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Journal of Virology, December 2008, p. 12449-12463, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.01708-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Initial B-Cell Responses to Transmitted Human Immunodeficiency Virus Type 1: Virion-Binding Immunoglobulin M (IgM) and IgG Antibodies Followed by Plasma Anti-gp41 Antibodies with Ineffective Control of Initial Viremia{triangledown} ,{dagger}

Georgia D. Tomaras,1,2,4* Nicole L. Yates,1,2,{ddagger} Pinghuang Liu,1,2,{ddagger} Li Qin,5 Genevieve G. Fouda,1,2 Leslie L. Chavez,6 Allan C. Decamp,5 Robert J. Parks,1,3 Vicki C. Ashley,1,2 Judith T. Lucas,1,2 Myron Cohen,7 Joseph Eron,7 Charles B. Hicks,3 Hua-Xin Liao,1,3 Steven G. Self,5 Gary Landucci,8 Donald N. Forthal,8 Kent J. Weinhold,1,2,4 Brandon F. Keele,9 Beatrice H. Hahn,9 Michael L. Greenberg,2,§ Lynn Morris,10 Salim S. Abdool Karim,11 William A. Blattner,12 David C. Montefiori,1,2 George M. Shaw,9 Alan S. Perelson,6 and Barton F. Haynes1,3,4

Duke Human Vaccine Institute,1 Departments of Surgery,2 Medicine,3 Immunology, Duke University School of Medicine, Durham, North Carolina 27710,4 Statistical Center for HIV/AIDS Research, Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington,5 Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico,6 University of North Carolina, Chapel Hill, North Carolina,7 University of California, Irvine, California,8 University of Alabama, Birmingham, Alabama,9 National Institute for Communicable Diseases, Johannesburg, South Africa,10 Centre for the AIDS Programme of Research in South Africa, University of KwaZulu Natal, Durban, South Africa,11 Division of Epidemiology and Prevention, Institute of Human Virology, University of Maryland, Baltimore, Maryland 21202,12

Received 11 August 2008/ Accepted 25 September 2008

A window of opportunity for immune responses to extinguish human immunodeficiency virus type 1 (HIV-1) exists from the moment of transmission through establishment of the latent pool of HIV-1-infected cells. A critical time to study the initial immune responses to the transmitted/founder virus is the eclipse phase of HIV-1 infection (time from transmission to the first appearance of plasma virus), but, to date, this period has been logistically difficult to analyze. To probe B-cell responses immediately following HIV-1 transmission, we have determined envelope-specific antibody responses to autologous and consensus Envs in plasma donors from the United States for whom frequent plasma samples were available at time points immediately before, during, and after HIV-1 plasma viral load (VL) ramp-up in acute infection, and we have modeled the antibody effect on the kinetics of plasma viremia. The first detectable B-cell response was in the form of immune complexes 8 days after plasma virus detection, whereas the first free plasma anti-HIV-1 antibody was to gp41 and appeared 13 days after the appearance of plasma virus. In contrast, envelope gp120-specific antibodies were delayed an additional 14 days. Mathematical modeling of the earliest viral dynamics was performed to determine the impact of antibody on HIV replication in vivo as assessed by plasma VL. Including the initial anti-gp41 immunoglobulin G (IgG), IgM, or both responses in the model did not significantly impact the early dynamics of plasma VL. These results demonstrate that the first IgM and IgG antibodies induced by transmitted HIV-1 are capable of binding virions but have little impact on acute-phase viremia at the timing and magnitude that they occur in natural infection.

* Corresponding author. Mailing address: Duke Human Vaccine Institute, Departments of Surgery and Immunology, Duke University Medical Center, Durham, NC 27710. Phone: (919) 681-5598. Fax: (919) 684-5230. E-mail: gdt{at}duke.edu

{triangledown} Published ahead of print on 8 October 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

{ddagger} N.L.Y. and P.L. contributed equally to this work.

§ Present address: b3 bio, Research Triangle Park, NC.

Journal of Virology, December 2008, p. 12449-12463, Vol. 82, No. 24
0022-538X/08/$08.00+0     doi:10.1128/JVI.01708-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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