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Featured researches published by Lynn Morris.


PLOS ONE | 2008

Establishing a cohort at high risk of HIV infection in South Africa: challenges and experiences of the CAPRISA 002 acute infection study.

Francois van Loggerenberg; Koleka Mlisana; Carolyn Williamson; Sara C. Auld; Lynn Morris; Clive M. Gray; Quarraisha Abdool Karim; Anneke Grobler; Nomampondo Barnabas; Itua Iriogbe; Salim Safurdeen. Abdool Karim

Objectives To describe the baseline demographic data, clinical characteristics and HIV-incidence rates of a cohort at high risk for HIV infection in South Africa as well as the challenges experienced in establishing and maintaining the cohort. Methodology/Principle Findings Between August 2004 and May 2005 a cohort of HIV-uninfected women was established for the CAPRISA 002 Acute Infection Study, a natural history study of HIV-1 subtype C infection. Volunteers were identified through peer-outreach. The cohort was followed monthly to determine HIV infection rates and clinical presentation of early HIV infection. Risk reduction counselling and male and female condoms were provided. After screening 775 individuals, a cohort of 245 uninfected high-risk women was established. HIV-prevalence at screening was 59.6% (95% CI: 55.9% to 62.8%) posing a challenge in accruing HIV-uninfected women. The majority of women (78.8%) were self-identified as sex-workers with a median of 2 clients per day. Most women (95%) reported more than one casual sexual partner in the previous 3 months (excluding clients) and 58.8% reported condom use in their last sexual encounter. Based on laboratory testing, 62.0% had a sexually transmitted infection at baseline. During 390 person-years of follow-up, 28 infections occurred yielding seroincidence rate of 7.2 (95% CI: 4.5 to 9.8) per 100 person-years. Despite the high mobility of this sex worker cohort retention rate after 2 years was 86.1%. High co-morbidity created challenges for ancillary care provision, both in terms of human and financial resources. Conclusions/Significance Challenges experienced were high baseline HIV-prevalence, lower than anticipated HIV-incidence and difficulties retaining participants. Despite challenges, we have successfully accrued this cohort of HIV-uninfected women with favourable retention, enabling us to study the natural history of HIV-1 during acute HIV-infection. Our experiences provide lessons for others establishing similar cohorts, which will be key for advancing the vaccine and prevention research agenda in resource-constrained settings.


Virology | 2009

High Titer HIV-1 V3-Specific Antibodies with Broad Reactivity but Low Neutralizing Potency in Acute Infection and Following Vaccination

Katie L. Davis; Elin S. Gray; Penny L. Moore; Julie M. Decker; Aidy Salomon; David C. Montefiori; Barney S. Graham; Michael C. Keefer; Abraham Pinter; Lynn Morris; Beatrice H. Hahn; George M. Shaw

Identifying the earliest neutralizing antibody specificities that are elicited following infection or vaccination by HIV-1 is an important objective of current HIV/AIDS vaccine research. We have shown previously that transplantation of HIV-1 V3 epitopes into an HIV-2 envelope (Env) scaffold provides a sensitive and specific means to detect and quantify HIV-1 V3 epitope specific neutralizing antibodies (Nabs) in human sera. Here, we employ this HIV-2/HIV-1 V3 scaffolding strategy to study the kinetics of development and breadth of V3-specific Nabs in longitudinal sera from individuals acutely infected with clade C or clade B HIV-1 and in human subjects immunized with clade B HIV-1 immunogens. HIV-2/HIV-1 chimeras containing V3 sequences matched to virus type (HIV-2 or HIV-1), subtype (clade B or C), or strain (autologous or heterologous) were used as test reagents. We found that by 3-8 weeks post infection, 12 of 14 clade C subjects had a median IC(50) V3-specific Nab titer of 1:700 against chimeric viruses containing a heterologous clade C V3. By 5 months post-infection, all 14 subjects were positive for V3-specific Nabs with median titers of 1:8000 against heterologous clade C V3 and 1:1300 against clade B V3. Two acutely infected clade B patients developed heterologous clade B V3-specific Nabs at titers of 1:300 and 1:1800 by 13 weeks of infection and 1:5000 and 1:11000 by 7 months of infection. Titers were not different against chimeras containing autologous clade B V3 sequences. Each of 10 uninfected normal human volunteers who were immunized with clade B HIV-1 Env immunogens, but none of five sham immunized control subjects, developed V3-specific Nabs titers as high as 1:3000 (median 1:1300; range 1:700-1:3000). None of the HIV-1 infected or vaccinated subjects had antibodies that neutralized primary HIV-1 virus strains. These results indicate that high-titer, broadly reactive V3-specific antibodies are among the first to be elicited during acute and early HIV-1 infection and following vaccination but these antibodies lack neutralizing potency against primary HIV-1 viruses, which effectively shield V3 from antibody binding to the functional Env trimer.


