Simulation of HIV-1 Molecular Evolution in Response to Chemokine Coreceptors and Antibodies
- 585 Downloads
The form of the neutralizing antibody response to human immunodeficiency virus type 1 (HIV-1) and the evolutionary response by the virus are poorly understood. In order for a virus particle (virion) to infect a cell, exterior envelope glycoprotein (gp120) molecules on the virion’s surface must interact with receptors on the cell’s surface. Antibodies that bind to gp120 may neutralize a virion by interfering with these interactions. Therefore, gp120 is expected to evolve in response to selection by both cell-surface receptors and antibodies. The rate of such adaptation and the constraints imposed by a response to one selective force on the response to the other are unknown. Here, I describe a simulation modeling approach to these problems. The population of viral genomes infecting a single patient is represented by the intensely studied third variable (V3) region of gp120, the main determinant of which chemokine coreceptor a virion uses to enter a cell, and an important target of neutralizing antibodies. Mutation and recombination are applied by realistically simulating the viral replication cycle. Selection by chemokine coreceptors is simulated by taking advantage of the fact that mean site-specific amino acid frequencies are measures of the site-specific marginal fitnesses of amino acids in relation to coreceptor interactions. Selection by antibodies is imposed by simulating the affinity maturation of B-cell lineages that produce neutralizing antibodies to HIV-1 V3. These simulations make clear predictions about the functional cost of adaptation to antibody surveillance, which may help explain the pattern of chemokine coreceptor usage by HIV-1.
KeywordsViral Population Affinity Maturation Neutralize Antibody Response Antibody Selection Chemokine Coreceptor
Unable to display preview. Download preview PDF.
- Cauerhff, A., Goldbaum, F.A., and Braden, B.C. (2004) Structural mechanism for affinity maturation of an anti-lysozyme antibody. Proc. Natl. Acad. Sci. USA 101:3539-3544.Google Scholar
- Coffin, J.M. (1999) In: K.A. Crandall (Ed.), The Evolution of HIV. Johns Hopkins University Press, Baltimore, pp. 3-40.Google Scholar
- da Silva, J. (2006b) In: A.Y. Zomaya (Ed.), Parallel Computing for Bioinformatics and Computational Biology. John Wiley & Sons, New York, pp. 29-57.Google Scholar
- Frank, S.A. (2002) Immunology and Evolution of Infectious Disease. Princeton University Press, Princeton.Google Scholar
- Gorny, M.K., Williams, C., Volsky, B., Revesz, K., Cohen, S., Polonis, V.R., Honnen, W.J., Kayman, S.C., Krachmarov, C., Pinter, A., and Zolla-Pazner, S. (2002) Human monoclonal antibodies specific for conformation-sensitive epitopes of V3 neutralize human immunodeficiency virus type 1 primary isolates from various clades. J. Virol. 76:9035-9045.PubMedCrossRefGoogle Scholar
- Toran, J.L., Kremer, L., Sanchez-Pulido, L., de Alboran, I.M., del Real, G., Llorente, M., Valencia, A., de Mon, M.A., and Martinez, A.C. (1999) Molecular analysis of HIV-1 gp120 antibody response using isotype IgM and IgG phage display libraries from a long-term non-progressor HIV-1-infected individual. Eur. J. Immunol. 29:2666-2675.PubMedCrossRefGoogle Scholar