Browsing by Author "Morris, Lynn."

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Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline Ig gene repertoire.
(American Association of Immunologists., 2015) Scheepers, Cathrine.; Shrestha, Ram K.; Lambson, Bronwen Elizabeth.; Jackson, Katherine J. L.; Wright, Imogen A.; Naicker, Dshanta Dyanedi.; Goosen, Mark.; Berrie, Leigh.; Ismail, Arshad.; Garrett, Nigel Joel.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Moore, Penelope L.; Travers, Simon A.; Morris, Lynn.
Abstract available in pdf.
Amino acid changes in the HIV-1 gp41 membrane proximal region control virus neutralization sensitivity.
(Elsevier., 2016) Bradley, Todd.; Trama, Ashley.; Tumba, Nancy Lola.; Gray, Elin Solomonovna.; Lu, Xiaozhi.; Madani, Navid.; Jahanbakhsh, Fatemeh.; Eaton, Amanda.; Xia, Shi-Mao.; Parks, Robert.; Lloyd, Krissey E.; Sutherland, Laura L.; Scearce, Richard M.; Bowman, Cindy M.; Barnett, Susan.; Abdool Karim, Salim Safurdeen.; Boyd, Scott D.; Melillo, Bruno.; Smith, Amos B.; Sodroski, Joseph.; Kepler, Thomas B.; Alam, Shabnam Munir.; Gao, Feng.; Bonsignori, Mattia.; Liao, Hua-Xin.; Moody, Michael Anthony.; Montefiori, David Charles.; Santra, Sampa.; Morris, Lynn.; Haynes, Barton F.
Abstract available in pdf.
Antibody light-chain-restricted recognition of the site of immune pressure in the RV144 HIV-1 vaccine trial is phylogenetically conserved.
(Cell Press., 2014) Wiehe, Kevin.; Easterhoff, David.; Luo, Kan.; Nicely, Nathan I.; Bradley, Todd.; Jaeger, Frederick H.; Dennison, Sally Moses.; Zhang, Ruijun.; Lloyd, Krissey E.; Stolarchuk, Christina.; Parks, Robert.; Sutherland, Laura L.; Scearce, Richard M.; Morris, Lynn.; Kaewkungwal, Jaranit.; Nitayaphan, Sorachai.; Pitisuttithum, Punnee.; Rerks-Ngarm, Supachai.; Sinangil, Faruk.; Phogat, Sanjay.; Michael, Nelson L.; Kim, Jerome H.; Kelsoe, Garnett.; Montefiori, David Charles.; Tomaras, Georgia D.; Bonsignori, Mattia.; Santra, Sampa.; Kepler, Thomas B.; Alam, Shabnam Munir.; Moody, Michael Anthony.; Liao, Hua-Xin.; Haynes, Barton F.
Abstract available in pdf.
Broad neutralization of human immunodeficiency virus type 1 mediated by plasma antibodies against the gp41 membrane proximal external region.
(American Society for Microbiology., 2009) Gray, Elin Solomonovna.; Madiga, Maphuti C.; Moore, Penelope L.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Binley, James M.; Shaw, George M.; Mascola, John R.; Morris, Lynn.
We identified three cross-neutralizing plasma samples with high-titer anti-membrane proximal external region (MPER) peptide binding antibodies from among 156 chronically human immunodeficiency virus type 1-infected individuals. In order to establish if these antibodies were directly responsible for the observed neutralization breadth, we used MPER-coated magnetic beads to deplete plasmas of these specific antibodies. Depletion of anti-MPER antibodies from BB34, CAP206, and SAC21 resulted in 77%, 68%, and 46% decreases, respectively, in the number of viruses neutralized. Antibodies eluted from the beads showed neutralization profiles similar to those of the original plasmas, with potencies comparable to those of the known anti-MPER monoclonal antibodies (MAbs), 4E10, 2F5, and Z13e1. The anti-MPER neutralizing antibodies in BB34 were present in the immunoglobulin G3 subclass-enriched fraction. Alanine scanning of the MPER showed that the antibodies from these three plasmas had specificities distinct from those of the known MAbs, requiring one to three crucial residues at positions 670, 673, and 674. These data demonstrate the existence of MPER-specific cross-neutralizing antibodies in plasma, although the ability to elicit such potent antiviral antibodies during natural infection appears to be rare. Nevertheless, the identification of three novel antibody specificities within the MPER supports its further study as a promising target for vaccine design.