Immunity | 2014

Antibody Light-Chain-Restricted Recognition of the Site of Immune Pressure in the RV144 HIV-1 Vaccine Trial Is Phylogenetically Conserved

Kevin Wiehe; David Easterhoff; Kan Luo; Nathan I. Nicely; Todd Bradley; Frederick H. Jaeger; S. Moses Dennison; Ruijun Zhang; Krissey E. Lloyd; Christina Stolarchuk; Robert Parks; Laura L. Sutherland; Richard M. Scearce; Lynn Morris; Jaranit Kaewkungwal; Sorachai Nitayaphan; Punnee Pitisuttithum; Supachai Rerks-Ngarm; Faruk Sinangil; Sanjay Phogat; Nelson L. Michael; Jerome H. Kim; Garnett Kelsoe; David C. Montefiori; Georgia D. Tomaras; Mattia Bonsignori; Sampa Santra; Thomas B. Kepler; S. Munir Alam; M. Anthony Moody

In HIV-1, the ability to mount antibody responses to conserved, neutralizing epitopes is critical for protection. Here we have studied the light chain usage of human and rhesus macaque antibodies targeted to a dominant region of the HIV-1 envelope second variable (V2) region involving lysine (K) 169, the site of immune pressure in the RV144 vaccine efficacy trial. We found that humans and rhesus macaques used orthologous lambda variable gene segments encoding a glutamic acid-aspartic acid (ED) motif for K169 recognition. Structure determination of an unmutated ancestor antibody demonstrated that the V2 binding site was preconfigured for ED motif-mediated recognition prior to maturation. Thus, light chain usage for recognition of the site of immune pressure in the RV144 trial is highly conserved across species. These data indicate that the HIV-1 K169-recognizing ED motif has persisted over the diversification between rhesus macaques and humans, suggesting an evolutionary advantage of this antibody recognition mode.


Infection, Genetics and Evolution | 2013

Evaluation of sequence ambiguities of the HIV-1 pol gene as a method to identify recent HIV-1 infection in transmitted drug resistance surveys.

Emmi Andersson; Wei Shao; Irene Bontell; Fatim Cham; Do Duy Cuong; Amogne Wondwossen; Lynn Morris; Gillian Hunt; Anders Sönnerborg; Silvia Bertagnolio; Frank Maldarelli; Michael R. Jordan

