - both in Texas; Medpharmics, Albuquerque, NM (Q.O.C.); John H. Stroger, Jr. Hospital of Cook County, Chicago (T.O.); Instituto de Ciencias Biomédicas, Facultad de Medicina Universidad de Chile, Santiago, Chile (S.L.V.); Clínica Internacional Sede Lima, Lima, Peru (A.G.B.); Clinical Research Partners, Richmond, VA (R.C.); the University of Vermont Larner College of Medicine and UVM Medical Center, Burlington (B.D.K.); Mercury Street Medical Group, Butte, MT (J.P.); and the Rollins School of Public Health at Emory University, Atlanta (D.B.).

Background: The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known.

Methods: In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru.

Results: A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose.

Conclusions: AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).
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http://dx.doi.org/10.1056/NEJMoa2105290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522798PMC
September 2021

The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination.

Nat Immunol 2021 10 23;22(10):1294-1305. Epub 2021 Sep 23.

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4 T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC + Alum, those immunized with ALVAC + MF59, the regimen in the HVTN702 trial that showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants that trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.
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http://dx.doi.org/10.1038/s41590-021-01026-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525330PMC
October 2021

RV144 vaccine imprinting constrained HIV-1 evolution following breakthrough infection.

Virus Evol 2021 9;7(2):veab057. Epub 2021 Jul 9.

US Military HIV Research Program, WRAIR, Silver Spring, MD 20910, USA.

The scale of the HIV-1 epidemic underscores the need for a vaccine. The multitude of circulating HIV-1 strains together with HIV-1's high evolvability hints that HIV-1 could adapt to a future vaccine. Here, we wanted to investigate the effect of vaccination on the evolution of the virus post-breakthrough infection. We analyzed 2,635 HIV-1 sequences sampled up to a year post-diagnosis from 110 vaccine and placebo participants who became infected in the RV144 vaccine efficacy trial. We showed that the Env signature sites that were previously identified to distinguish vaccine and placebo participants were maintained over time. In addition, fewer sites were under diversifying selection in the vaccine group than in the placebo group. These results indicate that HIV-1 would possibly adapt to a vaccine upon its roll-out.
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http://dx.doi.org/10.1093/ve/veab057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438874PMC
July 2021

Risk Factors for HIV sero-conversion in a high incidence cohort of men who have sex with men and transgender women in Bangkok, Thailand.

EClinicalMedicine 2021 Aug 17;38:101033. Epub 2021 Jul 17.

US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States.

Background: We measured Human Immunodeficiency (HIV) incidence, retention, and assessed risk factors for seroconversion among two previously unreported cohorts of men who have sex with men (MSM) and Transgender Women (TGW) in Bangkok, Thailand between 2017 and 2019.

Methods: We conducted an 18-month prospective cohort study of HIV-uninfected Thai cisgender men and TGW aged between 18 and 35 years who reported sex with men in the past six months and at least one additional risk factor for HIV infection. HIV and syphilis testing and computer-based behavioral questionnaires were administered at each visit. We utilized Poisson regression to calculate HIV incidence rates. A survival random forest model identified the most predictive risk factors for HIV sero-conversion and then used in a survival regression tree model to elucidate hazard ratios for individuals with groups of selected risk factors. Cox proportional hazards (pH) regression evaluated the strength of association between individual covariates and risk of sero-conversion.

Findings: From April 2017-October 2019, 1,184 participants were screened, 167 were found ineligible, and 1,017 enrolled. Over the 18-month study, visit retention was 93·4% (95% CI 91·6%-94·8%) and HIV incidence was 3·73 per 100 person-years (95% CI 2·79-5·87). Utilizing survival regression tree modeling, those who were 18-20 years of age, reported sexual attraction to mostly or only men, and had five or more lifetime sexual partners were 4·9 times more likely to seroconvert compared to other cohort participants. Factors associated with HIV incidence utilizing Cox pH regression included sexual attraction to mostly or only men (adjusted hazard ratio (aHR) 14·9 (95% CI 20·1-107·9), younger age (18-19 years, aHR 10·88 (95% CI 4·12-28·7), five or greater lifetime sexual partners (aHR 2·0, 95%CI 1·1-3·6), inconsistent condom use with casual partners (aHR 2·43, 95% CI 1·3-4·5), and prior HIV testing (adjusted HR 2·0, 95% CI 1·1-3·5).

Interpretation: Interpretation HIV incidence remains high among Bangkok-based MSM and TGW. These key populations expressed high interest in participating in efficacy evaluation of future prevention strategies and had high retention in this 18 month study.

Funding: Funding US National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS Interagency Agreements (DAIDS) and U.S. Department of the Army.
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http://dx.doi.org/10.1016/j.eclinm.2021.101033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413240PMC
August 2021

Factors associated with testing for HIV and hepatitis C among behaviorally vulnerable men in Germany: a cross-sectional analysis upon enrollment into an observational cohort.

AIDS Res Ther 2021 08 16;18(1):52. Epub 2021 Aug 16.

Institute of Virology, Medical Faculty, University Bonn, Bonn, Germany.

Background: HIV and hepatitis C virus (HCV) have shared routes of transmission among men who have sex with men (MSM). Routine testing facilitates early diagnosis and treatment, thereby preventing morbidity and onward transmission. We evaluated factors associated with HIV and HCV testing in a behaviorally vulnerable cohort of predominantly MSM.

Methods: From June 2018 through June 2019, the BRAHMS study enrolled adults at ten German outpatient clinics that serve gender and sexual minority populations. Participants completed behavioral questionnaires that captured prior experience with HIV and HCV testing. Multivariable robust Poisson regression was used to evaluate factors potentially associated with testing in the previous 6 months.

