Antigenicity and Immunogenicity of Transmitted/Founder, Consensus, and Chronic Envelope Glycoproteins of Human Immunodeficiency Virus Type 1

Liao, Hua‐Xin; Tsao, Chun-Yen; Alam, S. Munir; Muldoon, Mark; Vandergrift, Nathan; Ma, Benjiang; Lu, Xiaozhi; Sutherland, Laura L.; Scearce, Richard M.; Bowman, Cindy; Parks, Robert; Chen, Haiyan; Blinn, Julie; Lapedes, Alan S.; Watson, Sydeaka; Xia, Shi-Mao; Foulger, Andrew; Hahn, Beatrice H.; Shaw, George M.; Swanstrom, R.; Montefiori, David C.; Gao, Feng; Haynes, Barton F.; Korber, Bette

doi:10.1128/jvi.02297-12

Cited by 86 publications

(106 citation statements)

References 79 publications

(80 reference statements)

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…Only tier 1A viruses were neutralized at moderate to high levels, and similar to previous vaccine studies (12,17,19,35,36,48), almost no autologous neutralization was elicited (data not shown). This lack of autologous neutralization and limited heterologous neutralization compared to the moderate cross-clade neutralization breadth in the infected VC10014 and VC20013 subjects could be explained by several factors.…”

Section: Discussionsupporting

confidence: 87%

“…Therefore, despite testing Env immunogens derived from different subjects who developed moderate cross-clade neutralization breadth through distinct pathways (51) and with different kinetics, our data show that a common vaccine strategy based on Envs derived from the time points preceding, or contemporaneous with, the development of breadth is a promising approach to elicit NAbs in vaccinated animals. The potential of sequential immunization with early variants from broad neutralizers was also observed in recent studies showing that concomitant antibody maturation and virus evolution occurred in a subject with breadth (21) and that transmitter/founder Env immunogens elicited low, but broader NAb responses than consensus or chronic Envs (17).…”

Section: Discussionsupporting

confidence: 52%

“…Other vaccine studies in guinea pigs or rabbits comparing Envs derived from elite neutralizers, T/F sequences, and consensus Envs have resulted in similar, modest neutralization potency and breadth against panels of viruses and significant variation in individual animals (17,19). These studies, as well as our prior vaccine studies using sequentially derived Envs (47,48), have contributed to an appreciation of the antigenic properties of Env components and how combinations of Envs can be used, but there are still no clearly superior sequences that have been identified.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, a high degree of research effort has been devoted to understanding the development of NAbs in HIV infection (8)(9)(10) in order to inform development of an Env-based vaccine to elicit a broad cross-clade neutralizing response in animal models (7,11). Unfortunately, NAbs elicited by vaccination so far have shown weak to moderate potency and a low degree of neutralization breadth, despite the use of diverse envelopes (Envs) in the vaccines tested (12)(13)(14)(15)(16)(17)(18)(19) and novel approaches to develop re-combinant Env proteins that mimic the native trimeric Env protein (20). In addition, Envs isolated from different human subjects have divergent antigenic and immunogenic properties (11), further complicating the selection criteria for candidate immunogens.…”

mentioning

confidence: 99%

“…Emerging evidence from studies of HIV-infected subjects from the earliest time of infection suggests that founder and subsequent progeny viruses contribute to the broadly neutralizing antibody (bNAb) developmental pathway (17,21,22) and that accumulating amino acid changes driven by autologous NAbs (aNAbs) can account for the extensive variability of env (23)(24)(25), facilitating viral escape (26). Studies of neutralizing human monoclonal antibodies cloned from elite neutralizers reveal unusual characteristics employed to circumvent the evasive mechanisms of HIV Env.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits

Malherbe

Pissani

Sather

et al. 2014

J Virol

View full text Add to dashboard Cite

Identifying characteristics of the human immunodeficiency virus type 1 (HIV-1) envelope that are effective in generating broad, protective antibodies remains a hurdle to HIV vaccine design. Emerging evidence of the development of broad and potent neutralizing antibodies in HIV-infected subjects suggests that founder and subsequent progeny viruses may express unique antigenic motifs that contribute to this developmental pathway. We hypothesize that over the course of natural infection, B cells are programmed to develop broad antibodies by exposure to select populations of emerging envelope quasispecies variants. To test this hypothesis, we identified two unrelated subjects whose antibodies demonstrated increasing neutralization breadth against a panel of HIV-1 isolates over time. Full-length functional env genes were cloned longitudinally from these subjects from months after infection through 2.6 to 5.8 years of infection. Motifs associated with the development of breadth in published, cross-sectional studies were found in both subjects. We compared the immunogenicity of envelope vaccines derived from time points obtained during and after broadening of neutralization activity within these subjects. Rabbits were coimmunized four times with selected multiple gp160 DNAs and gp140-trimeric envelope proteins. The affinity of the polyclonal response increased as a function of boosting. The most rapid and persistent neutralization of multiclade tier 1 viruses was elicited by envelopes that were circulating in plasma at time points prior to the development of 50% neutralization breadth in both human subjects. The breadth elicited in rabbits was not improved by exposure to later envelope variants. These data have implications for vaccine development in describing a target time point to identify optimal envelope immunogens. IMPORTANCEVaccine protection against viral infections correlates with the presence of neutralizing antibodies; thus, vaccine components capable of generating potent neutralization are likely to be critical constituents in an effective HIV vaccine. However, vaccines tested thus far have elicited only weak antibody responses and very modest, waning protection. We hypothesized that B cells develop broad antibodies by exposure to the evolving viral envelope population and tested this concept using multiple envelopes from two subjects who developed neutralization breadth within a few years of infection. We compared different combinations of envelopes from each subject to identify the most effective immunogens and regimens. In each subject, use of HIV envelopes circulating during the early development and maturation of breadth generated more-potent antibodies that were modestly cross neutralizing. These data suggest a new approach to identifying envelope immunogens that may be more effective in generating protective antibodies in humans.A human immunodeficiency virus type 1 (HIV-1) envelope (Env) component that effectively stimulates the humoral arm of the adaptive immune response will be a critical ...

show abstract