Identification of recent HIV infection within populations is a public health priority for accurate estimation of HIV incidence rates and transmitted drug resistance at population level. Determining HIV incidence rates by prospective follow-up of HIV-uninfected individuals is challenging and serological assays have important limitations. HIV diversity within an infected host increases with duration of infection. We explore a simple bioinformatics approach to assess viral diversity by determining the percentage of ambiguous base calls in sequences derived from standard genotyping of HIV-1 protease and reverse transcriptase. Sequences from 691 recently infected (≤1 year) and chronically infected (>1 year) individuals from Sweden, Vietnam and Ethiopia were analyzed for ambiguity. A significant difference (p<0.0001) in the proportion of ambiguous bases was observed between sequences from individuals with recent and chronic infection in both HIV-1 subtype B and non-B infection, consistent with previous studies. In our analysis, a cutoff of <0.47% ambiguous base calls identified recent infection with a sensitivity and specificity of 88.8% and 74.6% respectively. 1,728 protease and reverse transcriptase sequences from 36 surveys of transmitted HIV drug resistance performed following World Health Organization guidance were analyzed for ambiguity. The 0.47% ambiguity cutoff was applied and survey sequences were classified as likely derived from recently or chronically infected individuals. 71% of patients were classified as likely to have been infected within one year of genotyping but results varied considerably amongst surveys. This bioinformatics approach may provide supporting population-level information to identify recent infection but its application is limited by infection with more than one viral variant, decreasing viral diversity in advanced disease and technical aspects of population based sequencing. Standardization of sequencing techniques and base calling and the addition of other parameters such as CD4 cell count may address some of the technical limitations and increase the usefulness of the approach.


Antimicrobial Agents and Chemotherapy | 2015

Impact of Drug Resistance-Associated Amino Acid Changes in HIV-1 Subtype C on Susceptibility to Newer Nonnucleoside Reverse Transcriptase Inhibitors

Adriaan E. Basson; Soo Yon Rhee; Chris M. Parry; Ziad El-Khatib; Salome Charalambous; Tulio de Oliveira; Deenan Pillay; Christopher J. Hoffmann; David Katzenstein; Robert W. Shafer; Lynn Morris

ABSTRACT The objective of this study was to assess the phenotypic susceptibility of HIV-1 subtype C isolates, with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated amino acid changes, to newer NNRTIs. A panel of 52 site-directed mutants and 38 clinically derived HIV-1 subtype C clones was created, and the isolates were assessed for phenotypic susceptibility to etravirine (ETR), rilpivirine (RPV), efavirenz (EFV), and nevirapine (NVP) in an in vitro single-cycle phenotypic assay. The amino acid substitutions E138Q/R, Y181I/V, and M230L conferred high-level resistance to ETR, while K101P and Y181I/V conferred high-level resistance to RPV. Y181C, a major NNRTI resistance-associated amino acid substitution, caused decreased susceptibility to ETR and, to a lesser extent, RPV when combined with other mutations. These included N348I and T369I, amino acid changes in the connection domain that are not generally assessed during resistance testing. However, the prevalence of these genotypes among subtype C sequences was, in most cases, <1%. The more common EFV/NVP resistance-associated substitutions, such as K103N, V106M, and G190A, had no major impact on ETR or RPV susceptibility. The low-level resistance to RPV and ETR conferred by E138K was not significantly enhanced in the presence of M184V/I, unlike for EFV and NVP. Among patient samples, 97% were resistant to EFV and/or NVP, while only 24% and 16% were resistant to ETR and RPV, respectively. Overall, only a few, relatively rare NNRTI resistance-associated amino acid substitutions caused resistance to ETR and/or RPV in an HIV-1 subtype C background, suggesting that these newer NNRTIs would be effective in NVP/EFV-experienced HIV-1 subtype C-infected patients.


Science immunology | 2017

Potent and broad HIV-neutralizing antibodies in memory B cells and plasma.

LaTonya D. Williams; Gilad Ofek; Sebastian Schätzle; Jonathan R. McDaniel; Xiaozhi Lu; Nathan I. Nicely; Liming Wu; Caleb S. Lougheed; Todd Bradley; Mark K. Louder; Krisha McKee; Robert T. Bailer; Sijy O’Dell; Ivelin S. Georgiev; Michael S. Seaman; Robert Parks; Dawn J. Marshall; Kara Anasti; Guang Yang; Xiaoyan Nie; Nancy Tumba; Kevin Wiehe; Kshitij Wagh; Bette T. Korber; Thomas B. Kepler; S. Munir Alam; Lynn Morris; Gift Kamanga; Myron S. Cohen; Mattia Bonsignori

