#HIV #infection predominantly affecting #children in #Sindh, #Pakistan, 2019: a cross-sectional study of an #outbreak (Lancet Infect Dis., abstract)

[Source: Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

HIV infection predominantly affecting children in Sindh, Pakistan, 2019: a cross-sectional study of an outbreak

Fatima Mir, MSCR, Faisal Mahmood, MBBS, Prof Amna Rehana Siddiqui, PhD, Prof Shehla Baqi, MBBS, Syed Hani Abidi, PhD, Abdul Momin Kazi, MPH, Apsara Ali Nathwani, MSc, Amerta Ladhani, MSc, Farah Naz Qamar, MSCR, Sajid Bashir Soofi, MBBS, Sikander Ali Memon, MBBS, Jamila Soomro, MPH, Saqib Ali Shaikh, MSc, Victoria Simms, PhD, Palwasha Khan, PhD, Prof Rashida Abbas Ferrand, PhD

Published: December 19, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30743-1

 

Summary

Background

In April 2019, an HIV screening camp for all ages was established in response to a report of an unusually large number of paediatric HIV diagnoses in Larkana, Pakistan. We aimed to understand the clinical profile of the children who registered for HIV care.

Methods

In this cross-sectional study, we review the outbreak response from the government, academia, and UN agencies in Larkana, Sindh, Pakistan. We report age-stratified and sex-stratified HIV prevalence estimated among individuals screened. For children who registered for HIV care, clinical history of previous injections and blood transfusions, HIV disease stage, hepatitis B and hepatitis C status, and CD4 count was abstracted from clinical records from Sindh AIDS Control Program HIV Clinic (Shaikh Zayed Childrens Hospital, Larkana, Pakistan) and analysed using percentages, χ 2 tests, and weight-for-age Z scores. We also analysed data for parents who were tested for HIV.

Findings

Between April 24, and July 15, 2019, 31 239 individuals underwent HIV testing, of whom 930 (3%) tested positive for HIV. Of these, 763 (82%) were younger than 16 years and 604 (79%) of these were aged 5 years and below. Estimated HIV prevalence was 3% overall; 7% (283 of 3803) in children aged 0–2 years, 6% (321 of 5412) in children aged 3–5 years, and 1% (148 of 11 251) in adults aged 16–49 years. Of the 591 children who registered for HIV care, 478 (81%) were 5 years or younger, 379 (64%) were boys, and 315 (53%) of 590 had a weight-for-age Z score of −3·2. Prevalence of hepatitis B surface antigen was 8% (48 of 574) and hepatitis C antibody positivity was 3% (15 of 574). Of children whose mothers tested for HIV, only 39 (11%) of 371 had HIV-positive mothers. Most children (404 [89%] of 453) reported multiple previous injections and 40 (9%) of 453 reported blood transfusions.

Interpretation

This HIV outbreak is unprecedented among children in Pakistan: a 54% increase in paediatric HIV diagnoses over the past 13 years. The outbreak was heavily skewed towards young children younger than 5 years, with a predominance of boys. Epidemiological and molecular studies are needed to understand the full extent of the outbreak and its drivers to guide HIV control strategies.

Funding

None.

Keywords: HIV/AIDS; Pediatrics; Pakistan.

—–

A generalized #HIV #vaccine #design #strategy for priming of broadly neutralizing antibody responses (Science, abstract)

[Source: Science, full page: (LINK). Abstract, edited.]

A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses

Jon M. Steichen1,2,3,*, Ying-Cing Lin4,*, Colin Havenar-Daughton3,5,*, Simone Pecetta4,*, Gabriel Ozorowski2,3,6,*, Jordan R. Willis1,2,3,*, Laura Toy3,5, Devin Sok1,2,3, Alessia Liguori1,2,3, Sven Kratochvil4, Jonathan L. Torres2,3,6, Oleksandr Kalyuzhniy1,2,3, Eleonora Melzi4, Daniel W. Kulp1,2,3,7, Sebastian Raemisch1,2,3, Xiaozhen Hu1,2,3, Steffen M. Bernard2,3,6, Erik Georgeson1,2,3, Nicole Phelps1,2,3, Yumiko Adachi1,2,3, Michael Kubitz1,2,3, Elise Landais1,2,3, Jeffrey Umotoy1,2,3, Amanda Robinson1,2,3, Bryan Briney1,2,3,8, Ian A. Wilson2,3,6,9, Dennis R. Burton1,2,3, Andrew B. Ward2,3,6, Shane Crotty3,5,10,†, Facundo D. Batista4,11,†, William R. Schief1,2,3,4,†

1 Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA. 2 IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. 3 Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037, USA. 4 The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA. 5 Division of Vaccine Discovery, La Jolla Institute for Immunology, La Jolla, CA 92037, USA. 6 Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. 7 Vaccine and Immune Therapy Center, The Wistar Institute, Philadelphia, PA 19104, USA. 8 Center for Viral Systems Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. 9 Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. 10 Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA. 11 Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.

