Neutralizing antibodies as a potential secondary protective mechanism during chronic SHIV infection in CD8+ T-cell-depleted macaques

Rasmussen, Robert A.a,c; Hofmann-Lehmann, Reginaa,c; Li, Pei-Lina,c; Vlasak, Josefa; Schmitz, Joern E.b,c; Reimann, Keith A.b,c; Kuroda, Marcelo J.b,c; Letvin, Norman L.b,c; Montefiori, David C.d; McClure, Harold M.e; Ruprecht, Ruth M.a,c

Basic Science

Objective: To directly examine the role of CD8+ T cells in controlling viremia and disease during chronic, low-level primate immunodeficiency virus infection in DNA prime/protein boost-vaccinated macaques.

Background: A cohort of macaques, vaccinated with either a DNA prime/HIV-1 gp160 boost regimen or with gp160 alone was previously protected partially from sequential challenges with non-pathogenic and pathogenic strains of chimeric simian/human immunodeficiency virus (SHIV). In this study, the effect of temporary ablation of CD8+ T cells in these animals was examined.

Methods: Animals were treated with an anti-CD8 antibody and CD8+ T-cell levels in peripheral blood, plasma viral loads, peripheral blood mononuclear cell-associated virus levels, neutralizing antibody (nAb) titers and simian immunodeficiency virus Gag-specific CD8+ T-cell numbers were followed.

Results: Plasma viremia rose sharply in direct synchrony with a rapid but transient drop in CD8+ T cells. However, although levels of cell-associated virus also rose concomitantly, peak levels were much lower than those in virus-challenged, naive animals. In addition, despite a rise of pathogenic SHIV89.6P RNA levels in three animals, CD4+ T-cell counts remained unchanged. In each of these animals, neutralizing antibody titers against the pathogenic SHIV89.6P strain were high.

Conclusions: The results indicate that CD8+ T cells play a key role in suppressing viremia in a chronically infected host. In addition, the results suggest that in the absence of CD8+ T cells, nAb may act as an effective second line of defense by limiting both the spread of infectious virus to new target cells and CD4+ T-cell loss.

From the aDepartment of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, the bDivision of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, the cDepartment of Medicine, Harvard Medical School, Boston, Massachusetts, the dDepartment of Surgery, Duke University Medical Center, Durham, North Carolina and eDivision of Research Resources and Division of Microbiology and Immunology, Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia, USA.

Correspondence to Dr. Ruth M. Ruprecht, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. Tel: +1 617 632-3719; Fax: +1 617 632-3112; e-mail: ruth_ruprecht@dfci.harvard.edu

Received: 11 May 2001;

revised: 29 October 2001; accepted: 2 January 2002.

Sponsorship: This work was supported in part by National Institutes of Health grants RO1 AI34266 to R.M.R., R21 AI46177, PO1 AI48240 awarded to R.A.R., R. H.-L., H.M.McC and R.M.R; U.S. Army grant DAMD17-94-J-4431 awarded to R.M.R.; National Institutes of Health grant RR13150 to K.A.R., National Institutes of Health grant AI85343 to N.L.L. and D.C.M., and H.M.M. supported in part by NIH/NCRR grant RR-00165 to the Yerkes Primate Center. Also supported by the Center for AIDS Research core grant IP3028691 awarded to Dana-Farber Cancer Institute as support for AIDS research efforts. R.H.-L. was supported by a grant from the Swiss National Science Foundation (fellowship number 823A-50315).

© 2002 Lippincott Williams & Wilkins, Inc.