Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site

Wu, Xueling; Wang, Charlene; O’Dell, Sijy; Li, Yuxing; Keele, Brandon F.; Yang, Zhongjia; Imamichi, Hiromi; Doria‐Rose, Nicole A.; Hoxie, James A.; Connors, Mark; Shaw, George M.; Wyatt, Richard T.; Mascola, John R.

doi:10.1128/jvi.07139-11

Cited by 77 publications

(98 citation statements)

References 84 publications

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“…Thus, production of less effective almost PVL Abs such as 3BNC55 may be selected in HIV-infected patients in response to evolution of viruses such as T250-4 that are resistant to PVL Abs. A similar in vivo selection scenario has been proposed for VRC03 and VRC06 (27).…”

Section: Resultsmentioning

confidence: 99%

“…We also examined sequences for HIV envelopes isolated from donor 45 (from whom VRC01, VRC03, and NIH45-46 were isolated) (20,23), including 3 early proviral clones sensitive to VRC01 and 26 later clones that were insensitive to VRC01, plus additional Env clones from other individuals with strongly HIV-1-neutralizing sera (27). Variation at the critical gp120 sites (279 gp120 , 280 gp120 , 456 gp120 , 458 gp120 , and 459 gp120 ) correctly predicted sensitivity to PVL Abs for all 29 gp120 sequences from donor 45 (Fig.…”

Section: G54wmentioning

confidence: 99%

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Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120

West¹,

Diskin²,

Nussenzweig

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

218

274

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A large number of anti–HIV-1 antibodies targeting the CD4-binding site (CD4bs) on the envelope glycoprotein gp120 have recently been reported. These antibodies, typified by VRC01, are remarkable for both their breadth and their potency. Crystal structures have revealed a common mode of binding for several of these antibodies; however, the precise relationship among CD4bs antibodies remains to be defined. Here we analyze existing structural and sequence data, propose a set of signature features for potent VRC01-like (PVL) antibodies, and verify the importance of these features by mutagenesis. The signature features explain why PVL antibodies derive from a single germ-line human V H gene segment and why certain gp120 sequences are associated with antibody resistance. Our results bear on vaccine development and structure-based design to improve the potency and breadth of anti-CD4bs antibodies.

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Section: Resultsmentioning

confidence: 99%

Section: G54wmentioning

confidence: 99%

Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120

West¹,

Diskin²,

Nussenzweig

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

218

274

View full text Add to dashboard Cite

show abstract

“…Therefore, the observed variation in SIVsmm more likely results from gradual accrual of mutations over time (i.e., genetic drift) than from rapid selection for immune evasion. In contrast, rapid immune escape is a major aspect of positive selection in HIV-1: most early mutations are concentrated within T cell epitopes (17,18,25,27), viruses within individuals continually evolve to escape from neutralizing antibodies during chronic infection (3,61,91), and HLA imprinting is evident in viruses circulating in different human populations (37,67).…”

Section: Discussionmentioning

confidence: 99%

Distinct Evolutionary Pressures Underlie Diversity in Simian Immunodeficiency Virus and Human Immunodeficiency Virus Lineages

Fischer

Apetrei

Santiago

et al. 2012

J Virol

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iSimian immunodeficiency virus (SIV) infection of rhesus macaques causes immune depletion and disease closely resembling human AIDS and is well recognized as the most relevant animal model for the human disease. Experimental investigations of viral pathogenesis and vaccine protection primarily involve a limited set of related viruses originating in sooty mangabeys (SIVsmm). The diversity of human immunodeficiency virus type 1 (HIV-1) has evolved in humans in about a century; in contrast, SIV isolates used in the macaque model evolved in sooty mangabeys over millennia. To investigate the possible consequences of such different evolutionary histories for selection pressures and observed diversity in SIVsmm and HIV-1, we isolated, sequenced, and analyzed 20 independent isolates of SIVsmm, including representatives of 7 distinct clades of viruses isolated from natural infection. We found SIVsmm diversity to be lower overall than HIV-1 M group diversity. Reduced positive selection (i.e., less diversifying evolution) was evident in extended regions of SIVsmm proteins, most notably in Gag p27 and Env gp120. In addition, the relative diversities of proteins in the two lineages were distinct: SIVsmm Env and Gag were much less diverse than their HIV-1 counterparts. This may be explained by lower SIV-directed immune activity in mangabeys relative to HIV-1-directed immunity in humans. These findings add an additional layer of complexity to the interpretation and, potentially, to the predictive utility of the SIV/macaque model, and they highlight the unique features of human and simian lentiviral evolution that inform studies of pathogenesis and strategies for AIDS vaccine design.

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“…Clinical studies on individuals with broadly cross-neutralizing Abs showed that these individuals had higher viral loads and that the breadth of NAbs did not affect disease progression (12,15,46), confounding a clear role for NAbs in preventing viral pathogenesis. Indeed, escape from neutralization was also observed in individuals from whom highly potent broadly cross-neutralizing antibodies were derived (7,8,65). Since clinical outcome and disease progression in HIV infection are affected by many other factors, such as host genetics, diversity of the infecting virus, and difference in routes of infection, it is difficult to evaluate the effect of NAbs on HIV-1 disease progression in such clinical studies.…”

mentioning

confidence: 99%

Sequential Evolution and Escape from Neutralization of Simian Immunodeficiency Virus SIVsmE660 Clones in Rhesus Macaques

Ourmanov

Kuwata

et al. 2012

J Virol

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Simian immunodeficiency virus (SIV) infection of rhesus macaques has become an important surrogate model for evaluating HIV vaccine strategies. The extreme resistance to neutralizing antibody (NAb) of many commonly used strains, such as SIVmac251/239 and SIVsmE543-3, limits their potential relevance for evaluating the role of NAb in vaccine protection. In contrast, SIVsmE660 is an uncloned virus that appears to be more sensitive to neutralizing antibody. To evaluate the role of NAb in this model, we generated full-length neutralization-sensitive molecular clones of SIVsmE660 and evaluated two of these by intravenous inoculation of rhesus macaques. All animals became infected and maintained persistent viremia that was accompanied by a decline in memory CD4+T cells in blood and bronchoalveolar lavage fluid. High titers of autologous NAb developed by 4 weeks postinoculation but were not associated with control of viremia, and neutralization escape variants were detected concurrently with the generation of NAb. Neutralization escape was associated with substitutions and insertion/deletion polymorphisms in the V1 and V4 domains of envelope. Analysis of representative variants revealed that escape variants also induced NAbs within a few weeks of their appearance in plasma, in a pattern that is reminiscent of the escape of human immunodeficiency virus type 1 (HIV-1) isolates in humans. Although early variants maintained a neutralization-sensitive phenotype, viruses obtained later in infection were significantly less sensitive to neutralization than the parental viruses. These results indicate that NAbs exert selective pressure that drives the evolution of the SIV envelope and that this model will be useful for evaluating the role of NAb in vaccine-mediated protection.

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Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site

Cited by 77 publications

References 84 publications

Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120

Structural basis for germ-line gene usage of a potent class of antibodies targeting the CD4-binding site of HIV-1 gp120

Distinct Evolutionary Pressures Underlie Diversity in Simian Immunodeficiency Virus and Human Immunodeficiency Virus Lineages

Sequential Evolution and Escape from Neutralization of Simian Immunodeficiency Virus SIVsmE660 Clones in Rhesus Macaques

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