15th Conference on Retroviruses and Opportunistic Infections Boston, Massachusetts - February 3-6, 2008

Conf Retrovir Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 19)

Lu-Ann Pozzi, D Pauley, S Sato, H Knight, D Walsh, A Carville, W Johnson, S Westmoreland, and S O'neil
New England Primate Res Ctr, Harvard Med Sch, Southborough, MA, US

BACKGROUND: Specific aspects of protection provided by humoral immune responses against lentiviral infections have not yet been identified. We used the simian immunodeficiency virus (SIV) -infected macaque model to examine the effect of B lymphocyte depletion on disease progression and outcome.

METHODS: We treated 5 pigtailed macaque monkeys 3 times with the CD20+ cell-depleting monoclonal antibody Rituxan, and 3 controls with human intravenous immunoglobulin (Ig). All macaques were inoculated with SIV_smmFGb 1 week after the first Rituxan treatment. Viral loads were determined in blood and cerebrospinal fluid (CSF). Total anti-SIV binding antibodies were measured by enzyme-linked immunosorbent assay (ELISA), and neutralizing antibody titers were evaluated using a secreted alkaline phosphatase reporter assay. Cell-mediated immune responses (CMI) were analyzed by interferon (IFN) -γ enzyme-linked immunosorbent spot (ELISpot) assay. Lymphocyte subsets, as well as markers of immune activation, were monitored by fluorescence-activated cell sorting (FACS). The extent of B cell depletion from lymphoid tissue was assessed by immunohistochemistry for CD20 and CD79a on peripheral lymph node biopsies collected at –1, +2, and +5 weeks post-inoculation.

RESULTS: Rituxan therapy completely eliminated CD20+ cells from peripheral circulation in treated animals through 24 weeks post-inoculation, and dramatically reduced the numbers of CD20+ and CD79a+ B lymphocytes in peripheral lymph nodes, although the extent of depletion in tissues varied. Of 5 depleted macaques, 4 were euthanized because they developed SIV encephalitis (SIVE) and AIDS by 42 weeks post-inoculation, with rapid disease progression occurring in 3 of 4 animals (survival of 6 to 10 weeks post-inoculation). None of the animals developed neutralizing antibody responses by 21 weeks post-inoculation, but 2 controls and 1 depleted animal developed weak neutralizing antibody responses by 40 weeks post-inoculation. All controls developed strong cell-mediated immunity responses against SIV Gag and Nef determinants that have persisted beyond 40 weeks post-inoculation, while cell-mediated immunity responses waned to below detection in 4 of 5 depleted macaques by 12 weeks post-inoculation, and in the remaining depleted animal by 40 weeks post-inoculation. Although viral loads at peak viremia were indistinguishable between CD20-depleted animals and controls, viral loads at set point were elevated in depleted animals.

CONCLUSIONS: Overall, CD20-depleted SIV_smmFGb-infected macaques had shortened survival post-inoculation, with 3 of 4 developing SIVE and AIDS by 10 weeks post-inoculation. All CD20-depleted animals failed to mount or maintain SIV-specific CMI responses, suggesting a correlation between B cell function and CD8+ T cell responses in the control of primate lentivirus infections.

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2008-02-03
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