Broadly neutralizing antibodies targeting the HIV-1 envelope V2 apex confer protection against a clade C SHIV challenge.
(American Association for the Advancement of Science., 2017) Julg, Boris.; Tartaglia, Lawrence J.; Keele, Brandon F.; Wagh, Kshitij.; Pegu, Amarendra.; Sok, Devin.; Abbink, Peter.; Schmidt, Stephen D.; Wang, Keyun.; Chen, Xuejun.; Joyce, M. Gordon.; Georgiev, Ivelin S.; Choe, Misook.; Kwong, Peter D.; Doria-Rose, Nicole A.; Le, Khoa.; Louder, Mark K.; Bailer, Robert T.; Moore, Penelope L.; Korber, Bette T. M.; Seaman, Michael S.; Abdool Karim, Salim Safurdeen.; Morris, Lynn.; Koup, Richard A.; Mascola, John R.; Burton, Dennis R.; Barouch, Dan H.
Abstract available in pdf.
Broadly neutralizing antibody specificities detected in the genital tract of HIV-1 infected women.
(Wolters Kluwer., 2016) Mkhize, Nonhlanhla N.; Durgiah, Raveshni.; Ashley, Vicki C.; Archary, Derseree.; Garrett, Nigel Joel.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Moore, Penelope L.; Yates, Nicole L.; Passmore, Jo-Ann Shelley.; Tomaras, Georgia D.; Morris, Lynn.
Abstract available in PDF file..
The C3-V4 region is a major target of autologous neutralizing antibodies in human immunodeficiency virus type 1 subtype C Infection.
(American Society for Microbiology., 2008) Moore, Penelope L.; Gray, Elin Solomonovna.; Choge, Isaac Ang'Ang'A.; Ranchobe, Nthabeleng.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Morris, Lynn.
The early autologous neutralizing antibody response in human immunodeficiency virus type 1 (HIV-1) subtype C infections is often characterized by high titers, but the response is type specific with little to no cross-neutralizing activity. The specificities of these early neutralizing antibodies are not known; however, the type specificity suggests that they may target the variable regions of the envelope. Here, we show that cross-reactive anti-V3 antibodies developed within 3 to 12 weeks in six individuals but did not mediate autologous neutralization. Using a series of chimeric viruses, we found that antibodies directed at the V1V2, V4, and V5 regions contributed to autologous neutralization in some individuals, with V1V2 playing a more substantial role. However, these antibodies did not account for the total neutralizing capacity of these sera against the early autologous virus. Antibodies directed against the C3-V4 region were involved in autologous neutralization in all four sera studied. In two sera, transfer of the C3-V4 region rendered the chimera as sensitive to antibody neutralization as the parental virus. Although the C3 region, which contains the highly variable α2-helix was not a direct target in most cases, it contributed to the formation of neutralization epitopes as substitution of this region resulted in neutralization resistance. These data suggest that the C3 and V4 regions combine to form important structural motifs and that epitopes in this region are major targets of the early autologous neutralizing response in HIV-1 subtype C infection.
Characterization of anti-HIV-1 neutralizing and binding antibodies in chronic HIV-1 subtype C infection.
(Elsevier., 2012) Archary, Derseree.; Rong, Rong.; Gordon, Michelle Lucille.; Boliar, Saikat.; Madiga, Maphuti C.; Gray, Elin Solomonovna.; Dugast, Anne-Sophie.; Hermanus, Tandile.; Goulder, Philip Jeremy Renshaw.; Coovadia, Hoosen Mahomed.; Werner, Lise.; Morris, Lynn.; Alter, Galit.; Derdeyn, Cynthia A.; Ndung'u, Peter Thumbi.
Neutralizing (nAbs) and high affinity binding antibodies may be critical for an efficacious HIV-1 vaccine. We characterized virus-specific nAbs and binding antibody responses over 21 months in eight HIV-1 subtype C chronically infected individuals with heterogeneous rates of disease progression. Autologous nAb titers of study exit plasma against study entry viruses were significantly higher than contemporaneous responses at study entry (p=0.002) and exit (p=0.01). NAb breadth and potencies against subtype C viruses were significantly higher than for subtype A (p=0.03 and p=0.01) or B viruses (p=0.03; p=0.05) respectively. Gp41-IgG binding affinity was higher than gp120-IgG (p=0.0002). IgG–FcγR1 affinity was significantly higher than FcγRIIIa (p<0.005) at study entry and FcγRIIb (p<0.05) or FcγRIIIa (p<0.005) at study exit. Evolving IgG binding suggests alteration of immune function mediated by binding antibodies. Evolution of nAbs was a potential marker of HIV-1 disease progression.