Results: Among 1017 participants with median age 33 (interquartile range 28-39) years, 1001 (98.4%) reported any lifetime history of HIV testing and 787 (77.4%) reported any HCV testing, including 16 (1.6%) known to be living with HCV. Testing within the last 6 months was reported by 921 (90.6%) and 513 (50.4%) for HIV and HCV, respectively. Recent HIV testing was more common among participants with higher education level and recent HCV testing. Recent HCV testing was more common among participants with non-cisgender identity, lifetime history of illicit drug use, hepatitis B immunity or infection, and recent HIV testing.

Conclusion: Prior testing for HIV was common in this cohort, but interventions are needed to improve HCV risk stratification and access to testing. HIV testing infrastructure can be successfully leveraged to support HCV testing, but differentiated preventive care delivery is needed for some vulnerable populations.
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http://dx.doi.org/10.1186/s12981-021-00378-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365908PMC
August 2021

Hepatitis B virus infection among men who have sex with men and transgender women living with or at risk for HIV: a cross sectional study in Abuja and Lagos, Nigeria.

BMC Infect Dis 2021 Jul 6;21(1):654. Epub 2021 Jul 6.

Department of Epidemiology and Public Health, University of Maryland, School of Medicine, Baltimore, MD, USA.

Background: Despite the development of a safe and efficacious hepatitis B vaccine in 1982, the hepatitis B virus (HBV) remains a public health burden in sub-Saharan Africa. Due to shared risk factors for virus acquisition, men who have sex with men (MSM) and transgender women (TGW) living with HIV are at increased risk of HBV. We estimated the prevalence of HBV and associated factors for MSM and TGW living with or without HIV in Nigeria.

Methods: Since March 2013, TRUST/RV368 has recruited MSM and TGW in Abuja and Lagos, Nigeria using respondent driven sampling. Participants with HIV diagnosis, enrollment as of June 2015, and available plasma were selected for a cross-sectional study and retrospectively tested for hepatitis B surface antigen and HBV DNA. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with prevalent HBV infection.

Results: A total of 717 MSM and TGW had a median age of 25 years (interquartile range [IQR]: 21-27), 5% self-reported HBV vaccination, 61% were living with HIV, 10% had prevalent HBV infection and 6% were HIV-HBV co-infected. HIV mono-infected as compared to HIV-HBV co-infected had a higher median CD4 T cell count [425 (IQR: 284-541) vs. 345 (IQR: 164-363) cells/mm, p = 0.03] and a lower median HIV RNA viral load [4.2 (IQR: 2.3-4.9) vs. 4.7 (IQR: 3.9-5.4) logcopies/mL, p < 0.01]. The only factor independently associated with HBV was self-report of condomless sex at last anal intercourse (OR: 2.2, 95% CI: 1.3, 3.6). HIV infection was not independently associated with HBV (OR: 1.0, 95% CI: 0.7-1.6).

Conclusion: HBV prevalence was moderately high but did not differ by HIV in this cohort of MSM and TGW. Recent condomless sex was associated with elevated HBV risk, reinforcing the need to increase communication and education on condom use among key populations in Nigeria. Evaluating use of concurrent HIV antiretroviral therapy with anti-HBV activity may confirm the attenuated HBV prevalence for those living with HIV.
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http://dx.doi.org/10.1186/s12879-021-06368-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259010PMC
July 2021

Timing HIV infection with a simple and accurate population viral dynamics model.

J R Soc Interface 2021 06 30;18(179):20210314. Epub 2021 Jun 30.

Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Clinical trials for HIV prevention can require knowledge of infection times to subsequently determine protective drug levels. Yet, infection timing is difficult when study visits are sparse. Using population nonlinear mixed-effects (pNLME) statistical inference and viral loads from 46 RV217 study participants, we developed a relatively simple HIV primary infection model that achieved an excellent fit to all data. We also discovered that Aptima assay values from the study strongly correlated with viral loads, enabling imputation of very early viral loads for 28/46 participants. Estimated times between infecting exposures and first positives were generally longer than prior estimates (average of two weeks) and were robust to missing viral upslope data. On simulated data, we found that tighter sampling before diagnosis improved estimation more than tighter sampling after diagnosis. Sampling weekly before and monthly after diagnosis was a pragmatic design for good timing accuracy. Our pNLME timing approach is widely applicable to other infections with existing mathematical models. The present model could be used to simulate future HIV trials and may help estimate protective thresholds from the recently completed antibody-mediated prevention trials.
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http://dx.doi.org/10.1098/rsif.2021.0314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241492PMC
June 2021

Limited Evidence for a Relationship between HIV-1 Glycan Shield Features in Early Infection and the Development of Neutralization Breadth.

J Virol 2021 08 10;95(17):e0079721. Epub 2021 Aug 10.

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

Identifying whether viral features present in acute HIV-1 infection predetermine the development of neutralization breadth is critical to vaccine design. Incorporating such features in vaccine antigens could initiate cross-reactive antibody responses that could sufficiently protect vaccinees from HIV-1 infection despite the uniqueness of each founder virus. To understand the relationship between Env determinants and the development of neutralization breadth, we focused on 197 individuals enrolled in two cohorts in Thailand and East Africa (RV144 and RV217) and followed since their diagnosis in acute or early HIV-1 infection. We analyzed the distribution of variable loop lengths and glycans, as well as the predicted density of the glycan shield, and compared these envelope features to the neutralization breadth data obtained 3 years after infection (  = 121). Our study revealed limited evidence for glycan shield features that associate with the development of neutralization breadth. While the glycan shield tended to be denser in participants who subsequently developed breadth, no significant relationship was found between the size of glycan holes and the development of neutralization breadth. The parallel analysis of 3,000 independent Env sequences showed no evidence of directional evolution of glycan shield features since the beginning of the epidemic. Together, our results highlight that glycan shield features in acute and early HIV-1 infection may not play a role determinant enough to dictate the development of neutralization breadth and instead suggest that the glycan shield's reactive properties that are associated with immune evasion may have a greater impact. A major goal of HIV-1 vaccine research is to design vaccine candidates that elicit potent broadly neutralizing antibodies (bNAbs). Different viral features have been associated with the development of bNAbs, including the glycan shield on the surface of the HIV-1 Envelope (Env). Here, we analyzed data from two cohorts of individuals who were followed from early infection to several years after infection spanning multiple HIV-1 subtypes. We compared Env glycan features in HIV-1 sequences obtained in early infection to the potency and breadth of neutralizing antibodies measured 1 to 3 years after infection. We found limited evidence of glycan shield properties that associate with the development of neutralization breadth in these cohorts. These results may have important implications for antigen design in future vaccine strategies and emphasize that HIV-1 vaccines will need to rely on a complex set of properties to elicit neutralization breadth.
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http://dx.doi.org/10.1128/JVI.00797-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354232PMC
August 2021