†Corresponding author. Email: schief@scripps.edu (W.R.S.); fbatista1@mgh.harvard.edu (F.D.B.); shane@lji.org (S.C.)

* These authors contributed equally to this work.

Science  06 Dec 2019: Vol. 366, Issue 6470, eaax4380  / DOI: 10.1126/science.aax4380

 

Engineering better bnAbs

A highly effective HIV vaccine has been the goal of vaccinologists for nearly 35 years. A successful vaccine would need to induce broadly neutralizing antibodies (bnAbs) that are capable of neutralizing multiple HIV strains (see the Perspective by Agazio and Torres). Steichen et al. report a strategy in which the first vaccine shot can lead to immune responses that generate desired bnAbs. By combining knowledge of human antibody repertoires and structure to guide design, they validated candidate immunogens through functional preclinical testing. Saunders et al. designed immunogens with differences in binding strength for bnAb precursors, which enabled selection of rare mutations after immunization. The immunogens promoted bnAb precursor maturation in humanized mice and macaques.

Science, this issue p. eaax4380, p. eaay7199; see also p. 1197

 

Structured Abstract

INTRODUCTION

HIV newly infects 1.8 million people each year, making development of an HIV vaccine a global health priority. Nearly all licensed vaccines protect by inducing antibodies, but highly variable pathogens such as HIV and influenza virus have eluded traditional vaccine strategies. The discoveries of broadly neutralizing antibodies (bnAbs) that bind to conserved epitopes on the surface proteins of these viruses have inspired vaccine design strategies to induce bnAbs. Antibodies are produced by B cells, and highly effective antibodies like bnAbs acquire affinity-enhancing mutations when a bnAb-precursor B cell mutates and matures from the original naïve B cell (or germline) state. Among several new vaccine strategies, germline-targeting vaccine design aims to induce bnAbs by first stimulating bnAb-precursor B cells and then shepherding B cell affinity maturation with a series of rationally designed boosting immunogens. A key rationale for this strategy is that germline-reverted forms of bnAbs—precursors with all recognizable amino acid mutations reverted to germline—typically have no detectable affinity for HIV envelope (Env). Thus, for a vaccine to initiate bnAb induction, a germline-targeting priming immunogen with appreciable affinity for bnAb precursors must be engineered.

RATIONALE

Most HIV bnAbs (and most antibodies to any pathogen) bind to their target by using their heavy chain complementarity-determining region 3 (HCDR3) as a major binding determinant. Hence, an optimal HIV vaccine that induces multiple bnAbs, and a general solution to germline-targeting vaccine design that could be applied broadly to other pathogens, will need to work with HCDR3-dependent antibodies. However, the need to design germline-targeting immunogens to initiate HCDR3-dependent bnAb responses faces major technical challenges. Although each B cell expresses a single unique antibody, different B cells produce diverse antibodies encoded by different combinations of antibody genes, with the greatest antibody genetic diversity encoded in the HCDR3 portion of the molecule. The exceptional diversity in the human B cell repertoire makes any single HCDR3 sequence an impractical vaccine target. Rather, a pool of precursors sharing a set of bnAb-associated genetic features must be identified and targeted. Thus, owing to the enormous diversity of human antibodies, a germline-targeting immunogen should have affinity for diverse bnAb precursors in order to succeed in diverse vaccine recipients.

RESULTS

Herein we report a solution to the above challenges. Using the strongly HCDR3-dependent bnAb BG18 that binds a conserved site on HIV Env as a high-value target and a proof of principle, we demonstrate a method to identify pools of potential bnAb precursors in an ultradeep human antibody sequence database, guided by key genetic features that enable bnAb structural recognition of the antigen. We then use a representative set of those potential bnAb precursors as design targets to guide our engineering of HIV Env immunogens that bind to diverse potential bnAb precursors. Lastly, we provide critical preclinical validation of immunogen design by assessing these immunogens for (i) their ability to select rare potential bnAb-precursor naïve B cells from the blood of healthy human donors, (ii) their modes of binding to bnAb precursors, and (iii) their capacity to prime rare bnAb-precursor B cells with physiologically relevant affinities in a mouse model.