Plasma is a source of broadly neutralizing antibodies for recombinant antibodies with enhanced potency and breadth. Engineering HIV immunity For rapidly mutating viruses such as HIV, antibodies that can neutralize more than one strain may have real potential as a therapeutic. Now, Williams et al. examine the ontogeny of broadly neutralizing antibodies (bnAbs) to the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41. They found similar clonal lineages of an MPER bnAb from both memory B cells and plasma, highlighting the viability of plasma as a source of bnAbs. These lineages shared an autoreactive unmutated common ancestor, suggesting that tolerance must be overcome for bnAb induction. The authors then engineered chimeric antibodies from the plasma and memory B cells that neutralized most HIV-1 strains. Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41, is broadly neutralizing. However, the ontogeny of distal MPER antibodies and the relationship of memory B cell to plasma bnAbs are poorly understood. HIV-1–specific memory B cell flow sorting and proteomic identification of anti-MPER plasma antibodies from an HIV-1–infected individual were used to isolate broadly neutralizing distal MPER bnAbs of the same B cell clonal lineage. Structural analysis demonstrated that antibodies from memory B cells and plasma recognized the envelope gp41 bnAb epitope in a distinct orientation compared with other distal MPER bnAbs. The unmutated common ancestor of this distal MPER bnAb was autoreactive, suggesting lineage immune tolerance control. Construction of chimeric antibodies of memory B cell and plasma antibodies yielded a bnAb that potently neutralized most HIV-1 strains.


PLOS Pathogens | 2016

Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization

Cecilia Rademeyer; Bette T. Korber; Michael S. Seaman; Elena E. Giorgi; R. Thebus; Alexander Robles; Daniel J. Sheward; Kshitij Wagh; Jetta Garrity; Brittany R. Carey; Hongmei Gao; Kelli M. Greene; Haili Tang; Gama Bandawe; Jinny C. Marais; Thabo E. Diphoko; Peter Hraber; Nancy Tumba; Penny L. Moore; Glenda Gray; James G. Kublin; M. Juliana McElrath; Marion Vermeulen; Keren Middelkoop; Linda-Gail Bekker; Michael Hoelscher; Leonard Maboko; Joseph Makhema; Merlin L. Robb; Salim Safurdeen. Abdool Karim

The development of biomedical interventions to reduce acquisition of HIV-1 infection remains a global priority, however their potential effectiveness is challenged by very high HIV-1 envelope diversity. Two large prophylactic trials in high incidence, clade C epidemic regions in southern Africa are imminent; passive administration of the monoclonal antibody VRC01, and active immunization with a clade C modified RV144-like vaccines. We have created a large representative panel of C clade viruses to enable assessment of antibody responses to vaccines and natural infection in Southern Africa, and we investigated the genotypic and neutralization properties of recently transmitted clade C viruses to determine how viral diversity impacted antibody recognition. We further explore the implications of these findings for the potential effectiveness of these trials. A panel of 200 HIV-1 Envelope pseudoviruses was constructed from clade C viruses collected within the first 100 days following infection. Viruses collected pre-seroconversion were significantly more resistant to serum neutralization compared to post-seroconversion viruses (p = 0.001). Over 13 years of the study as the epidemic matured, HIV-1 diversified (p = 0.0009) and became more neutralization resistant to monoclonal antibodies VRC01, PG9 and 4E10. When tested at therapeutic levels (10ug/ml), VRC01 only neutralized 80% of viruses in the panel, although it did exhibit potent neutralization activity against sensitive viruses (IC50 titres of 0.42 μg/ml). The Gp120 amino acid similarity between the clade C panel and candidate C-clade vaccine protein boosts (Ce1086 and TV1) was 77%, which is 8% more distant than between CRF01_AE viruses and the RV144 CRF01_AE immunogen. Furthermore, two vaccine signature sites, K169 in V2 and I307 in V3, associated with reduced infection risk in RV144, occurred less frequently in clade C panel viruses than in CRF01_AE viruses from Thailand. Increased resistance of pre-seroconversion viruses and evidence of antigenic drift highlights the value of using panels of very recently transmitted viruses and suggests that interventions may need to be modified over time to track the changing epidemic. Furthermore, high divergence such as that observed in the older clade C epidemic in southern Africa may impact vaccine efficacy, although the correlates of infection risk are yet to be defined in the clade C setting. Findings from this study of acute/early clade C viruses will aid vaccine development, and enable identification of new broad and potent antibodies to combat the HIV-1 C-clade epidemic in southern Africa.