Associations Between Antibody Fc-Mediated Effector Functions and Long-Term Sequelae in Ebola Virus Survivors.

Front Immunol 2021 20;12:682120. Epub 2021 May 20.

Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.

Antibodies that mediate non-neutralizing functions play an important role in the immune response to Ebola virus (EBOV) and are thought to impact disease outcome. EBOV has also been associated with long term sequelae in survivors, however, the extent to which antibodies that mediate non-neutralizing functions are associated with the development of these sequelae is unknown. Here, the presence of antibodies mediating different effector functions and how they relate to long-term sequelae two years after the 2007 Bundibugyo Ebola virus (BDBV) outbreak was investigated. The majority of survivors demonstrated robust antibody effector functional activity and demonstrated persistent polyfunctional antibody profiles to the EBOV glycoprotein (GP) two years after infection. These functions were strongly associated with the levels of GP-specific IgG1. The odds of developing hearing loss, one of the more common sequelae to BDBV was reduced when antibodies mediating antibody dependent cellular phagocytosis (ADCP), antibody dependent complement deposition (ADCD), or activating NK cells (ADNKA) were observed. In addition, hearing loss was associated with increased levels of several pro-inflammatory cytokines and levels of these pro-inflammatory cytokines were associated with lower ADCP. These results are indicating that a skewed antibody profile and persistent inflammation may contribute to long term outcome in survivors of BDBV infection.
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http://dx.doi.org/10.3389/fimmu.2021.682120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173169PMC
May 2021

Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19.

N Engl J Med 2021 06 21;384(23):2187-2201. Epub 2021 Apr 21.

From Janssen Vaccines and Prevention, Leiden, the Netherlands (J. Sadoff, G. Shukarev, G. Scheper, M.L.G., H.S., J.V.H., M.D.); South African Research Council, Cape Town, South Africa (G.G.); Janssen Research and Development, Beerse, Belgium (A.V., C.T., H.F., B.S., K.O., M.F.R., N.C., T.T., K.H., J.R.G., F.S.); Janssen Research and Development, Spring House, PA (V.C.); Evandro Chagas National Institute of Infectious Diseases-Fiocruz, Rio de Janeiro (B.G.); the University of Alabama at Birmingham, Birmingham (P.A.G.); the National Institute of Allergy and Infectious Diseases, Rockville (K.L.T., M.A.M.), Walter Reed Army Institute of Research, Silver Spring (M.L.R.), and the Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore (K.M.N.) - all in Maryland; Biomedical Advanced Research and Development Authority, Washington, DC (J.T.); the Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston (D.H.B.); Janssen Research and Development, Raritan, NJ (J. Stoddard); and Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle (L.C.).

Background: The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a prefusion-stabilized conformation.

Methods: In an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×10 viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe-critical coronavirus disease 2019 (Covid-19) with an onset at least 14 days and at least 28 days after administration among participants in the per-protocol population who had tested negative for SARS-CoV-2. Safety was also assessed.

Results: The per-protocol population included 19,630 SARS-CoV-2-negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe-critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval [CI], 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe-critical Covid-19 (76.7% [adjusted 95% CI, 54.6 to 89.1] for onset at ≥14 days and 85.4% [adjusted 95% CI, 54.2 to 96.9] for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe-critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe-critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19-related), and 16 in the placebo group (5 were Covid-19-related).

Conclusions: A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe-critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722.).
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http://dx.doi.org/10.1056/NEJMoa2101544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220996PMC
June 2021

Clinical laboratory reference values in adults in Kisumu County, Western Kenya; hematology, chemistry and CD4.

PLoS One 2021 30;16(3):e0249259. Epub 2021 Mar 30.

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States of America.

Background: Clinical laboratory reference intervals (RIs) are essential for diagnosing and managing patients in routine clinical care as well as establishing eligibility criteria and defining adverse events in clinical trials, but may vary by age, gender, genetics, nutrition and geographic location. It is, therefore, critical to establish region-specific reference values in order to inform clinical decision-making.

Methods: We analyzed data from a prospective observational HIV incidence cohort study in Kombewa, Kenya. Study participants were healthy males and females, aged 18-35 years, without HIV. Median and 95% reference values (2.5th percentile to 97.5th percentile) were calculated for laboratory parameters including hematology, chemistry studies, and CD4 T cell count. Standard Deviation Ratios (SDR) and Bias Ratios (BR) are presented as measures of effect magnitude. Findings were compared with those from the United States and other Kenyan studies.

Results: A total of 299 participants were analyzed with a median age of 24 years (interquartile range: 21-28). Ratio of males to females was 0.9:1. Hemoglobin range (2.5th-97.5th percentiles) was 12.0-17.9 g/dL and 9.5-15.3 g/dL in men and women respectively. In the cohort, MCV range was 59-95fL, WBC 3.7-9.2×103/μL, and platelet 154-401×103/μL. Chemistry values were higher in males; the creatinine RI was 59-103 μmol/L in males vs. 46-76 μmol/L in females (BRUL>.3); and the alanine transferase range was 8.8-45.3 U/L in males vs. 7.5-36.8 U/L in females (SDR>.3). The overall CD4 T cell count RI was 491-1381 cells/μL. Some parameters including hemoglobin, neutrophil, creatinine and ALT varied with that from prior studies in Kenya and the US.