CONCLUSION

Overall, we demonstrate a new approach to defining diverse precursors for a target antibody and designing vaccine immunogens that take advantage of that information. The approach lays out a generalizable pathway for the development and preclinical validation of germline-targeting immunogens to stimulate precursors for HCDR3-dependent antibodies.

 

Abstract

Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer–based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naïve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.

Keywords: HIV/AIDS; Vaccines.

——

Human Immunodeficiency Virus (#HIV)–Infected CCR6+ #Rectal CD4+ T Cells and HIV #Persistence On #Antiretroviral Therapy (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Human Immunodeficiency Virus (HIV)–Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy

Jenny L Anderson, Gabriela Khoury, Rémi Fromentin, Ajantha Solomon, Nicolas Chomont, Elizabeth Sinclair, Jeffrey M Milush, Wendy Hartogensis, Peter Bacchetti, Michael Roche, Carolin Tumpach, Matthew Gartner, Matthew C Pitman, Christine Lorrie Epling, Rebecca Hoh, Frederick M Hecht, Ma Somsouk, Paul U Cameron, Steven G Deeks, Sharon R Lewin

The Journal of Infectious Diseases, jiz509, https://doi.org/10.1093/infdis/jiz509

Published: 04 December 2019

 

Abstract

Background

Identifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy.

Methods

Cell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry.

Results

Integrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines.

Conclusions

HIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues.

HIV reservoir, latency, persistence, chemokine receptor, CCR6, CXCR3, chemokines, rectal tissue, lymph node

Issue Section: Major Article

Keywords: HIV/AIDS; Antivirals; Immunopathology.

——

#SIV #Infection of Rhesus #Macaques Results in Delayed #Zika Virus #Clearance (MBio, abstract)

[Source: MBio, full page: (LINK). Abstract, edited.]

Simian Immunodeficiency Virus Infection of Rhesus Macaques Results in Delayed Zika Virus Clearance

Carol L. Vinton, Samuel J. Magaziner, Kimberly A. Dowd, Shelly J. Robertson, Emerito Amaro-Carambot, Erik P. Karmele, Alexandra M. Ortiz, Carly E. Starke, Joseph C. Mudd, Stephen S. Whitehead, Sonja M. Best, Theodore C. Pierson, Heather D. Hickman, Jason M. Brenchley

Salim Abdool Karim, Editor

DOI: 10.1128/mBio.02790-19

 

ABSTRACT

Flaviviruses are controlled by adaptive immune responses but are exquisitely sensitive to interferon-stimulated genes (ISGs). How coinfections, particularly simian immunodeficiency viruses (SIVs), that induce robust ISG signatures influence flavivirus clearance and pathogenesis is unclear. Here, we studied how Zika virus (ZIKV) infection is modulated in SIV-infected nonhuman primates. We measured ZIKV replication, cellular ZIKV RNA levels, and immune responses in non-SIV-infected and SIV-infected rhesus macaques (RMs), which we infected with ZIKV. Coinfected animals had a 1- to 2-day delay in peak ZIKV viremia, which was 30% of that in non-SIV-infected animals. However, ZIKV viremia was significantly prolonged in SIV-positive (SIV+) RMs. ISG levels at the time of ZIKV infection were predictive for lower ZIKV viremia in the SIV+ RMs, while prolonged ZIKV viremia was associated with muted and delayed adaptive responses in SIV+ RMs.

 

IMPORTANCE

Immunocompromised individuals often become symptomatic with infections which are normally fairly asymptomatic in healthy individuals. The particular mechanisms that underlie susceptibility to coinfections in human immunodeficiency virus (HIV)-infected individuals are multifaceted. ZIKV and other flaviviruses are sensitive to neutralizing antibodies, whose production can be limited in HIV-infected individuals but are also sensitive to type I interferons, which are expressed at high levels in HIV-infected individuals. Data in this study highlight how individual components of the innate and adaptive immune responses which become perturbed in HIV-infected individuals influence ZIKV infection.

