Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 Dec;82(24):12449-63.
doi: 10.1128/JVI.01708-08. Epub 2008 Oct 8.

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

Georgia D Tomaras  1 , Nicole L Yates, Pinghuang Liu, Li Qin, Genevieve G Fouda, Leslie L Chavez, Allan C Decamp, Robert J Parks, Vicki C Ashley, Judith T Lucas, Myron Cohen, Joseph Eron, Charles B Hicks, Hua-Xin Liao, Steven G Self, Gary Landucci, Donald N Forthal, Kent J Weinhold, Brandon F Keele, Beatrice H Hahn, Michael L Greenberg, Lynn Morris, Salim S Abdool Karim, William A Blattner, David C Montefiori, George M Shaw, Alan S Perelson, Barton F Haynes
Affiliations

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

Georgia D Tomaras et al. J Virol. 2008 Dec.

Abstract

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.

PubMed Disclaimer

Figures

FIG. 1.
FIG. 1.
(A) VL kinetics of 21 HIV+ seroconversion plasma donor panels (eclipse phase clade B infection) were determined. The alignment of the subjects was by T0, the first day that VL reached 100 copies/ml. (B) Histogram displaying the total number of samples studied for each day, relative to the first detectable day of viremia (T0). Bins represent intervals of 10 days.
FIG. 2.
FIG. 2.
(A) Kaplan Meier plot of anti-gp41 and anti-gp120 antibody responses in the eclipse phase clade B plasma donor cohort. The solid line shows the increasing percentage of the population that develops HIV-specific antibody responses at each time interval following the calculated T0. The dashed lines indicate the upper and lower point-wise confidence intervals, respectively. (B) Pairwise comparison of the timing of anti-Env antibody responses compared anti-Gag (p24, p17, and p55) and anti-Pol (p31) responses in the eclipse phase clade B plasma donor cohort. The solid line (from left to right) indicates the median day of antibody elevation from T0, and the gaps in the line indicate the HIV-specific antibody responses that group together relative to their time of elevation from T0. The values above the lines are q values for pairwise tests of differences between adjacent groups of antibody specificities. ns, no statistically significant pairwise difference within the group of antibody specificity. The median time for appearance of IgG anti-gp41 antibody was 13.5 days (A), while the median time for appearance of IgG gp120 antibody was 28 days (B).
FIG. 3.
FIG. 3.
Anti-gp41 IgM antibodies are the first detectable HIV antibodies, and autologous gp140-transmitted Env or consensus Env gp140 proteins are equally sensitive for the detection of the first antibody isotypes in HIV infection. IgM antibodies (A), IgG antibodies (B), and IgA antibodies (C) were detected using either consensus gp140 (ConB) or autologous Env (6246 Env). The asterisk indicates the plasma sample from which the autologous gp140 Env was derived. The consensus gp160 oligomer detects anti-gp41 antibodies at the same time as autologous gp140 Env oligomers. MFI, mean fluorescence intensity.
FIG. 4.
FIG. 4.
Kinetics of anti-gp41-specific antibody isotypes in acute HIV infection. Representative examples of sequential development (A) and simultaneous development (B) of early HIV-specific antibody responses are shown. (C) The percentage of patients in each of the three cohorts that displayed different kinetic patterns. (D) Simultaneous development of Gag-specific antibody responses. Anti-p55 antibodies of the IgM, IgG, and IgA isotypes were measured for all subjects in the eclipse phase clade B cohort. Subject 12007 could not be aligned to T0 due to the large interval between the first RNA-positive sample and the last RNA-negative sample. However, the short interval between antibody-positive and antibody-negative responses enabled measurement of antibody isotype kinetics, so the panel was aligned to T0 as the first RNA-positive sample. Pt, patient.
FIG. 5.
FIG. 5.
HIV immune complexes produced at a median time of 8.0 days after T0. The detection of immune complexes for patients (Pt) 9015, 12008, 9077, 9079, 9021, and 9076 are aligned to T0 and plotted in comparison to the detection of free antibody (Ab) responses.
FIG. 6.
FIG. 6.
Ontogeny of complement binding antibodies during acute HIV-1 infection in times post-T0. Two representative patients (Pt) from the eclipse phase cohort (6240 and 6246) that had detectable HIV-specific antibodies were assessed for complement activation with an early virus isolate, HIV QH0692, and a laboratory-adapted isolate, HIV SF162.
FIG. 7.
FIG. 7.
(A) No hypergammaglobulinemia observed within the first 40 days of acute infection. Total antibody levels were measured at the first HIV-negative (HIV−)sample and the last sample in the panel (HIV+). The median concentration across panels is indicated. (B) Detection of rheumatoid factor (RF) during HIV acute phase viremia. IgM rheumatoid factor was measured using standard ELISA detection with positive rheumatoid factor controls. VL is measured in RNA copies/ml. Pt, patient.
FIG. 8.
FIG. 8.
Modeling the effect of antibody on plasma viremia in AHI with the target cell-limited model. The target cell-limited model is the best-fitting model for the plasma donors studied except 9032. For 9032, a model with virion clearance enhanced by the sum of anti-gp41 IgM and IgG provides the best fit.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aasa-Chapman, M. M., A. Hayman, P. Newton, D. Cornforth, I. Williams, P. Borrow, P. Balfe, and A. McKnight. 2004. Development of the antibody response in acute HIV-1 infection. Aids 18371-381. - PubMed
    1. Alam, S. M., R. M. Scearce, R. J. Parks, K. Plonk, S. G. Plonk, L. L. Sutherland, M. K. Gorny, S. Zolla-Pazner, S. Vanleeuwen, M. A. Moody, S. M. Xia, D. C. Montefiori, G. D. Tomaras, K. J. Weinhold, S. A. Karim, C. B. Hicks, H. X. Liao, J. Robinson, G. M. Shaw, and B. F. Haynes. 2008. Human immunodeficiency virus type 1 gp41 antibodies that mask membrane proximal region epitopes: antibody binding kinetics, induction, and potential for regulation in acute infection. J. Virol. 82115-125. - PMC - PubMed
    1. Berberian, L., L. Goodglick, T. J. Kipps, and J. Braun. 1993. Immunoglobulin VH3 gene products: natural ligands for HIV gp120. Science 2611588-1591. - PubMed
    1. Brenchley, J. M., T. W. Schacker, L. E. Ruff, D. A. Price, J. H. Taylor, G. J. Beilman, P. L. Nguyen, A. Khoruts, M. Larson, A. T. Haase, and D. C. Douek. 2004. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J. Exp. Med. 200749-759. - PMC - PubMed
    1. Carne, C. A., R. S. Tedder, A. Smith, S. Sutherland, S. G. Elkington, H. M. Daly, F. E. Preston, and J. Craske. 1985. Acute encephalopathy coincident with seroconversion for anti-HTLV-III. Lancet 21206-1208. - PubMed

Publication types

Substances

LinkOut - more resources