Conclusion: This study not only provides clinical reference intervals for a population in Kisumu County but also highlights the variations in comparable settings, accentuating the requirement for region-specific reference values to improve patient care, scientific validity, and quality of clinical trials in Africa.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249259PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009432PMC
October 2021

Multi-omics analyses reveal that HIV-1 alters CD4 T cell immunometabolism to fuel virus replication.

Nat Immunol 2021 04 25;22(4):423-433. Epub 2021 Mar 25.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Individuals infected with human immunodeficiency virus type-1 (HIV-1) show metabolic alterations of CD4 T cells through unclear mechanisms with undefined consequences. We analyzed the transcriptome of CD4 T cells from patients with HIV-1 and revealed that the elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the US Food and Drug Administration-approved drug metformin, which targets mitochondrial respiratory chain complex-I, suppresses HIV-1 replication in human CD4 T cells and humanized mice. In patients, HIV-1 peak viremia positively correlates with the expression of NLRX1, a mitochondrial innate immune receptor. Quantitative proteomics and metabolic analyses reveal that NLRX1 enhances OXPHOS and glycolysis during HIV-1-infection of CD4 T cells to promote viral replication. At the mechanistic level, HIV infection induces the association of NLRX1 with the mitochondrial protein FASTKD5 to promote expression of mitochondrial respiratory complex components. This study uncovers the OXPHOS pathway in CD4 T cells as a target for HIV-1 therapy.
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http://dx.doi.org/10.1038/s41590-021-00898-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087183PMC
April 2021

Dynamics of Human Immunodeficiency Virus-1 Genetic Diversification During Acute Infection.

Open Forum Infect Dis 2020 Oct 12;7(10):ofaa429. Epub 2020 Sep 12.

US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

We analyzed human immunodeficiency virus envelope diversity in 98 acute infections. The within-host genetic diversity, divergence from transmitted/founder (T/F) strain, and the observed frequency of multiple T/F infections increased with Fiebig stage. These data identify rapid viral dynamics during acute infection with implications for clinical trials conducted in this setting.
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http://dx.doi.org/10.1093/ofid/ofaa429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958800PMC
October 2020

B cell engagement with HIV-1 founder virus envelope predicts development of broadly neutralizing antibodies.

Cell Host Microbe 2021 04 3;29(4):564-578.e9. Epub 2021 Mar 3.

U.S. Military HIV Research Program, Center of Infectious Disease Research, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, USA. Electronic address:

Determining which immunological mechanisms contribute to the development of broad neutralizing antibodies (bNAbs) during HIV-1 infection is a major goal to inform vaccine design. Using samples from a longitudinal HIV-1 acute infection cohort, we found key B cell determinants within the first 14-43 days of viremia that predict the development of bNAbs years later. Individuals who develop neutralization breadth had significantly higher B cell engagement with the autologous founder HIV envelope (Env) within 1 month of initial viremia. A higher frequency of founder-Env-specific naive B cells was associated with increased B cell activation and differentiation and predictive of bNAb development. These data demonstrate that the initial B cell interaction with the founder HIV Env is important for the development of broadly neutralizing antibodies and provide evidence that events within HIV acute infection lead to downstream functional outcomes.
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http://dx.doi.org/10.1016/j.chom.2021.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245051PMC
April 2021

TLR7 agonist, N6-LS and PGT121 delayed viral rebound in SHIV-infected macaques after antiretroviral therapy interruption.

PLoS Pathog 2021 02 18;17(2):e1009339. Epub 2021 Feb 18.

Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

Toll-like receptor 7 (TLR7) agonist and PGT121 (broadly neutralizing antibody, bnAb) administration previously delayed viral rebound and induced SHIV remission. We evaluated the impact of GS-986 (TLR7 agonist) and dual bnAbs on viral rebound after antiretroviral therapy (ART) interruption. Rhesus macaques inoculated with SHIV-1157ipd3N4 were initiated on daily suppressive ART from Day 14 post SHIV inoculation. Active arm animals (n = 8) received GS-986, N6-LS and PGT121 after plasma viral suppression, starting from week 14. GS-986 induced immune activation and SHIV-specific T cell responses but not viral expression in all the active arm animals. After ART interruption, median time to viral rebound was 6 weeks in the active and 3 weeks in the control arm (p = 0.024). In this animal model, the administration of the combination of GS-986 and dual bnAbs was associated with a modest delay in viral rebound. This strategy should be further evaluated to better understand the underlying mechanisms for the induction of virus-specific immune responses and delay in viral rebound.
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http://dx.doi.org/10.1371/journal.ppat.1009339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924766PMC
February 2021

Factors influencing estimates of HIV-1 infection timing using BEAST.

PLoS Comput Biol 2021 02 1;17(2):e1008537. Epub 2021 Feb 1.

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.

While large datasets of HIV-1 sequences are increasingly being generated, many studies rely on a single gene or fragment of the genome and few comparative studies across genes have been done. We performed genome-based and gene-specific Bayesian phylogenetic analyses to investigate how certain factors impact estimates of the infection dates in an acute HIV-1 infection cohort, RV217. In this cohort, HIV-1 diagnosis corresponded to the first RNA positive test and occurred a median of four days after the last negative test, allowing us to compare timing estimates using BEAST to a narrow window of infection. We analyzed HIV-1 sequences sampled one week, one month and six months after HIV-1 diagnosis in 39 individuals. We found that shared diversity and temporal signal was limited in acute infection, and insufficient to allow timing inferences in the shortest HIV-1 genes, thus dated phylogenies were primarily analyzed for env, gag, pol and near full-length genomes. There was no one best-fitting model across participants and genes, though relaxed molecular clocks (73% of best-fitting models) and the Bayesian skyline (49%) tended to be favored. For infections with single founders, the infection date was estimated to be around one week pre-diagnosis for env (IQR: 3-9 days) and gag (IQR: 5-9 days), whilst the genome placed it at a median of 10 days (IQR: 4-19). Multiply-founded infections proved problematic to date. Our ability to compare timing inferences to precise estimates of HIV-1 infection (within a week) highlights that molecular dating methods can be applied to within-host datasets from early infection. Nonetheless, our results also suggest caution when using uniform clock and population models or short genes with limited information content.
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http://dx.doi.org/10.1371/journal.pcbi.1008537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877758PMC
February 2021

Longitudinal Analysis of Peripheral and Colonic CD161 CD4 T Cell Dysfunction in Acute HIV-1 Infection and Effects of Early Treatment Initiation.

