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 Apr;82(7):3725-35.
doi: 10.1128/JVI.02408-07. Epub 2008 Jan 23.

Short-lived infected cells support virus replication in sooty mangabeys naturally infected with simian immunodeficiency virus: implications for AIDS pathogenesis

Shari N Gordon  1 , Richard M Dunham, Jessica C Engram, Jacob Estes, Zichun Wang, Nichole R Klatt, Mirko Paiardini, Ivona V Pandrea, Cristian Apetrei, Donald L Sodora, Ha Youn Lee, Ashley T Haase, Michael D Miller, Amitinder Kaur, Silvija I Staprans, Alan S Perelson, Mark B Feinberg, Guido Silvestri
Affiliations

Short-lived infected cells support virus replication in sooty mangabeys naturally infected with simian immunodeficiency virus: implications for AIDS pathogenesis

Shari N Gordon et al. J Virol. 2008 Apr.

Abstract

Sooty mangabeys (SMs) naturally infected with simian immunodeficiency virus (SIV) do not develop AIDS despite high levels of virus replication. At present, the mechanisms underlying this disease resistance are poorly understood. Here we tested the hypothesis that SIV-infected SMs avoid immunodeficiency as a result of virus replication occurring in infected cells that live significantly longer than human immunodeficiency virus (HIV)-infected human cells. To this end, we treated six SIV-infected SMs with potent antiretroviral therapy (ART) and longitudinally measured the decline in plasma viremia. We applied the same mathematical models used in HIV-infected individuals and observed that SMs naturally infected with SIV also present a two-phase decay of viremia following ART, with the bulk (92 to 99%) of virus replication sustained by short-lived cells (average life span, 1.06 days), and only 1 to 8% occurring in longer-lived cells. In addition, we observed that ART had a limited impact on CD4(+) T cells and the prevailing level of T-cell activation and proliferation in SIV-infected SMs. Collectively, these results suggest that in SIV-infected SMs, similar to HIV type 1-infected humans, short-lived activated CD4(+) T cells, rather than macrophages, are the main source of virus production. These findings indicate that a short in vivo life span of infected cells is a common feature of both pathogenic and nonpathogenic primate lentivirus infections and support a model for AIDS pathogenesis whereby the direct killing of infected cells by HIV is not the main determinant of disease progression.