Science Translational Medicine | 2017

Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide

S. Munir Alam; Baptiste Aussedat; Yusuf Vohra; R. Ryan Meyerhoff; Evan M. Cale; William E. Walkowicz; Nathan A. Radakovich; Kara Anasti; Lc Armand; Robert Parks; Laura L. Sutherland; Richard M. Scearce; M. Gordon Joyce; Marie Pancera; Aliaksandr Druz; Ivelin S. Georgiev; Tarra Von Holle; Amanda Eaton; Christopher B. Fox; Steven G. Reed; Mark K. Louder; Robert T. Bailer; Lynn Morris; Salim Abdool-Karim; Myron S. Cohen; Hua-Xin Liao; David C. Montefiori; Peter K. Park; Alberto Fernández-Tejada; Kevin Wiehe

A synthetic glycopeptide mimics a key neutralizing epitope on the HIV-1 envelope and can be used to isolate HIV-1 broadly neutralizing antibodies. Guiding anti-glycan antibodies Although it typically evades the immune system, HIV does have sites of vulnerability that can be targeted in vaccine design. One such site is a glycan near the V3 loop of the envelope protein, but antibodies recognizing this epitope are often not detected in people infected with HIV. Alam et al. designed a synthetic glycopeptide that can identify B cells targeting this epitope and also used it to immunize macaques. Bonsignori et al. used this synthetic glycopeptide and other baits to study the V3-glycan antibody responses of an HIV-infected individual that developed broadly neutralizing antibodies. They also examined viral evolution over time and found clues as to why these types of antibodies do not develop more often. These tools and findings could pave the way for a vaccine that protects against diverse strains of HIV. A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) third variable loop (V3). We have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man9-V3). V3-glycan bnAbs bound to Man9-V3 glycopeptide and native-like gp140 trimers with similar affinities. Fluorophore-labeled Man9-V3 glycopeptides bound to bnAb memory B cells and were able to be used to isolate a V3-glycan bnAb from an HIV-1–infected individual. In rhesus macaques, immunization with Man9-V3 induced V3-glycan-targeted antibodies. Thus, the Man9-V3 glycopeptide closely mimics an HIV-1 V3-glycan bnAb epitope and can be used to isolate V3-glycan bnAbs.


Science Translational Medicine | 2017

Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge

Boris Julg; Lawrence J. Tartaglia; Brandon F. Keele; Kshitij Wagh; Amarendra Pegu; Devin Sok; Peter Abbink; Stephen D. Schmidt; Xuejun Chen; Gordon M. Joyce; Ivelin S. Georgiev; Misook Choe; Peter D. Kwong; Nicole A. Doria-Rose; Khoa Le; Mark K. Louder; Robert T. Bailer; Penny L. Moore; Bette T. Korber; Michael S. Seaman; Salim Safurdeen. Abdool Karim; Lynn Morris; Richard A. Koup; John R. Mascola; Dennis R. Burton; Dan H. Barouch

