Browsing by Author "Shaw, George M."

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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.
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.
High titer HIV-1 V3-specific antibodies with broad reactivity but low neutralizing potency in acute infection and following vaccination.
(Elsevier, 2008) Davis, Katie L.; Gray, Elin Solomonovna.; Moore, Penelope L.; Decker, Julie M.; Salomon, Aidy.; Montefiori, David Charles.; Graham, Barney S.; Keefer, Michael C.; Pinter, Abraham.; Morris, Lynn.; Hahn, Beatrice H.; Shaw, George M.
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 IC50 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.
Initial B-Cell responses to transmitted human immunodeficiency virus type 1: virion-binding immunoglobulin M (IgM) and IgG antibodies followed by plasma anti-gp41 antibodies with ineffective control of initial viremia.
(American Society for Microbiology., 2008) Tomaras, Georgia D.; Yates, Nicole L.; Liu, Pinghuang.; Qin, Li.; Fouda, Genevieve Giny.; Chavez, Leslie L.; Decamp, Allan C.; Parks, Robert J.; Ashley, Vicki C.; Lucas, Judith T.; Cohen, Myron S.; Eron, Joseph J.; Hick, Charles B.; Liao, Hua-Xin.; Self, Steven G.; Landucci, Gary.; Forthal, Donald N.; Weinhold, Kent J.; Keele, Brandon F.; Hahn, Beatrice H.; Greenberg, Michael L.; Morris, Lynn.; Abdool Karim, Salim Safurdeen.; Blattner, William A.; Montefiori, David Charles.; Shaw, George M.; Perelson, Alan S.; Haynes, Barton F.
A window of opportunity for immune responses to extinguish human immunodeficiency virus type 1 (HIV-1) exists from the moment of transmission through establishment of the latent pool of HIV-1-infected cells. A critical time to study the initial immune responses to the transmitted/founder virus is the eclipse phase of HIV-1 infection (time from transmission to the first appearance of plasma virus), but, to date, this period has been logistically difficult to analyze. To probe B-cell responses immediately following HIV-1 transmission, we have determined envelope-specific antibody responses to autologous and consensus Envs in plasma donors from the United States for whom frequent plasma samples were available at time points immediately before, during, and after HIV-1 plasma viral load (VL) ramp-up in acute infection, and we have modeled the antibody effect on the kinetics of plasma viremia. The first detectable B-cell response was in the form of immune complexes 8 days after plasma virus detection, whereas the first free plasma anti-HIV-1 antibody was to gp41 and appeared 13 days after the appearance of plasma virus. In contrast, envelope gp120-specific antibodies were delayed an additional 14 days. Mathematical modeling of the earliest viral dynamics was performed to determine the impact of antibody on HIV replication in vivo as assessed by plasma VL. Including the initial anti-gp41 immunoglobulin G (IgG), IgM, or both responses in the model did not significantly impact the early dynamics of plasma VL. These results demonstrate that the first IgM and IgG antibodies induced by transmitted HIV-1 are capable of binding virions but have little impact on acute-phase viremia at the timing and magnitude that they occur in natural infection.
Neutralizing antibody responses in acute human immunodeficiency virus type 1 subtype C infection.
(American society for Microbiology., 2007-03-22) Moore, Penelope L.; Decker, Julie M.; Bibollet-Ruche, F.; Li, Hui.; Leseka, N.; Gray, Elin Solomonovna.; Choge, Isaac Ang'Ang'A.; Abdool Karim, Salim Safurdeen.; Treurnicht, Florette K.; Mlisana, Koleka Patience.; Shaw, George M.; Williamson, Carolyn.; Morris, Lynn.
The study of the evolution and specificities of neutralizing antibodies during the course of human immunodeficiency virus type 1 (HIV-1) infection may be important in the discovery of possible targets for vaccine design. In this study, we assessed the autologous and heterologous neutralization responses of 14 HIV-1 subtype C-infected individuals, using envelope clones obtained within the first 2 months postinfection. Our data show that potent but relatively strain-specific neutralizing antibodies develop within 3 to 12 months of HIV-1 infection. The magnitude of this response was associated with shorter V1-to-V5 envelope lengths and fewer glycosylation sites, particularly in the V1-V2 region. Anti-MPER antibodies were detected in 4 of 14 individuals within a year of infection, while antibodies to CD4-induced (CD4i) epitopes developed to high titers in 12 participants, in most cases before the development of autologous neutralizing antibodies. However, neither anti-MPER nor anti-CD4i antibody specificity conferred neutralization breadth. These data provide insights into the kinetics, potency, breadth, and epitope specificity of neutralizing antibody responses in acute HIV-1 subtype C infection.
Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants.
(American Society for Microbiology., 2008) Abrahams, Melissa-Rose.; Anderson, Jeffrey A.; Giorgi, Elena E.; Seoighe, Cathal.; Mlisana, Koleka Patience.; Liu, Pinghuang.; Athreya, G. S.; Treurnicht, Florette K.; Keele, Brandon F.; Wood, N.; Salazar-Gonzalez, Jesus F.; Bhattacharya, Tanmoy.; Chu, Haitao.; Hoffman, Irving F.; Galvin, S.; Mapanje, Clement.; Kazembe, P.; Thebus, Ruwayhida.; Fiscus, Susan A.; Hide, Winston.; Cohen, Myron S.; Abdool Karim, Salim Safurdeen.; Haynes, Barton F.; Shaw, George M.; Hahn, Beatrice H.; Korber, Bette T. M.; Swanstrom, Ronald.; Williamson, Carolyn.
Identifying the specific genetic characteristics of successfully transmitted variants may prove central to the development of effective vaccine and microbicide interventions. Although human immunodeficiency virus transmission is associated with a population bottleneck, the extent to which different factors influence the diversity of transmitted viruses is unclear. We estimate here the number of transmitted variants in 69 heterosexual men and women with primary subtype C infections. From 1,505 env sequences obtained using a single genome amplification approach we show that 78% of infections involved single variant transmission and 22% involved multiple variant transmissions (median of 3). We found evidence for mutations selected for cytotoxic-T-lymphocyte or antibody escape and a high prevalence of recombination in individuals infected with multiple variants representing another potential escape pathway in these individuals. In a combined analysis of 171 subtype B and C transmission events, we found that infection with more than one variant does not follow a Poisson distribution, indicating that transmission of individual virions cannot be seen as independent events, each occurring with low probability. While most transmissions resulted from a single infectious unit, multiple variant transmissions represent a significant fraction of transmission events, suggesting that there may be important mechanistic differences between these groups that are not yet understood.
Vertical T cell immunodominance and epitope entropy determine HIV-1 escape.
(American Society for Clinical Investigation., 2012) Liu, Michael K. P.; Hawkins, Natalie.; Ritchie, Adam J.; Ganusov, Vitaly.; Whale, Victoria.; Brackenridge, Simon.; Li, Hui.; Pavlicek, Jeffrey W.; Cai, Fangping.; Abrahams, Melissa-Rose.; Treurnicht, Florette K.; Hraber, Peter.; Riou, Catherine.; Gray, Clive M.; Ferrari, Guido.; Tanner, Rachel.; Ping, Li-Hua.; Anderson, Jeffrey A.; Swanstrom, Ronald.; Cohen, Myron S.; Abdool Karim, Salim Safurdeen.; Haynes, Barton F.; Borrow, Persephone.; Perelson, Alan S.; Shaw, George M.; Hahn, Beatrice H.; Williamson, Carolyn.; Korber, Bette T. M.; Gao, Feng.; Self, Steven G.; McMichael, Andrew.; Goonetilleke, Nilu.
HIV-1 accumulates mutations in and around reactive epitopes to escape recognition and killing by CD8+ T cells. Measurements of HIV-1 time to escape should therefore provide information on which parameters are most important for T cell–mediated in vivo control of HIV-1. Primary HIV-1–specific T cell responses were fully mapped in 17 individuals, and the time to virus escape, which ranged from days to years, was measured for each epitope. While higher magnitude of an individual T cell response was associated with more rapid escape, the most significant T cell measure was its relative immunodominance measured in acute infection. This identified subject-level or “vertical” immunodominance as the primary determinant of in vivo CD8+ T cell pressure in HIV-1 infection. Conversely, escape was slowed significantly by lower population variability, or entropy, of the epitope targeted. Immunodominance and epitope entropy combined to explain half of all the variability in time to escape. These data explain how CD8+ T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV-1 escape should be considered in the context of immunodominance.