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Comparative Study
. 2008 Feb;82(3):1175-84.
doi: 10.1128/JVI.00450-07. Epub 2007 Nov 21.

Early divergence in lymphoid tissue apoptosis between pathogenic and nonpathogenic simian immunodeficiency virus infections of nonhuman primates

M-C Cumont  1 , O Diop, B Vaslin, C Elbim, L Viollet, V Monceaux, S Lay, G Silvestri, R Le Grand, M Müller-Trutwin, B Hurtrel, J Estaquier
Affiliations
Comparative Study

Early divergence in lymphoid tissue apoptosis between pathogenic and nonpathogenic simian immunodeficiency virus infections of nonhuman primates

M-C Cumont et al. J Virol. 2008 Feb.

Abstract

The events that contribute to the progression to AIDS during the acute phase of a primate lentiviral infection are still poorly understood. In this study, we used pathogenic and nonpathogenic simian models of simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) and African green monkeys (AGMs), respectively, to investigate the relationship between apoptosis in lymph nodes and the extent of viral replication, immune activation, and disease outcome. Here, we show that, in SIVmac251-infected RMs, a marked increased in lymphocyte apoptosis is evident during primary infection at the level of lymph nodes. Interestingly, the levels of apoptosis correlated with the extent of viral replication and the rate of disease progression to AIDS, with higher apoptosis in RMs of Indian genetic background than in those of Chinese origin. In stark contrast, no changes in the levels of lymphocyte apoptosis were observed during primary infection in the nonpathogenic model of SIVagm-sab infection of AGMs, despite similarly high rates of viral replication. A further and early divergence between SIV-infected RMs and AGMs was observed in terms of the dynamics of T- and B-cell proliferation in lymph nodes, with RMs showing significantly higher levels of cycling cells (Ki67(+)) in the T-cell zones in association with relatively low levels of Ki67(+) in the B-cell zones, whereas AGMs displayed a low frequency of Ki67(+) in the T-cell area but a high proportion of Ki67(+) cells in the B-cell area. As such, this study suggests that species-specific host factors determine an early immune response to SIV that predominantly involves either cellular or humoral immunity in RMs and AGMs, respectively. Taken together, these data are consistent with the hypotheses that (i) high levels of T-cell activation and lymphocyte apoptosis are key pathogenic factors during pathogenic SIV infection of RMs and (ii) low T-cell activation and apoptosis are determinants of the AIDS resistance of SIVagm-infected AGMs, despite high levels of SIVagm replication.

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Figures

FIG. 1.
FIG. 1.
(A) Survival by month. The percentages of survival in three different groups of SIV-infected monkeys (Indian RMs and Chinese RMs infected with SIVmac251 and AGMs infected with SIVagm.sab92018) during the follow-up period of this study are shown. Clinical progression toward disease was continuously evaluated. The animals were killed due to a wasting syndrome with cachexia and opportunistic infections. (B) Viremia. Shown are kinetic analyses of viremia in SIV-infected Indian and Chinese RMs and in AGMs.
FIG. 2.
FIG. 2.
SIV RNA+ cells (A) and immunohistochemical analysis of apoptotic cells (B), of cycling cells (C), and of TiA-1 (D) in LNs from Indian and Chinese SIVmac251-infected RMs and SIVagm-infected AGMs at different time points after infection. Magnification, ×100.
FIG. 2.
FIG. 2.
SIV RNA+ cells (A) and immunohistochemical analysis of apoptotic cells (B), of cycling cells (C), and of TiA-1 (D) in LNs from Indian and Chinese SIVmac251-infected RMs and SIVagm-infected AGMs at different time points after infection. Magnification, ×100.
FIG. 3.
FIG. 3.
Productive SIV infection in LNs from Indian and Chinese SIVmac251-infected RMs and SIVagm-infected AGMs at different time points postinfection. Quantitative assessment of SIV RNA+ cells is shown. Statistical significance was assessed using paired Student t tests. The error bars represent standard deviations.
FIG. 4.
FIG. 4.
(A) Quantitative assessment of apoptotic cells measured by the Tunel method in LNs from Indian and Chinese SIVmac251-infected RMs and SIVagm-infected AGMs at different time points postinfection. Statistical significance was assessed using paired Student t tests. The error bars represent standard deviations. (B) Correlation between the extent of viral replication (log SIV RNA+) and the extent of apoptosis at the peak. Each symbol represents one individual RM, either Indian (○) or Chinese (•).
FIG. 5.
FIG. 5.
Quantitative assessment of Ki67 in the T-cell area (A) and B-cell area (%GCKi67+) (B) in LNs from Indian and Chinese SIVmac251-infected RMs and SIVagm-infected AGMs at different time points postinfection. Statistical significance was assessed using paired Student t tests. The error bars represent standard deviations.
FIG. 6.
FIG. 6.
Dynamics of HLA-DR on CD4+ and CD8+ T cells in LNs. Flow cytometry was used to quantify the percentages of T cells expressing HLA-DR gating on CD3+ cells of Indian and Chinese SIVmac251-infected RMs and SIV-infected AGMs at different time points postinfection. The data shown were calculated as follows: DR+ CD4/CD8+/(DR+ CD4/CD8+ + DR− CD4/CD8+) × 100. Statistical significance was assessed using paired Student t tests. Error bars represent standard deviations.
FIG. 7.
FIG. 7.
Quantitative assessment of TiA-1 cells in LNs from Indian and Chinese SIVmac251-infected RMs and SIVagm-infected AGMs at different time points postinfection. Statistical significance was assessed using paired Student t tests. The error bars represent standard deviations.
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