Comparison of viral env proteins from acute and chronic infections with subtype C human immunodeficiency virus type 1 identifies differences in glycosylation and CCR5 utilization and suggests a new strategy for immunogen design.
(American Society for Microbiology., 2013) Ping, Li-Hua.; Joseph, Sarah B.; Anderson, Jeffrey A.; Abrahams, Melissa-Rose.; Salazar-Gonzalez, Jesus F.; Kincer, Laura P.; Treurnicht, Florette K.; Arney, Leslie.; Ojeda, Suany.; Zhang, Ming.; Keys, Jessica.; Potter, E. Lake.; Chu, Haitao.; Moore, Penelope L.; Salazar-Gonzalez, Maria.; Iyer, Shilpa.; Jabara, Cassandra.; Kirchherr, Jennifer.; Mapanje, Clement.; Ngandu, Nobubelo K.; Seoighe, Cathal.; Hoffman, Irving F.; Gao, Feng.; Tang, Yuyang.; Labranche, Celia.; Lee, Benhur.; Saville, Andrew.; Vermeulen, Marion.; Fiscus, Susan A.; Morris, Lynn.; Abdool Karim, Salim Safurdeen.; Haynes, Barton F.; Shaw, George M.; Korber, Bette T. M.; Hahn, Beatrice H.; Cohen, Myron S.; Montefiori, David Charles.; Williamson, Carolyn.; Swanstrom, Ronald.
Understanding human immunodeficiency virus type 1 (HIV-1) transmission is central to developing effective prevention strategies, including a vaccine.We compared phenotypic and genetic variation in HIV-1 env genes from subjects in acute/early infection and subjects with chronic infections in the context of subtype C heterosexual transmission.We found that the transmitted viruses all used CCR5 and required high levels of CD4 to infect target cells, suggesting selection for replication in T cells and not macrophages after transmission. In addition, the transmitted viruses were more likely to use a maraviroc-sensitive conformation of CCR5, perhaps identifying a feature of the target T cell.We confirmed an earlier observation that the transmitted viruses were, on average, modestly under-glycosylated relative to the viruses from chronically infected subjects. This difference was most pronounced in comparing the viruses in acutely infected men to those in chronically infected women. These features of the transmitted virus point to selective pressures during the transmission event.We did not observe a consistent difference either in heterologous neutralization sensitivity or in sensitivity to soluble CD4 between the two groups, suggesting similar conformations between viruses from acute and chronic infection. However, the presence or absence of glycosylation sites had differential effects on neutralization sensitivity for different antibodies.We suggest that the occasional absence of glycosylation sites encoded in the conserved regions of env, further reduced in transmitted viruses, could expose specific surface structures on the protein as antibody targets.
Cooperation between strain-specific and broadly neutralizing responses limited viral escape and prolonged the exposure of the broadly neutralizing epitope.
(American Society for Microbiology., 2017) Anthony, Colin S.; York, Talita.; Bekker, Valerie.; Matten, David.; Selhorst, Philippe.; Ferreria, Roux-Cil.; Garrett, Nigel Joel.; Abdool Karim, Salim Safurdeen.; Morris, Lynn.; Wood, Natasha T.; Moore, Penelope L.; Williamson, Carolyn.
Abstract available in pdf.
Delineating antibody recognition in polyclonal sera from patterns of HIV-1 isolate neutralization.
(American Association for the Advancement of Science., 2012) Georgiev, Ivelin S.; Doria-Rose, Nicole A.; Zhou, Tongqing.; Do Kwon, Young.; Staupe, Ryan P.; Moquin, Stephanie.; Chuang, Gwo-Yu.; Louder, Mark K.; Schmidt, Stefan.; Altae-Tran, Han R.; Bailer, Robert T.; McKee, Krisha.; Nason, Martha.; O'Dell, Sijy.; Ofek, Gilad.; Pancera, Marie.; Srivatsan, Sanjay.; Shapiro, Lawrence.; Connors, Mark.; Migueles, Stephen A.; Morris, Lynn.; Nishimura, Yoshiaki.; Martin, Malcolm A.; Mascola, John R.; Kwong, Peter D.