Viruses 2020 12 11;12(12). Epub 2020 Dec 11.

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.

CD161 expression on CD4 T cells is associated with a Th17 functional phenotype, as well as with an innate capacity to respond to interleukin (IL)-12 and IL-18 without T cell receptor (TCR) stimulation. Chronic HIV-1 infection is associated with loss of the CD161 CD4 T cell population, and non-human primate studies suggest that their depletion is associated with disease progression. However, the dynamics of the CD161 CD4 T cell population during acute HIV-1 infection remains unknown. In this study, we characterize peripheral blood CD161 CD4 T cells in detail, and examine how they are affected during the earliest stages of HIV-1 infection. Unbiased surface proteome screening and principal component analysis indicated that CD161 CD4 T cells are relatively phenotypically homogeneous between donors, and are intermediates between conventional CD4 T cells and innate-like T cells. In acute untreated HIV-1 infection, the circulating CD161 CD4 T cell population decreased in frequency, as did absolute cell counts starting from peak viral load, with elevated levels of activation and exhaustion markers expressed throughout acute HIV-1 infection. The capacity of these cells to respond to stimulation with IL-12 and IL-18 was also reduced. Early initiation of anti-retroviral treatment (ART) during acute HIV-1 infection restored the functionality of peripheral blood CD161 CD4 T cells, but not their frequency. In contrast, early ART initiation prevented the decline of colonic CD161 CD4 T cells that otherwise started during acute infection. Furthermore, loss of peripheral and colonic CD161 CD4 T cells in untreated infection was associated with levels of viral load. These results suggest that acute HIV-1 infection has profound effects on the CD161 CD4 T cell population that could not be completely prevented by the initiation of ART.
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http://dx.doi.org/10.3390/v12121426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764746PMC
December 2020

RV144 HIV-1 vaccination impacts post-infection antibody responses.

PLoS Pathog 2020 12 8;16(12):e1009101. Epub 2020 Dec 8.

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.

The RV144 vaccine efficacy clinical trial showed a reduction in HIV-1 infections by 31%. Vaccine efficacy was associated with stronger binding antibody responses to the HIV Envelope (Env) V1V2 region, with decreased efficacy as responses wane. High levels of Ab-dependent cellular cytotoxicity (ADCC) together with low plasma levels of Env-specific IgA also correlated with decreased infection risk. We investigated whether B cell priming from RV144 vaccination impacted functional antibody responses to HIV-1 following infection. Antibody responses were assessed in 37 vaccine and 63 placebo recipients at 6, 12, and 36 months following HIV diagnosis. The magnitude, specificity, dynamics, subclass recognition and distribution of the binding antibody response following infection were different in RV144 vaccine recipients compared to placebo recipients. Vaccine recipients demonstrated increased IgG1 binding specifically to V1V2, as well as increased IgG2 and IgG4 but decreased IgG3 to HIV-1 Env. No difference in IgA binding to HIV-1 Env was detected between the vaccine and placebo recipients following infection. RV144 vaccination limited the development of broadly neutralizing antibodies post-infection, but enhanced Fc-mediated effector functions indicating B cell priming by RV144 vaccination impacted downstream antibody function. However, these functional responses were not associated with clinical markers of disease progression. These data reveal that RV144 vaccination primed B cells towards specific binding and functional antibody responses following HIV-1 infection.
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http://dx.doi.org/10.1371/journal.ppat.1009101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748270PMC
December 2020

A randomized trial of vorinostat with treatment interruption after initiating antiretroviral therapy during acute HIV-1 infection.

J Virus Erad 2020 Sep 18;6(3):100004. Epub 2020 Jul 18.

SEARCH, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Objective And Design: A randomized, open-label pilot study in individuals treated with antiretroviral therapy (ART) since acute HIV infection (AHI) with a regimen including a histone deacetylase inhibitor to induce HIV from latency and control HIV replication during subsequent treatment interruption (TI).

Methods: Fifteen participants who initiated ART at AHI were randomized to vorinostat/hydroxychloroquine/maraviroc (VHM) plus ART (n ​= ​10) or ART alone (n ​= ​5). The VHM arm received three 14-day vorinostat cycles within 10 weeks before TI. ART was resumed for plasma viral load (VL) ​> ​1,000 HIV RNA copies/mL. Primary outcome was proportion of participants on VHM ​+ ​ART versus ART only with VL ​< ​50 copies/mL for 24 weeks after TI.

Results: Fifteen participants on ART (median: 178 weeks: range 79-295) enrolled. Two on VHM ​+ ​ART experienced serious adverse events. Fourteen participants underwent TI; all experienced VL rebound with no difference in time between arms: VHM ​+ ​ART (n ​= ​9) median: 4 weeks and ART only (n ​= ​5) median: 5 weeks. VHM induced a 2.2-fold increase in VL (p ​= ​0.008) by single-copy HIV RNA assay after the first cycle. Neopterin levels increased significantly following the first two cycles. After VHM treatment, the frequencies of peripheral blood mononuclear cells harboring total HIV DNA and cell-associated RNA were unchanged. All participants achieved VL suppression following ART re-initiation.