PubMed Disclaimer

Figures

FIG. 1.
FIG. 1.
Antiretroviral therapy suppressed viral replication in SIV-infected SMs. (A) Plasma viral load of six SMs chronically infected with SIV, designated FAy, FCy, FDv, FEy, FUs, and FVs, before, during (shaded), and after ART. SMs were treated with PMPA and FTC for 42 days.
FIG. 2.
FIG. 2.
Modest increases in CD4+ T cells in SMs treated with ART. (A) Plasma viral load is on the right y axis, and the CD4+ T-cell count is on the left y axis for each of the SMs before, during (shaded), and after ART. (B) Average fraction of CD3+ CD4+ T cells in peripheral blood 42 days before the initiation of ART, after 6 weeks of continuous ART, and 21 days after the termination of ART. Friedman's test demonstrated that the means were not significantly different. (C) Average fraction of CD3+ CD4+ (red) and CD3+ CD8+ (blue) T cells in peripheral blood (left) and lymph nodes (right) before, during (shaded), and after ART.
FIG. 3.
FIG. 3.
Reduced T-cell proliferation during ART treatment in SMs. (A) Plasma viral load is on the right y axis, and the number of CD4+ KI67+ T cells is on the left y axis for each of the SMs before, during (shaded), and after ART. (B) Percentage of CD4+ KI67+ (left) and CD8+ KI67+ (right) T cells in the peripheral blood of each of the SIV-infected SMs before, during (shaded), and after ART. The average fractions of CD4+ KI67+ T cells (left) and CD8+ KI67+ T cells (right) in peripheral blood 42 days before the initiation of ART, after 6 weeks of continuous ART, and 21 days after the termination of ART are shown. Friedman's test was used to compare the differences in the means. Statistically significant differences were observed in the percentage of CD8+ KI67+ T cells (α = 0.012); thus, Dunn's comparison posttest was performed (depicted by an asterisk). (C) Immunohistochemical analysis of Ki67 (brown) and CD3 (pink) staining in lymph node tissue before, during, and after therapy.
FIG. 4.
FIG. 4.
Minor reductions in levels of activated T cells in ART treated SIV-infected SMs. (A) Average fraction of CD4+ T cells (left) expressing CD25+ (red) and CD69+ (blue), as well as the average fraction of CD8+ T cells (right) expressing CD25+ (red) and CD69+ (blue) in peripheral blood before, during (shaded), and after ART. (B) Mean percentage of CD4+ CD25+, CD4+ CD69+ (left), and CD8+ CD25+, CD8+ CD69+ (right) T cells in peripheral blood 42 days before the initiation of ART, after 6 weeks of continuous ART, and 21 days after the termination of ART. Friedman's test was used to compare the differences in the means. Statistically significant differences were observed in the percentage of CD8+ CD25+ T cells (α = 0.0055); thus, Dunn's comparison posttest was performed (depicted by an asterisk).
FIG. 5.
FIG. 5.
SIV-specific IFN-γ ELISPOT responses in SMs. IFN-γ ELISPOT responses in six SMs naturally infected with SIV were measured by peptide stimulation before, during, and after treatment with PMPA and FTC. The magnitudes of IFN-γ ELISPOT responses to SIV proteins are shown on the y axis, and individual time points are indicated on the x axis. Colored bars depict the frequency of the IFN-γ ELISPOT response to each tested SIV protein. Numbers on the tops of columns denote the number of SIV proteins testing positive.
FIG. 6.
FIG. 6.
SMs have a short in vivo life span of SIV-infected cells. (A) Plasma concentrations of SIV RNA (in copies/ml) for the six SIV-infected animals after treatment with ART was begun on day zero. (B)The two-phase decay model of Perelson et al. (38) was fit using nonlinear least-squares regression to the viral load data (circles) for each animal (FAy, FDv, FUs, FCy, FEy, and FVs), and the death rates, d (of short-lived infected cells) and m (of long-lived cells) were estimated as described in Materials and Methods. The solid line shows the best-fit theoretical curve. The half-lives of short- and long-lived infected cells were computed from the best-fit parameters as the ln 2/d and ln 2/m, where ln 2 is the natural logarithm of 2 (0.693).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Autran, B., G. Carcelain, T. S. Li, C. Blanc, D. Mathez, R. Tubiana, C. Katlama, P. Debre, and J. Leibowitch. 1997. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277112-116. - PubMed
    1. Bostik, P., A. E. Mayne, F. Villinger, K. P. Greenberg, J. D. Powell, and A. A. Ansari. 2001. Relative resistance in the development of T cell anergy in CD4+ T cells from simian immunodeficiency virus disease-resistant sooty mangabeys. J. Immunol. 166506-516. - PubMed
    1. Bostik, P., E. S. Noble, A. E. Mayne, L. Gargano, F. Villinger, and A. A. Ansari. 2006. Central memory CD4 T cells are the predominant cell subset resistant to anergy in SIV disease resistant sooty mangabeys. AIDS 20181-188. - PubMed
    1. Brandin, E., R. Thorstensson, S. Bonhoeffer, and J. Albert. 2006. Rapid viral decay in simian immunodeficiency virus-infected macaques receiving quadruple antiretroviral therapy. J. Virol. 809861-9864. - PMC - PubMed
    1. Broussard, S. R., S. I. Staprans, R. White, E. M. Whitehead, M. B. Feinberg, and J. S. Allan. 2001. Simian immunodeficiency virus replicates to high levels in naturally infected African green monkeys without inducing immunologic or neurologic disease. J. Virol. 752262-2275. - PMC - PubMed

Publication types

Substances

LinkOut - more resources