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Journal of Virology, June 2008, p. 6039-6044, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.02753-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Small Intestine CD4+ T Cells Are Profoundly Depleted during Acute Simian-Human Immunodeficiency Virus Infection, Regardless of Viral Pathogenicity{triangledown}

Yoshinori Fukazawa,1,{dagger} Ariko Miyake,1,2,{dagger} Kentaro Ibuki,1 Katsuhisa Inaba,1 Naoki Saito,1 Makiko Motohara,1 Reii Horiuchi,1 Ai Himeno,1 Kenta Matsuda,1 Megumi Matsuyama,1 Hidemi Takahashi,3 Masanori Hayami,1 Tatsuhiko Igarashi,1 and Tomoyuki Miura1*

Laboratory of Primate Model, Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, 53 Shogoinkawaramachi, Sakyo-ku, Kyoto 606-8507, Japan,1 Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 162-8640, Japan,2 Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan3

Received 27 December 2007/ Accepted 27 March 2008


   ABSTRACT
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To analyze the relationship between acute virus-induced injury and the subsequent disease phenotype, we compared the virus replication and CD4+ T-cell profiles for monkeys infected with isogenic highly pathogenic (KS661) and moderately pathogenic (#64) simian-human immunodeficiency viruses (SHIVs). Intrarectal infusion of SHIV-KS661 resulted in rapid, systemic, and massive virus replication, while SHIV-#64 replicated more slowly and reached lower titers. Whereas KS661 systemically depleted CD4+ T cells, #64 caused significant CD4+ T-cell depletion only in the small intestine. We conclude that SHIV, regardless of pathogenicity, can cause injury to the small intestine and leads to CD4+ T-cell depletion in infected animals during acute infection.


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The highly pathogenic simian-human immunodeficiency virus (SHIV) SHIV-C2/1-KS661 (KS661), which was derived from SHIV-89.6 (23), replicates to high titers and causes the irreversible depletion of the circulating CD4+ T cells during the acute phase of intravenous infection, followed by AIDS-like disease within 1 year (23). We previously reported that KS661 massively replicates and depletes CD4+ T cells in both peripheral and mucosal lymphoid tissues during the initial 4 weeks postinfection (16). On the other hand, the isogenic SHIV-#64 (#64), which was derived from SHIV-89.6P, is moderately pathogenic. The genomic sequences of the two SHIVs differ by only 0.16%, resulting in a total of six amino acid changes in the products of the pol, env-gp41, and rev genes. The intravenous inoculation of rhesus macaques with #64 induces plasma viral burdens comparable to those induced by KS661 during the acute phase of infection and causes a transient reduction of the circulating CD4+ T lymphocytes (10). After the acute phase, the viral loads decline to undetectable levels and the populations of CD4+ T cells recover to preinfection levels.

To clarify the relationship between acute viral replication kinetics and subsequent clinical courses for these isogenic SHIVs with distinct pathogenicities, we examined proviral DNA, infectious-virus-producing cells (IVPCs), and CD4+ T-cell depletion in peripheral and mucosal lymphoid tissues of 17 infected (Table 1) and 7 uninfected adult rhesus macaques (Macaca mulatta). Both Chinese and Indian rhesus monkeys were randomly assigned to these groups. The monkeys were used in accordance with the institutional regulations approved by the Committee for Experimental Use of Nonhuman Primates of the Institute for Virus Research, Kyoto University, Kyoto, Japan. The animals were inoculated via intrarectal infusion as described previously (17). Following serial euthanasia, tissues were collected and analyzed up to 27 days postinfection (dpi) as described previously (16, 17).


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  		TABLE 1. Experimental schedule for individual monkeysa

 
Gross virus replication was assessed by measuring plasma viral loads by reverse transcriptase PCR (16). By 6 dpi, plasma viral RNA levels became detectable in all the KS661-infected macaques (Fig. 1A) and three of seven #64-infected macaques (animals MM372, MM391, and MM374) (Fig. 1B). Although the plasma viral loads of the two groups at 13 dpi, when the virus loads reached their initial peaks, were not significantly different (P = 0.1673), the average load (± the standard deviation) in KS661-infected monkeys (9.3 x 108 ± 15.9 x 108 copies/ml) was about 10 times higher than that in #64-infected monkeys (6.3 x 107 ± 11.6 x 107 copies/ml). These results suggest that KS661 spread faster and reached a somewhat higher titer than did #64 when the viruses were inoculated intrarectally.


Figure 1
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  		FIG. 1. Plasma viral RNA loads and profiles of circulating CD4+ T cells for monkeys intrarectally infected with highly pathogenic KS661 and moderately pathogenic #64. (A and B) Plasma viral RNA loads were measured by quantitative reverse transcriptase PCR. The detection limit of this assay was 103 copies/ml. (C and D) Levels of CD4+ T cells in peripheral blood samples from monkeys infected with KS661 and #64. The absolute number of CD3+ CD4+ cells in peripheral blood immediately before infection (day 0 postinfection) was defined as 100% for each monkey.