Conclusions: Administration of VHM increased HIV VL in plasma, but this was not sustained. VHM did not impact time to viral rebound following TI and had no impact on the size of the HIV reservoir, suggesting that HIV reservoir elimination will require alternative treatment strategies.
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http://dx.doi.org/10.1016/j.jve.2020.100004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646672PMC
September 2020

A randomized trial of vorinostat with treatment interruption after initiating antiretroviral therapy during acute HIV-1 infection.

J Virus Erad 2020 Sep 18;6(3):100004. Epub 2020 Jul 18.

SEARCH, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Objective And Design: A randomized, open-label pilot study in individuals treated with antiretroviral therapy (ART) since acute HIV infection (AHI) with a regimen including a histone deacetylase inhibitor to induce HIV from latency and control HIV replication during subsequent treatment interruption (TI).

Methods: Fifteen participants who initiated ART at AHI were randomized to vorinostat/hydroxychloroquine/maraviroc (VHM) plus ART (n ​= ​10) or ART alone (n ​= ​5). The VHM arm received three 14-day vorinostat cycles within 10 weeks before TI. ART was resumed for plasma viral load (VL) ​> ​1,000 HIV RNA copies/mL. Primary outcome was proportion of participants on VHM ​+ ​ART versus ART only with VL ​< ​50 copies/mL for 24 weeks after TI.

Results: Fifteen participants on ART (median: 178 weeks: range 79-295) enrolled. Two on VHM ​+ ​ART experienced serious adverse events. Fourteen participants underwent TI; all experienced VL rebound with no difference in time between arms: VHM ​+ ​ART (n ​= ​9) median: 4 weeks and ART only (n ​= ​5) median: 5 weeks. VHM induced a 2.2-fold increase in VL (p ​= ​0.008) by single-copy HIV RNA assay after the first cycle. Neopterin levels increased significantly following the first two cycles. After VHM treatment, the frequencies of peripheral blood mononuclear cells harboring total HIV DNA and cell-associated RNA were unchanged. All participants achieved VL suppression following ART re-initiation.

Conclusions: Administration of VHM increased HIV VL in plasma, but this was not sustained. VHM did not impact time to viral rebound following TI and had no impact on the size of the HIV reservoir, suggesting that HIV reservoir elimination will require alternative treatment strategies.
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http://dx.doi.org/10.1016/j.jve.2020.100004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646672PMC
September 2020

Frequent and Durable Anti-HIV Envelope VIV2 IgG Responses Induced by HIV-1 DNA Priming and HIV-MVA Boosting in Healthy Tanzanian Volunteers.

Vaccines (Basel) 2020 Nov 13;8(4). Epub 2020 Nov 13.

Department of Global Public Health, Karolinska Institutet, 17177 Stockholm, Sweden.

We evaluated antibody responses to the human immunodeficiency virus (HIV) envelope variable regions 1 and 2 (V1V2) in 29 vaccinees who had received three HIV-1 DNA immunizations and two HIV-modified vaccinia virus Ankara (MVA) boosts in the phase I/II HIVIS03 vaccine trial. Twenty vaccinees received a third HIV-MVA boost after three years in the HIVIS06 trial. IgG and IgG antibody subclasses to gp70V1V2 proteins of HIV-1 A244, CN54, Consensus C, and Case A2 were analysed using an enzyme-linked immunosorbent assay (ELISA). Cyclic V2 peptides of A244, Consensus C, and MN were used in a surface plasmon resonance (SPR) assay. Four weeks after the second HIV-MVA, anti-V1V2 IgG antibodies to A244 were detected in 97% of HIVIS03 vaccinees, in 75% three years later, and in 95% after the third HIV-MVA. Anti-CN54 V1V2 IgG was detectable in 48% four weeks after the second HIV-MVA. The SPR data supported the findings. The IgG response was predominantly IgG1. Four weeks after the second HIV-MVA, 85% of vaccinees had IgG1 antibodies to V1V2 A244, which persisted in 25% for three-years. IgG3 and IgG4 antibodies to V1V2 A244 were rare. In conclusion, the HIV-DNA/MVA vaccine regimen induced durable V1V2 IgG antibody responses in a high proportion of vaccinees.
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http://dx.doi.org/10.3390/vaccines8040681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711440PMC
November 2020

Frequent Anti-V1V2 Responses Induced by HIV-DNA Followed by HIV-MVA with or without CN54rgp140/GLA-AF in Healthy African Volunteers.

Microorganisms 2020 Nov 4;8(11). Epub 2020 Nov 4.

Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, Sweden.

Antibody responses that correlated with reduced risk of HIV acquisition in the RV144 efficacy trial were assessed in healthy African volunteers who had been primed three times with HIV-DNA (subtype A, B, C) and then randomized into two groups; group 1 was boosted twice with HIV-MVA (CRF01_AE) and group 2 with the same HIV-MVA coadministered with subtype C envelope (Env) protein (CN54rgp140/GLA-AF). The fine specificity of plasma Env-specific antibody responses was mapped after the final vaccination using linear peptide microarray technology. Binding IgG antibodies to the V1V2 loop in CRF01_AE and subtype C Env and Env-specific IgA antibodies were determined using enzyme-linked immunosorbent assay. Functional antibody-dependent cellular cytotoxicity (ADCC)-mediating antibody responses were measured using luciferase assay. Mapping of linear epitopes within HIV-1 Env demonstrated strong targeting of the V1V2, V3, and the immunodominant region in gp41 in both groups, with additional recognition of two epitopes located in the C2 and C4 regions in group 2. A high frequency of V1V2-specific binding IgG antibody responses was detected to CRF01_AE (77%) and subtype C antigens (65%). In conclusion, coadministration of CN54rgp140/GLA-AF with HIV-MVA did not increase the frequency, breadth, or magnitude of anti-V1V2 responses or ADCC-mediating antibodies induced by boosting with HIV-MVA alone.
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http://dx.doi.org/10.3390/microorganisms8111722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693996PMC
November 2020

Retention of a cohort of men who have sex with men and transgender women at risk for and living with HIV in Abuja and Lagos, Nigeria: a longitudinal analysis.