Serum characterization and antibody isolation are transforming our understanding of the humoral immune response to viral infection. Here, we show that epitope specificities of HIV-1–neutralizing antibodies in serum can be elucidated from the serum pattern of neutralization against a diverse panel of HIV-1 isolates. We determined “neutralization fingerprints” for 30 neutralizing antibodies on a panel of 34 diverse HIV-1 strains and showed that similarity in neutralization fingerprint correlated with similarity in epitope. We used these fingerprints to delineate specificities of polyclonal sera from 24 HIV-1–infected donors and a chimeric siman-human immunodeficiency virus–infected macaque. Delineated specificities matched published specificities and were further confirmed by antibody isolation for two sera. Patterns of virus-isolate neutralization can thus afford a detailed epitope-specific understanding of neutralizing-antibody responses to viral infection.
Development of broadly neutralizing antibodies from autologous neutralizing antibody responses.
(Lippincott Williams & Wilkins., 2014) Derdeyn, Cynthia A.; Moore, Penelope L.; Morris, Lynn.
Abstract available in pdf.
The development of CD4 binding site antibodies during HIV-1 infection.
(American Society for Microbiology., 2012) Lynch, Rebecca M.; Tran, Lillian.; Louder, Mark K.; Schmidt, Stephen D.; Cohen, Myron S.; DerSimonian, Rebecca.; Euler, Zelda.; Gray, Elin Solomonovna.; Abdool Karim, Salim Safurdeen.; Kirchherr, Jennifer.; Montefiori, David Charles.; Sibeko, Sengeziwe.; Soderberg, Kelly.; Tomaras, Georgia D.; Yang, Zhi-Yong.; Nabel, Gary J.; Schuitemaker, Hanneke.; Morris, Lynn.; Haynes, Barton F.; Mascola, John R.
Broadly neutralizing antibodies to the CD4 binding site (CD4bs) of gp120 are generated by some HIV-1-infected individuals, but little is known about the prevalence and evolution of this antibody response during the course of HIV-1 infection. We analyzed the sera of 113 HIV-1 seroconverters from three cohorts for binding to a panel of gp120 core proteins and their corresponding CD4bs knockout mutants. Among sera collected between 99 and 258 weeks post-HIV-1 infection, 88% contained antibodies to the CD4bs and 47% contained antibodies to resurfaced stabilized core (RSC) probes that react preferentially with broadly neutralizing CD4bs antibodies (BNCD4), such as monoclonal antibodies (MAbs) VRC01 and VRC-CH31. Analysis of longitudinal serum samples from a subset of 18 subjects revealed that CD4bs antibodies to gp120 arose within the first 4 to 16 weeks of infection, while the development of RSC-reactive antibodies was more varied, occurring between 10 and 152 weeks post-HIV-1 infection. Despite the presence of these antibodies, serum neutralization mediated by RSC-reactive antibodies was detected in sera from only a few donors infected for more than 3 years. Thus, CD4bs antibodies that bind a VRC01-like epitope are often induced during HIV-1 infection, but the level and potency required to mediate serum neutralization may take years to develop. An improved understanding of the immunological factors associated with the development and maturation of neutralizing CD4bs antibodies during HIV-1 infection may provide insights into the requirements for eliciting this response by vaccination.
Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies.
(Macmillan Publishers Limited., 2014) Doria-Rose, Nicole A.; Schramm, Chaim A.; Gorman, Jason.; Moore, Penelope L.; Bhiman, Jinal N.; DeKosky, Brandon J.; Ernandes, Michael J.; Georgiev, Ivelin S.; Kim, Helen J.; Pancera, Marie.; Staupe, Ryan P.; Altae-Tran, Han R.; Bailer, Robert T.; Crooks, Ema T.; Druz, Aliaksandr.; Garrett, Nigel Joel.; Hoi, Kam H.; Kong, Rui.; Louder, Mark K.; Longo, Nancy S.; McKee, Krisha.; Nonyane, Molati.; O’Dell, Sijy.; Roark, Ryan S.; Rudicell, Rebecca S.; Schmidt, Stephen D.; Sheward, Daniel J.; Soto, Cinque.; Wibmer, Constantinos Kurt.; Yang, Yongping.; Zhang, Zhenhai.; Mullikin, James C.; Binley, James M.; Sanders, Rogier W.; Wilson, Ian A.; Moore, John P.; Ward, Andrew B.; Georgiou, George.; Williamson, Carolyn.; Abdool Karim, Salim Safurdeen.; Morris, Lynn.; Kwong, Peter D.; Shapiro, Lawrence.; Mascola, John R.
Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development.
Differences in HIV-1 neutralization breadth in two geographically distinct cohorts in Africa.
(Oxford University Press., 2015) Bandawe, Gama P.; Moore, Penelope L.; Werner, Lise.; Gray, Elin Solomonovna.; Sheward, Daniel J.; Madiga, Maphuti C.; Nofemela, Andile.; Thebus, Ruwayhida.; Marais, Jinny C.; Maboko, Leonard.; Abdool Karim, Salim Safurdeen.; Hoelscher, Michael.; Morris, Lynn.; Williamson, Carolyn.
Abstract available in pdf.
Distinct genital tract HIV-specific antibody profiles associated with Tenofovir gel.
(Nature., 2016) Archary, Derseree.; Seaton, Kelly E.; Passmore, Jo-Ann Shelley.; Werner, Lise.; Deal, Aaron W.; Dunphy, Laura J.; Arnold, Kelly B.; Yates, Nicole L.; Lauffenburger, Douglas A.; Bergin, Philip.; Liebenberg, Lenine Julie.; Samsunder, Natasha.; Mureithi, Marianne W.; Altfeld, Marcus.; Garrett, Nigel Joel.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Morris, Lynn.; Tomaras, Georgia D.
Abstract available in PDF file.
Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women.
(American Association for the Advancement of Science., 2010) Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Fröhlich, Janet Ann.; Grobler, Anna Christina.; Baxter, Cheryl.; Mansoor, Leila Essop.; Kharsany, Ayesha Bibi Mahomed.; Sibeko, Sengeziwe.; Mlisana, Koleka Patience.; Omar, Zaheen.; Gengiah, Tanuja Narayansamy.; Maarschalk, Silvia.; Arulappan, Natasha.; Mlotshwa, Mukelisiwe.; Morris, Lynn.; Taylor, Douglas.
The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18- to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use.
Establishing a cohort at high risk of HIV infection in South Africa: challenges and experiences of the CAPRISA 002 Acute Infection Study.
(Plos., 2007) van Loggerenberg, Francois.; Mlisana, Koleka Patience.; Williamson, Carolyn.; Auld, Sara C.; Morris, Lynn.; Gray, Clive M.; Abdool Karim, Quarraisha.; Grobler, Anna Christina.; Barnabas, Nomampondo.; Iriogbe, Itua.; Abdool Karim, Salim Safurdeen.
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.
Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape.
(Nature Publishing Group., 2012) Moore, Penelope L.; Gray, Elin Solomonovna.; Wibmer, Constantinos Kurt.; Bhiman, Jinal N.; Nonyane, Molati.; Hermanus, Tandile.; Sheward, Daniel J.; Bajimaya, Shringkhala.; Abrahams, Melissa-Rose.; Tumba, Nancy Lola.; Ping, Li-Hua.; Ngandu, Nobubelo K.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Swanstrom, Ronald.; Seaman, Michael S.; Williamson, Carolyn.; Morris, Lynn.;
Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful, a minority of individuals naturally develop these antibodies after many years of infection. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1–infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes.
Features of recently transmitted HIV-1 clade C viruses that impact antibody recognition : implications for active and passive immunization.
(Public Library of Science., 2016) Rademeyer, Cecilia.; Korber, Bette T. M.; Seaman, Michael S.; Giorgi, Elena E.; Thebus, Ruwayhida.; Robles, Alexander.; Sheward, Daniel J.; Wagh, Kshitij.; Garrity, Jetta.; Carey, Brittany R.; Gao, Hongmei.; Greene, Kelli M.; Tang, Haili.; Bandawe, Gama P.; Marais, Jinny C.; Diphoko, Thabo E.; Hraber, Peter.; Tumba, Nancy Lola.; Moore, Penelope L.; Gray, Glenda Elizabeth.; Kublin, James.; McElrath, Margaret Juliana.; Vermeulen, Marion.; Middelkoop, Keren.; Bekker, Linda-Gail.; Hoelscher, Michael.; Maboko, Leonard.; Makhema, Joseph.; Robb, Merlin L.; Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Kim, Jerome H.; Hahn, Beatrice H.; Gao, Feng.; Swanstrom, Ronald.; Morris, Lynn.; Montefiori, David Charles.; Williamson, Carolyn.
Abstract available in PDF file.