Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection

doi:10.1084/jem.193.2.169

Published online 15 January 2001.

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© The Rockefeller University Press, 0022-1007/2001/1/169/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 2, January 15, 2001 169-180

Original Article

Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection

Marcus Altfeld^a, Eric S. Rosenberg^a, Raj Shankarappa^d, Joia S. Mukherjee^a, Frederick M. Hecht^c, Robert L. Eldridge^a, Marylyn M. Addo^a, Samuel H. Poon^a, Mary N. Phillips^a, Gregory K. Robbins^a, Paul E. Sax^e, Steve Boswell^f, James O. Kahn^b^,c, Christian Brander^a, Philip J.R. Goulder^a, Jay A. Levy^b, James I. Mullins^d, and Bruce D. Walker^a

^a Partners AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129
^b Department of Medicine, University of California, San Francisco, California 94143
^c Positive Health Program, University of California at San Francisco, San Francisco, California 94143
^d Department of Microbiology, University of Washington, Seattle, Washington 98195
^e Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
^f Fenway Community Health Center, Boston, Massachusetts 02116
MGH-East, CNY 5212, 149 13th St., Charlestown, MA 02129.617-726-4691617-724-8332

bwalker{at}helix.mgh.harvard.edu

Immune responses induced during the early stages of chronicviral infections are thought to influence disease outcome. UsingHIV as a model, we examined virus-specific cytotoxic T lymphocytes(CTLs), T helper cells, and viral genetic diversity in relationto duration of infection and subsequent response to antiviraltherapy. Individuals with acute HIV-1 infection treated beforeseroconversion had weaker CTL responses directed at fewer epitopesthan persons who were treated after seroconversion. However,treatment-induced control of viremia was associated with thedevelopment of strong T helper cell responses in both groups.After 1 yr of antiviral treatment initiated in acute or earlyinfection, all epitope-specific CTL responses persisted despiteundetectable viral loads. The breadth and magnitude of CTL responsesremained significantly less in treated acute infection thanin treated chronic infection, but viral diversity was also significantlyless with immediate therapy. We conclude that early treatmentof acute HIV infection leads to a more narrowly directed CTLresponse, stronger T helper cell responses, and a less diversevirus population. Given the need for T helper cells to maintaineffective CTL responses and the ability of virus diversificationto accommodate immune escape, we hypothesize that early therapyof primary infection may be beneficial despite induction ofless robust CTL responses. These data also provide rationalefor therapeutic immunization aimed at broadening CTL responsesin treated primary HIV infection.

Key Words: cytotoxic T lymphocytes • T helper cell responses • viral evolution • cytotoxic T lymphocyte epitopes • human leukocyte antigen

Abbreviations used in this paper: Elispot, enzyme-linked immunospot;HAART, highly active antiretroviral therapy; HMA, heteroduplexmobility assay; RD, relative diversity; RT, reverse transcriptase;SFC, spot-forming cell; SI, stimulation index.

The online version of this article contains supplemental material.

R. Shankarappa and J.S. Mukherjee contributed equally to thiswork.

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Barouch, D. H., Santra, S., Tenner-Racz, K., Racz, P., Kuroda, M. J., Schmitz, J. E., Jackson, S. S., Lifton, M. A., Freed, D. C., Perry, H. C., Davies, M.-E., Shiver, J. W., Letvin, N. L. (2002). Potent CD4+ T Cell Responses Elicited by a Bicistronic HIV-1 DNA Vaccine Expressing gp120 and GM-CSF. J. Immunol. 168: 562-568 [Abstract] [Full Text]
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