J Int AIDS Soc 2020 10;23 Suppl 6:e25592

Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.

Introduction: Men who have sex with men (MSM), and transgender women (TGW), face specific obstacles to retention in care, particularly in settings with stigmatization such as sub-Saharan Africa. We evaluated the impacts of HIV status and other factors on loss-to-follow-up (LTFU) and visit adherence among MSM and TGW in Abuja and Lagos, Nigeria.

Methods: TRUST/RV368 is an open cohort that provides comprehensive and integrated prevention and treatment services for HIV and sexually transmitted infections (STIs) at community venues supportive of sexual and gender minorities. Recruitment began in March 2013 and participants were followed every three months for up to 18 months. LTFU was defined as not presenting for an expected visit in the past 180 days. Visit adherence was calculated as a rate of completed visits adjusted by the number of three-month intervals elapsed since enrolment. HIV and other factors predictive of LTFU and visit adherence were evaluated using Cox proportional hazards and Poisson regression models, respectively.

Results: A total of 1447 participants who completed enrolment evaluations over two visits as of November 2018 were included in these analyses. Their median age was 24 years (interquartile range [IQR]: 21 to 28) and 53% (n = 766) were living with HIV. LTFU occurred in 56% (n = 808) and visit adherence was 0.62 (95% confidence interval: 0.61 to 0.64) visits per three-month interval. Participants at risk and living with HIV had median follow-up times of 12 months (IQR: 6 to 22), and 21 months (IQR: 12 to 30), respectively (p < 0.01). After controlling for other factors, LTFU was less common among participants living with HIV or other STIs and more common among those who did not own a cell phone, sold sex and had never undergone HIV testing prior to enrolment. These factors had parallel associations with visit adherence.

Conclusions: Retention was suboptimal in Nigerian clinics designed to serve MSM and TGW. Particularly high LTFU and low visit adherence among participants at risk for HIV could complicate deployment of HIV prevention interventions. Marketing the benefits of testing, improving access to cell phones and nurturing more trust with clients may improve retention among marginalized communities in Nigeria.
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http://dx.doi.org/10.1002/jia2.25592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527765PMC
October 2020

Central Nervous System Safety During Brief Analytic Treatment Interruption of Antiretroviral Therapy Within 4 Human Immunodeficiency Virus Remission Trials: An Observational Study in Acutely Treated People Living With Human Immunodeficiency Virus.

Clin Infect Dis 2021 10;73(7):e1885-e1892

Yale University, New Haven, Connecticut, USA.

Background: The central nervous system (CNS) is a likely reservoir of human immunodeficiency virus (HIV), vulnerable to viral rebound, inflammation, and clinical changes upon stopping antiretroviral therapy (ART). It is critical to evaluate the CNS safety of studies using analytic treatment interruption (ATI) to assess HIV remission.

Methods: Thirty participants who started ART during acute HIV infection underwent CNS assessments across 4 ATI remission trials. ART resumption occurred with plasma viral load >1000 copies/mL. CNS measures included paired pre- vs post-ATI measures of mood, cognitive performance, and neurologic examination, with elective cerebrospinal fluid (CSF) sampling, brain diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS).

Results: Median participant age was 30 years old and 29/30 were male. Participants' median time on ART before ATI was 3 years, and ATI lasted a median of 35 days. Post-ATI, there were no differences in median mood scores or neurologic findings and cognitive performance improved modestly. During ATI, a low level of CSF HIV-1 RNA was detectable in 6 of 20 participants with plasma viremia, with no group changes in CSF immune activation markers or brain DTI measures. Mild worsening was identified in post-ATI basal ganglia total choline MRS, suggesting an alteration in neuronal membranes.

Conclusion: No adverse CNS effects were observed with brief, closely monitored ATI in participants with acutely treated HIV, except an MRS alteration in basal ganglia choline. Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations.
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http://dx.doi.org/10.1093/cid/ciaa1344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492357PMC
October 2021

Oral sex practices among men who have sex with men and transgender women at risk for and living with HIV in Nigeria.

PLoS One 2020 4;15(9):e0238745. Epub 2020 Sep 4.

Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States of America.

Background: Men who have sex with men (MSM) and transgender women (TGW) are at risk for sexually transmitted infections (STIs), including those of the oropharynx. We estimated the prevalence and factors associated with oral sex practices and characterized oropharyngeal STIs among a cohort of MSM and TGW in Nigeria.

Methods: From 2013 to 2018, TRUST/RV368 recruited MSM and TGW into HIV/STI diagnosis and treatment at community-based clinics in Nigeria. Participants who completed HIV testing and oral sex questions at enrollment were selected. Cross-sectional analyses with bivariate and multivariable logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs). Oropharyngeal swab testing for Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) began in 2014 and for those with diagnostic results at enrollment, the unadjusted association of oral sex practices with oropharyngeal STIs was conducted.

Results: A total of 1342 participants had a median age of 25 years (interquartile range: 22-29), 58% were living with HIV, and 69% reported oral sex practices. Factors associated with increased odds of engaging in oral sex included living with HIV (adjusted [a]OR: 1.4, 95% CI: 1.1-1.8), self-identifying as a woman (aOR:1.8, 95% CI: 1.1-2.8), mobile phone ownership (aOR:2.3, 95% CI: 1.3-3.9), receptive anal sex (aOR:1.7, 95% CI:1.3-2.3) and multiple male sexual partners (2 to 4 vs. ≤1, aOR:1.5, 95% CI: 1.0-2.2; 5+ vs ≤1, aOR:2.9, 95% CI:1.9-4.3). Oropharyngeal STI prevalence was 7% (52/752) and higher among those who engaged in oral sex compared to those who did not (unadjusted OR: 2.5, 95% CI:1.2-5.3).