Keywords: HIV/AIDS; Zika Virus; SIV; Immunology; Animal models.

——-

#TB, #HIV, and viral #hepatitis #diagnostics in eastern #Europe and central #Asia: high time for integrated and people-centred services (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Tuberculosis, HIV, and viral hepatitis diagnostics in eastern Europe and central Asia: high time for integrated and people-centred services

Masoud Dara, MD  †, Soudeh Ehsani, MD, Antons Mozalevskis, MD, Elena Vovc, MD, Daniel Simões, MPH, Ana Avellon Calvo, PhD, Jordi Casabona i Barbarà, PhD, Otar Chokoshvili, MPH, Irina Felker, PhD, Sven Hoffner, PhD, Gulmira Kalmambetova, PhD, Ecatarina Noroc, MD, Natalia Shubladze, PhD, Alena Skrahina, MD, Rasim Tahirli, MD, Prof Tengiz Tsertsvadze, PhD,

Published: November 15, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30524-9

 

Summary

Globally, high rates (and in the WHO European region an increasing prevalence) of co-infection with tuberculosis and HIV and HIV and hepatitis C virus exist. In eastern European and central Asian countries, the tuberculosis, HIV, and viral hepatitis programmes, including diagnostic services, are separate vertical structures. In this Personal View, we consider underlying reasons for the poor integration for these diseases, particularly in the WHO European region, and how to address this with an initial focus on diagnostic services. In part, this low integration has reflected different diagnostic development histories, global funding sources, and sample types used for diagnosis (eg, typically sputum for tuberculosis and blood for HIV and hepatitis C). Cooperation between services improved as patients with tuberculosis needed routine testing for HIV and vice versa, but financial, infection control, and logistical barriers remain. Multidisease diagnostic platforms exist, but to be used optimally, appropriate staff training and sensible understanding of different laboratory and infection control risks needs rapid implementation. Technically these ideas are all feasible. Poor coordination between these vertical systems remains unhelpful. There is a need to increase political and operational integration of diagnostic and treatment services and bring them closer to patients.

Keywords: Public Health; European Region; TB; HIV/AIDS; Viral hepatitis.

——

The #Threat of Emerging and Re-emerging #Infections in #Indonesia (Acta Med Indones., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Acta Med Indones. 2019 Jul;51(3):195-196.

The Threat of Emerging and Re-emerging Infections in Indonesia.

Nelwan EJ1.

Author information: 1 Department of Internal Medicine, Faculty of Medicine Universitas Indonesia – Cipto Mangunkusumo Hospital, Jakarta, Indonesia. erni.juwita@ui.ac.id.

 

Abstract

Human immunodeficiency virus (HIV) is one example of an emerging infection with total of 386 district of all province in Indonesia reported having such infection; with cumulative number of HIV infected patient from the year 1987 to 2014 is 150,296 while AIDS is 55,799 patients. The access to care only available for 153,887 patients among all HIV/AIDS patients of whom 70% are eligible for anti-retroviral (ARV) treatment and of these only half adhered to ARV treatment. In addition to that, there is an increased risk of other emerging diseases such as Zika virus, Monkey pox or Hanta pulmonary syndrome since a sporadic cases were reported around the region.

Beside new diseases, tuberculosis, dengue virus, malaria and diphteria are continuously reported in Indonesia and classified as re-emerging illnesses. On this edition data on diphteria epidemiology in Indonesia will be shown by Karyanti et al.6 A recent outbreak of diphteria in Indonesia which involved almost all province in the country has led to a response named ORI (outbreak response of Immunization). Regardless of immunization, proper treatment including the distribution of anti-toxin and antibiotics are needed to stop the spread of this particular bacteria, further decreasing the mortality rate. In conclusion, the author of this paper mentioned that immunization gap needs to be handle systematically. Immunization data released on 2017 showed that complete immunization was given only to 20% of targeted group, while almost 75% were either unvaccinated or unknown. During the outbreak of diphteria in Indonesia, the WHO also reported several countries with similar problem such as Bangladesh, Haiti and Yamen. It was shown that a coordination between doctors in clinic/hospital with public health officer to conduct an epidemiological investigation, in conjunction with giving prophylaxis and assuring the logistics of anti-diphteria toxin and antibiotics were accessible were  the key of success in eliminating diphteria like it was in Bangladesh.

