S021-06 OA. Potent and broad neutralizing antibodies from HIV-1 non-clade B infected donor reveal a new HIV-1 vaccine target

Phogat, SK; Walker, Laura M.; Wagner, Denise; Chan-Hui, Po-Ying; Simek, Melissa; Phung, Pham; Wrin, Terri; Mitcham, Jennifer L.; Investigator, P; Kaminsky, Stephen M.; Zamb, Timothy J.; Moyle, Matthew; Koff, Wayne C.; Burton, Dennis R.

doi:10.1186/1742-4690-6-s3-o6

Cited by 2 publications

(1 citation statement)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Four of these sites were also targeted by at least one of the non-bNAb donors, indicating that strain-specific V1V2 antibodies overlapped somewhat with bNAbs. Many of these sites (160/162, 166, 169, and 181) have previously been reported to mediate escape from V1V2-directed bNAbs (17, 49–51), and all are located proximal to one another at the apex of the envelope trimer (Fig. 4B).…”

Section: Resultsmentioning

confidence: 89%

Positive Selection at Key Residues in the HIV Envelope Distinguishes Broad and Strain-Specific Plasma Neutralizing Antibodies

Mabvakure

Scheepers

Garrett

et al. 2019

J Virol

View full text Add to dashboard Cite

The development of HIV broadly neutralizing antibodies (bNAbs) has previously been shown to be associated with viral evolution and high levels of genetic diversity in the HIV envelope (Env) glycoprotein. However, few studies have examined Env evolution in those who fail to develop neutralization breadth in order to assess whether bNAbs result from distinct evolutionary pathways. We compared Env evolution in eight HIV-1-infected participants who developed bNAbs to six donors with similar viral loads who did not develop bNAbs over three years of infection. We focused on Env V1V2 and C3V4, as these are major targets for both strain-specific neutralizing antibodies (nAbs) and bNAbs. Overall evolutionary rates (ranging from 9.92 × 10−3to 4.1 × 10−2substitutions/site/year) and viral diversity (from 1.1% to 6.5%) across Env, and within targeted epitopes, did not distinguish bNAb donors from non-bNAb donors. However, bNAb participants had more positively selected residues within epitopes than those without bNAbs, and several of these were common among bNAb donors. A comparison of the kinetics of strain-specific nAbs and bNAbs indicated that selection pressure at these residues increased with the onset of breadth. These data suggest that highly targeted viral evolution rather than overall envelope diversity is associated with neutralization breadth. The association of shared positively selected sites with the onset of breadth highlights the importance of diversity at specific positions in these epitopes for bNAb development, with implications for the development of sequential and cocktail immunization strategies.IMPORTANCEMillions of people are still being infected with HIV decades after the first recognition of the virus. Currently, no vaccine is able to elicit bNAbs that will prevent infection by global HIV strains. Several studies have implicated HIV Env diversity in the development of breadth. However, Env evolution in individuals who fail to develop breadth despite mounting potent strain-specific neutralizing responses has not been well defined. Using longitudinal neutralization, epitope mapping, and sequence data from 14 participants, we found that overall measures of viral diversity were similar in all donors. However, the number of positively selected sites within Env epitopes was higher in bNAb participants than in strain-specific donors. We further identified common sites that were positively selected as bNAbs developed. These data indicate that while viral diversity is required for breadth, this should be highly targeted to specific residues to shape the elicitation of bNAbs by vaccination.

show abstract

Section: Resultsmentioning

confidence: 89%

Positive Selection at Key Residues in the HIV Envelope Distinguishes Broad and Strain-Specific Plasma Neutralizing Antibodies

Mabvakure

Scheepers

Garrett

et al. 2019

J Virol

View full text Add to dashboard Cite

show abstract

Fight fire with fire: the need for a vaccine based on intrinsic disorder and structural flexibility

Uversky

2022

Explor Immunol

View full text Add to dashboard Cite

The absence of advancement in finding efficient vaccines for several human viruses, such as hepatitis C virus (HCV), human immunodeficiency virus type 1 (HIV-1), and herpes simplex viruses (HSVs) despite 30, 40, and even 60 years of research, respectively, is unnerving. Among objective reasons for such failure are the highly glycosylated nature of proteins used as primary vaccine targets against these viruses and the presence of neotopes and cryptotopes, as well as high mutation rates of the RNA viruses HCV and HIV-1 and the capability to establish latency by HSVs. However, the lack of success in utilization of the structure-based reverse vaccinology for these viruses is likely to be related to the presence of highly flexible and intrinsically disordered regions in human antibodies (Abs) and the major immunogens of HIV-1, HCV, and HSVs, their surface glycoproteins. This clearly calls for moving from the rational structure-based vaccinology to the unstructural vaccinology based on the utilization of tools designed for the analysis of disordered and flexible proteins, while looking at intrinsically disordered viral antigens and their interactions with intrinsically disordered/flexible Abs.

show abstract

S021-06 OA. Potent and broad neutralizing antibodies from HIV-1 non-clade B infected donor reveal a new HIV-1 vaccine target

Cited by 2 publications

References 0 publications

Positive Selection at Key Residues in the HIV Envelope Distinguishes Broad and Strain-Specific Plasma Neutralizing Antibodies

Positive Selection at Key Residues in the HIV Envelope Distinguishes Broad and Strain-Specific Plasma Neutralizing Antibodies

Fight fire with fire: the need for a vaccine based on intrinsic disorder and structural flexibility

Contact Info

Product

Resources

About