Neutralizing antibodies to the HIV-1 envelope V2 apex protect macaques against SHIV challenge at very low serum concentrations. Potently protective antibodies HIV is thought to be an elusive virus, but there are multiple epitopes on HIV that can be targeted by neutralizing antibodies, such as the V2 loop of the envelope protein. Julg et al. reasoned that potent anti-V2 HIV antibodies given prophylactically could prevent infection from taking place. They tested this in nonhuman primates with a novel clade C SHIV strain and observed protection at very low concentrations of circulating neutralizing antibody, suggesting that passive immunization with these types of antibodies might be protective in people. Neutralizing antibodies to the V2 apex antigenic region of the HIV-1 envelope (Env) trimer are among the most prevalent cross-reactive antibodies elicited by natural infection. Two recently described V2-specific antibodies, PGDM1400 and CAP256-VRC26.25, have demonstrated exquisite potency and neutralization breadth against HIV-1. However, little data exist on the protective efficacy of V2-specific neutralizing antibodies. We created a novel SHIV-325c viral stock that included a clade C HIV-1 envelope and was susceptible to neutralization by both of these antibodies. Rhesus macaques received a single infusion of either antibody at three different concentrations (2, 0.4, and 0.08 mg/kg) before challenge with SHIV-325c. PGDM1400 was fully protective at the 0.4 mg/kg dose, whereas CAP256-VRC26.25-LS was fully protective even at the 0.08 mg/kg dose, which correlated with its greater in vitro neutralization potency against the challenge virus. Serum antibody concentrations required for protection were <0.75 μg/ml for CAP256-VRC26.25-LS. These data demonstrate unprecedented potency and protective efficacy of V2-specific neutralizing antibodies in nonhuman primates and validate V2 as a potential target for the prevention of HIV-1 infection in passive immunization strategies in humans.


PLOS ONE | 2015

Randomized Cross-Sectional Study to Compare HIV-1 Specific Antibody and Cytokine Concentrations in Female Genital Secretions Obtained by Menstrual Cup and Cervicovaginal Lavage

Derseree Archary; Lenine J. Liebenberg; Lise. Werner; Sahil. Tulsi; Nelisile. Majola; Nivashnee Naicker; Sarah Dlamini; Thomas J. Hope; Natasha Samsunder; Salim Safurdeen. Abdool Karim; Lynn Morris; Jo-Ann S. Passmore; Nigel Garrett

Introduction Optimizing methods for genital specimen collection to accurately characterize mucosal immune responses is a priority for the HIV prevention field. The menstrual cup (MC) has been proposed as an alternative to other methods including cervicovaginal lavage (CVL), but no study has yet formally compared these two methods. Methods Forty HIV-infected, antiretroviral therapy-naïve women from the CAPRISA 002 acute HIV infection cohort study were randomized to have genital fluid collected using the MC with subsequent CVL, or by CVL alone. Qualitative data, which assessed levels of comfort and acceptability of MC using a 5-point Likert scale, was collected. Luminex multiplex assays were used to measure HIV-specific IgG against multiple gene products and 48 cytokines. Results The majority (94%) of participants indicated that insertion, wearing and removal of the MC was comfortable. Nineteen MCs with 18 matching, subsequent CVLs and 20 randomized CVLs were available for analysis. Mucosal IgG responses against four HIV-antigens were detected in 99% of MCs compared to only 80% of randomized CVLs (p = 0.029). Higher specific antibody activity and total antibodies were observed in MCs compared to CVL (all p<0.001). In MCs, 42/48 (88%) cytokines were in the detectable range in all participants compared to 27/48 (54%) in CVL (p<0.001). Concentrations of 22/41 cytokines (53.7%) were significantly higher in fluid collected by MC. Both total IgG (r = 0.63; p = 0.005) and cytokine concentrations (r = 0.90; p<0.001) correlated strongly between MC and corresponding post-MC CVL. Conclusions MC sampling improves the detection of mucosal cytokines and antibodies, particularly those present at low concentrations. MC may therefore represent an ideal tool to assess immunological parameters in genital secretions, without interfering with concurrent collection of conventional CVL samples.

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Salim Safurdeen. Abdool Karim

Centre for the AIDS Programme of Research in South Africa

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Ivelin S. Georgiev

National Institutes of Health

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Nigel Garrett

Centre for the AIDS Programme of Research in South Africa

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Penny L. Moore

University of the Witwatersrand

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Mark K. Louder

National Institutes of Health

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Robert T. Bailer

National Institutes of Health

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