The goal of this project is to understand how HIV-1 in neutralized by antibodies to its envelope glycoproteins and how primary viruses resist these antibodies. Understanding the neutralizing antibody response to HIV-1 infection is relevant to a full comprehension of viral pathogenesis, and is of particular importance to the rational development of HIV-1 vaccines based, at least in part, on the induction of humoral immunity. In principle, the binding of neutralizing antibodies to HIV virions will reduce their infectivity for CD4+ target cells. However, despite an extremely vigorous antibody response to its envelope glycoproteins, HIV neutralization titers during natural infection are generally weak. Furthermore, no experimental vaccine has yet induced strong, cross-neutralizing antibodies active against primary viruses. We believe that resistance mechanisms evolved by HIV-1 to counter neutralizing antibodies contribute significantly to this problem. During the first four years of this grant, the PI's group helped to characterize and understand these resistance mechanisms. To continue and extend this work he proposed in the 1st Specific Aim to refine and use novel assays of HIV-1 INTERACTIONS WITH cd4+ target cells, and to determine how inhibition of virus binding correlates with neutralization of infectivity. The role of the co-receptors CCR5 and CXCR4 in the neutralization of HIV-1 binding and entry will also be studied. In the second specific aim, he will asses the influence of viral phenotype (co-receptor usage) on the sensitivity of primary HIV-1 isolates to neutralizing antibodies.
His third aim i s to develop new assays for HIV-1 neutralization based on co-receptor transfected cells engineered to express reporter genes such as beta- galactosidase, luciferase and green fluorescent protein, then to use these assays to re-assess the capacity of serum antibodies to neutralize HIV-1.
|Ringe, Rajesh P; Ozorowski, Gabriel; Yasmeen, Anila et al. (2017) Improving the Expression and Purification of Soluble, Recombinant Native-Like HIV-1 Envelope Glycoprotein Trimers by Targeted Sequence Changes. J Virol 91:|
|Acharya, Kriti; Rashad, Adel A; Moraca, Francesca et al. (2017) Recognition of HIV-inactivating peptide triazoles by the recombinant soluble Env trimer, BG505 SOSIP.664. Proteins 85:843-851|
|Sullivan, Jonathan T; Sulli, Chidananda; Nilo, Alberto et al. (2017) High-Throughput Protein Engineering Improves the Antigenicity and Stability of Soluble HIV-1 Envelope Glycoprotein SOSIP Trimers. J Virol 91:|
|Ringe, Rajesh P; Ozorowski, Gabriel; Rantalainen, Kimmo et al. (2017) Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers. J Virol 91:|
|Eggink, Dirk; de Taeye, Steven W; Bontjer, Ilja et al. (2016) HIV-1 Escape from a Peptidic Anchor Inhibitor through Stabilization of the Envelope Glycoprotein Spike. J Virol 90:10587-10599|
|DeSantis, Michael C; Kim, Jin H; Song, Hanna et al. (2016) Quantitative Correlation between Infectivity and Gp120 Density on HIV-1 Virions Revealed by Optical Trapping Virometry. J Biol Chem 291:13088-97|
|van Gils, Marit J; van den Kerkhof, Tom L G M; Ozorowski, Gabriel et al. (2016) An HIV-1 antibody from an elite neutralizer implicates the fusion peptide as a site of vulnerability. Nat Microbiol 2:16199|
|Klasse, P J (2016) How to assess the binding strength of antibodies elicited by vaccination against HIV and other viruses. Expert Rev Vaccines 15:295-311|
|Behrens, Anna-Janina; Vasiljevic, Snezana; Pritchard, Laura K et al. (2016) Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1 Envelope Glycoprotein. Cell Rep 14:2695-706|
|Klasse, P J; LaBranche, Celia C; Ketas, Thomas J et al. (2016) Sequential and Simultaneous Immunization of Rabbits with HIV-1 Envelope Glycoprotein SOSIP.664 Trimers from Clades A, B and C. PLoS Pathog 12:e1005864|
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