Conclusions: Oral sex was common and associated with an increased odds of oropharyngeal STIs among MSM and TGW from Nigeria. In the absence of screening and treatment guidelines, condoms continue to be the mainstay for oral STI prevention. A pre-exposure prophylaxis for bacterial STIs would complement current prevention strategies to curb transmission.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238745PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473579PMC
November 2020

Adjuvanted HIV-1 vaccine promotes antibody-dependent phagocytic responses and protects against heterologous SHIV challenge.

PLoS Pathog 2020 09 3;16(9):e1008764. Epub 2020 Sep 3.

US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.

To augment HIV-1 pox-protein vaccine immunogenicity using a next generation adjuvant, a prime-boost strategy of recombinant modified vaccinia virus Ankara and multimeric Env gp145 was evaluated in macaques with either aluminum (alum) or a novel liposomal monophosphoryl lipid A (MPLA) formulation adsorbed to alum, ALFA. Binding antibody responses were robust and comparable between arms, while antibody-dependent neutrophil and monocyte phagocytotic responses were greatly enhanced by ALFA. Per-exposure vaccine efficacy against heterologous tier 2 SHIV mucosal challenge was 90% in ALFA-adjuvanted males (P = 0.002), while alum conferred no protection. Half of the ALFA-adjuvanted males remained uninfected after the full challenge series, which spanned seven months after the last vaccination. Antibody-dependent monocyte and neutrophil phagocytic responses both strongly correlated with protection. Significant sex differences in infection risk were observed, with much lower infection rates in females than males. In humans, MPLA-liposome-alum adjuvanted gp120 also increased HIV-1-specific phagocytic responses relative to alum. Thus, next-generation liposome-based adjuvants can drive vaccine elicited antibody effector activity towards potent phagocytic responses in both macaques and humans and these responses correlate with protection. Future protein vaccination strategies aiming to improve functional humoral responses may benefit from such adjuvants.
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http://dx.doi.org/10.1371/journal.ppat.1008764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505435PMC
September 2020

HIV status disclosure by Nigerian men who have sex with men and transgender women living with HIV: a cross-sectional analysis at enrollment into an observational cohort.

BMC Public Health 2020 Aug 26;20(1):1282. Epub 2020 Aug 26.

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.

Background: Men who have sex with men (MSM) and transgender women (TGW) are disproportionately impacted by HIV and may face barriers to HIV status disclosure with negative ramifications for HIV prevention and care. We evaluated HIV status disclosure to sexual partners, HIV treatment outcomes, and stigma patterns of MSM and TGW in Abuja and Lagos, Nigeria.

Methods: Previously-diagnosed MSM and TGW living with HIV who enrolled in the TRUST/RV368 cohort from March 2013 to August 2018 were asked, "Have you told your (male/female) sexual partners (MSP/FSP) that you are living with HIV?" In separate analyses, robust Poisson regression models were used to estimate risk ratios (RRs) and 95% confidence intervals (95% CIs) for characteristics associated with HIV status disclosure to MSP and FSP. Self-reported stigma indicators were compared between groups.

Results: Of 493 participants living with HIV, 153 (31.0%) had disclosed their HIV status to some or all MSP since being diagnosed. Among 222 with FSP, 34 (15.3%) had disclosed to some or all FSP. Factors independently associated with disclosure to MSP included living in Lagos (RR 1.58 [95% CI 1.14-2.20]) and having viral load < 50 copies/mL (RR 1.67 [95% CI 1.24-2.25]). Disclosure to FSP was more common among participants who were working in entertainment industries (RR 6.25 [95% CI 1.06-36.84]) or as drivers/laborers (RR 6.66 [95% CI 1.10-40.36], as compared to unemployed) and also among those married/cohabiting (RR 3.95 [95% CI 1.97-7.91], as compared to single) and prescribed ART (RR 2.27 [95% CI 1.07-4.83]). No differences in self-reported stigma indicators were observed by disclosure status to MSP but disclosure to FSP was associated with a lower likelihood of ever having been assaulted (26.5% versus 45.2%, p = 0.042).

Conclusions: HIV status disclosure to sexual partners was uncommon among Nigerian MSM and TGW living with HIV but was associated with improved HIV care outcomes. Disclosure was not associated with substantially increased experiences of stigma. Strategies to encourage HIV status disclosure may improve HIV management outcomes in these highly-marginalized populations with a high burden of HIV infection.
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http://dx.doi.org/10.1186/s12889-020-09315-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448976PMC
August 2020

Evaluation of HIV-1 neutralizing and binding antibodies in maternal-infant transmission in Thailand.

Virology 2020 09 24;548:152-159. Epub 2020 Jun 24.

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA. Electronic address:

Despite anti-retroviral therapy (ART) interventions for HIV+ pregnant mothers, over 43,000 perinatal infections occur yearly. Understanding risk factors that lead to mother-to-child transmission (MTCT) of HIV are critical. We evaluated maternal and infant plasma binding and neutralizing antibody responses in a drug-naïve, CRF01_AE infected MTCT cohort from Thailand to determine associations with transmission risk. Env V3-specific IgG and neutralizing antibody responses were significantly higher in HIV- infants, as compared to HIV+ infants. In fact, infant plasma neutralizing antibodies significantly associated with non-transmission. Conversely, increased maternal Env V3-specific IgG and neutralizing antibody responses were significantly associated with increased transmission risk, after controlling for maternal viral load. Our results highlight the importance of evaluating both maternal and infant humoral immune responses to better understand mechanisms of protection, as selective placental antibody transport may have a role in MTCT. This study further emphasizes the complex role of Env-specific antibodies in MTCT of CRF01_AE HIV.
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http://dx.doi.org/10.1016/j.virol.2020.05.007DOI Listing
September 2020
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