9th Conference on Retroviruses and Opportunistic Infections Seattle, Washington - February 24 -February 28, 2002

Conf Retroviruses Opportunistic Infect 2002 Feb 24-28;9:abstract no. 23
Veazey R, Ling B, Lackner A, Marx P; Tulane Regional Primate Res. Ctr., Covington, LA

BACKGROUND: Sooty mangabey monkeys are the natural host species for simian immunodeficiency virus (SIVsm). Despite high levels of viral replication and persistence, sooty mangabeys infected with SIVsm do not develop AIDS, maintain relatively stable CD4⁺ T-cell counts, and live an apparently normal lifespan. In contrast, when inoculated into macaques, SIVsm results in an AIDS-like disease, with progressive declines in CD4⁺ T-cell counts, development of opportunistic infections, and death, usually within 1-3 years of infection. Determining the mechanism(s) by which the sooty mangabey evades disease progression and AIDS could be of major importance in designing effective treatment strategies and/or vaccines for HIV-1 infection in humans.

METHODS: In this study, we demonstrate that there is a marked and selective down-regulation of CCR5 expression specifically on CD4⁺ T-cells in the blood of SIV-infected sooty mangabeys. In a cross-sectional study, blood from 19 naturally SIV-infected sooty mangabeys was compared with blood from 6 uninfected magabeys for expression of CD4, CD8, CD45RA, CXCR4, and CCR5 co-expression on CD4⁺ and CD8+ T-cell subsets and monocytes by 3-4 color flow cytometry. Percentages of monocytes and CD4⁺ and CD8+ T cells co-expressing chemokine receptors were compared using identical gates and a Student's t-test.

RESULTS: Surprisingly, every mangabey that was SIV-infected had minimal to undetectable levels of CCR5 on their CD4⁺ lymphocytes. In contrast, all uninfected mangabeys had levels of CCR5 on their CD4⁺ T cells comparable to those of uninfected humans and rhesus macaques (2-19% of CD4⁺ T cells). There was a significant (p<0.006) difference between the level of CCR5 on CD4⁺ T-cells between infected and uninfected mangabeys, although there were no significant differences in percentages or absolute numbers of CD4⁺ T lymphocytes between these groups. Monocytes in the infected group also had lower mean expression of CCR5 compared to uninfected mangabeys, but these differences were not as significant (p<0.06). By simultaneously examining CCR5 expression on the CD8+ lymphocytes, it was demonstrated that this down-regulation of CCR5 was selective for the CD4⁺ T cells, as CCR5 expression by CD8+ T cells of both infected and uninfected groups were similar.

CONCLUSIONS: These results suggest that natural SIVsm infection in sooty mangabeys may result in marked CCR5 co-receptor down-modulation specifically on CD4⁺ T cells and monocytes, resulting in fewer host viral target cells and thus, prevention of disease progression. We hypothesize that SIVsm infection in the sooty mangabey population has forced sooty mangabeys to adapt this CCR5 down regulation as a means to control disease progression. Furthermore, these data provide additional evidence that CCR5 expression is not required for normal host immunologic maintenance, and may be safely utilized as a target for vaccination and/or treatment strategies to prevent AIDS in humans.

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Copyright © 2002 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.