Adherence to treatment are multifactorial for all illnesses. First, is the duration of treatment and the potential adverse event due to the medication. The Ministry of Health of the Republic of Indonesia has support the early diagnosis of HIV and delivering treatment as soon as possible, in order to avoid transmission of the disease. Second, looking at another side of the story for HIV infected patients, receiving ARV treatment as a long life treatment could possibly cause an adverse event somewhere along the line. Budiman et.al reported factors that might contribute to liver injury. His study shows that measuring baseline liver function test AST routinely might minimize the toxicity of ARV to patients particularly with a low body mass index. Last, despite the adherence to treatment and procedures in minimizing the risk of adverse event to medication, we are now facing the primary resistance virus that transmitted in the community as mentioned by Megasari et al.8 on her report regarding the transmission of drug resistance HIV virus to naïve patients in Bali.

The Indonesian government through the Indonesian Ministry of Health has established a collaboration and one health approaches to tackle the threat of diseases in the country, particularly in infectious diseases.

KEYWORDS: AIDS; HIV; Infection; Virus

PMID: 31699941

Keywords: Indonesia; Public Health; Diphtheria; HIV/AIDS.

——

#DNA #priming and #gp120 #boosting induces #HIV-specific #antibodies in a #RCT (J Clin Invest., abstract)

[Source: Journal of Clinical Investigation, full page: (LINK). Abstract, edited.]

DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trial

Nadine G. Rouphael,1 Cecilia Morgan,2 Shuying S. Li,2 Ryan Jensen,2 Brittany Sanchez,2 Shelly Karuna,2 Edith Swann,3 Magdalena E. Sobieszczyk,4 Ian Frank,5 Gregory J. Wilson,6 Hong-Van Tieu,7 Janine Maenza,2,8 Aliza Norwood,9 James Kobie,10 Faruk Sinangil,11 Giuseppe Pantaleo,12 Song Ding,13 M. Juliana McElrath,2 Stephen C. De Rosa,2 David C. Montefiori,14 Guido Ferrari,14 Georgia D. Tomaras,14 Michael C. Keefer,10 and the HVTN 105 Protocol Team and the NIAID HIV Vaccine Trials Network15

First published September 30, 2019

 

Abstract

BACKGROUND.

RV144 is the only preventive HIV vaccine regimen demonstrating efficacy in humans. Attempting to build upon RV144 immune responses, we conducted a phase 1, multicenter, randomized, double-blind trial to assess the safety and immunogenicity of regimens substituting the DNA-HIV-PT123 (DNA) vaccine for ALVAC-HIV in different sequences or combinations with AIDSVAX B/E (protein).

METHODS.

One hundred and four HIV-uninfected participants were randomized to 4 treatment groups (T1, T2, T3, and T4) and received intramuscular injections at 0, 1, 3, and 6 months (M): T1 received protein at M0 and M1 and DNA at M3 and M6; T2 received DNA at M0 and M1 and protein at M3 and M6; T3 received DNA at M0, M1, M3, and M6 with protein coadministered at M3 and M6; and T4 received protein and DNA coadministered at each vaccination visit.

RESULTS.

All regimens were well tolerated. Antibodies binding to gp120 and V1V2 scaffold were observed in 95%–100% of participants in T3 and T4, two weeks after final vaccination at high magnitude. While IgG3 responses were highest in T3, a lower IgA/IgG ratio was observed in T4. Binding antibodies persisted at 12 months in 35%–100% of participants. Antibody-dependent cell-mediated cytotoxicity and tier 1 neutralizing-antibody responses had higher response rates for T3 and T4, respectively. CD4+ T cell responses were detectable in all treatment groups (32%–64%) without appreciable CD8+ T cell responses.

CONCLUSION.

The DNA/protein combination regimens induced high-magnitude and long-lasting HIV V1V2–binding antibody responses, and early coadministration of the 2 vaccines led to a more rapid induction of these potentially protective responses.

TRIAL REGISTRATION.

ClinicalTrials.gov NCT02207920.

FUNDING.

National Institute of Allergy and Infectious Diseases (NIAID) grants UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069511, UM1 AI069470, UM1 AI069534, P30 AI450008, UM1 AI069439, UM1 AI069481, and UM1 AI069496; the National Center for Advancing Translational Sciences, NIH (grant UL1TR001873); and the Bill & Melinda Gates Foundation (grant OPP52845).

Keywords: HIV/AIDS; Vaccines.

——