 
Levels of peripheral blood CD4+ T lymphocytes in all the KS661-infected monkeys decreased substantially within 4 weeks (Fig. 1C). On the other hand, the reductions in the levels of CD4+ T cells varied among the #64-infected monkeys (Fig. 1D). For example, MM378 did not exhibit any appreciable changes, even though the plasma viral RNA load in this monkey reached 2.6 x 107 copies/ml by 21 dpi (Fig. 1 B and D). These data suggest that the decline in circulating CD4+ T cells in KS661-infected animals was more severe and more reproducible than that in the #64-infected monkeys.

Another highly pathogenic SHIV, SHIV-DH12R, is known to cause systemic and synchronous replication events in animals following intravenous inoculation (6). To reveal the spread of virus in monkeys following intrarectal infection, we measured proviral DNA loads in a variety of tissues as described previously (16). KS661 proviral DNA was detected not only in samples from the rectums, the site of virus inoculation, but also in peripheral blood mononuclear cells and some lymph nodes (LN) at 6 dpi (Fig. 2A), suggesting that the virus was already spreading systemically. At 13 dpi, when the viral RNA loads in peripheral blood increased to the highest titers, proviral DNA levels in all of the tissues examined also increased, with levels in most monkeys exceeding 104 copies/µg of DNA. The levels of proviral DNA in all the tissues declined remarkably by 27 dpi. In contrast, #64 proviral DNA was detected only in the rectum of one (MM390) of the two monkeys examined at 6 dpi (Fig. 2A). At 13 dpi, the amount of proviral DNA in each tissue sample from #64-infected monkeys (<104 copies/µg of DNA) was considerably smaller than that in each sample from the KS661-infected monkeys. However, unlike the KS661 proviral DNA levels, the #64 proviral DNA levels in most tissues were maintained up to 27 dpi. These results suggest that #64 spread more slowly than KS661 and that the amounts of proviral DNA in a variety of tissues from the #64-infected animals were smaller than those in the tissues from KS661-infected animals around the initial peak of plasma viremia.


Figure 2
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  		FIG. 2. (A) Proviral DNA loads in tissues of KS661- and #64-infected monkeys at 6, 13, and 27 dpi. Viral burdens were determined by quantitative PCR and expressed as the numbers of viral DNA copies per microgram of total DNA extracted from tissue homogenates. PBMC, peripheral blood mononuclear cells; Ing., inguinal; Ax., axillary; Mes., mesenteric; BM, bone marrow; *, not done. (B) Numbers of IVPCs in tissues of KS661- and #64-infected monkeys at 6, 13, and 27 dpi. Numbers of IVPCs were determined by an infectious plaque assay and were expressed as the numbers of PFU per 106 cells. Jej., jejunum; Rec., rectum; iEL, intraepithelial lymphocytes; *, not done.

 
Because the amount of proviral DNA measured by PCR may include nonreplicating remnants of the viral genome, we also measured the number of IVPCs in each tissue sample by a plaque assay as described previously (9, 15). Briefly, cells prepared from infected animals were mixed with human T-lymphoid M8166 indicator cells, resuspended in culture medium containing 0.4% agarose, and plated into petri dishes. The plaques that formed in the cell layer were counted after 10 days of cultivation, and the number of IVPCs was calculated. For the KS661-infected monkeys, high numbers of IVPCs in all the tissue samples examined at 13 dpi were detected (Fig. 2B). Among these samples, the thymus and mesenteric LN samples harbored especially high numbers of IVPCs (more than 500/106 cells) at 13 dpi. The numbers of IVPCs declined remarkably from 13 to 27 dpi. We concluded that KS661 replicated systemically and synchronously in a variety of tissues, including the intestinal tract, at 13 dpi. In contrast, #64 production patterns in different tissues were not synchronous. Among #64-infected monkeys at 6 dpi, virus production was most active in the jejunum lamina propria lymphocytes (LPL) of MM390 (166 IVPCs/106 cells). At 13 dpi, interestingly, mesenteric LN became the center of virus production in two of the three monkeys examined (MM372 and MM373; 259 and 160 IVPCs/106 cells). In the other monkey (MM391), the jejunum had the highest number of IVPCs, followed by the mesenteric LN. These results suggested that the virus that replicated in the jejunum spread directly into the mesenteric LN via the flow of lymphatic fluid. At 27 dpi, the thymus tissues of both monkeys examined (MM374 and MM378) exhibited the highest numbers of IVPCs. In summary, the systemic dissemination of #64 was slower than that of KS661, and it was particularly delayed in the thymus during the acute phase.

Systemic CD4+ cell depletion is the signature of disease induced by highly pathogenic SHIVs (7, 8, 22). We therefore compared the frequencies of CD4+ cells in tissues from the animals infected with KS661 and #64, in addition to those of the circulating CD4+ T lymphocytes. As representatives of the major virus-producing organs, the thymus, the mesenteric LN, and the jejunum were selected for examination. CD4 cell numbers were measured by immunohistochemistry analyses as described previously (18). Uninfected thymus tissue contained abundant CD4+ cells that were stained brown (Fig. 3A, panel a), while the tissue collected from the KS661-infected animal at 27 dpi harbored few such cells (Fig. 3A, panel b). #64 caused virtually no CD4+ cell depletion in the thymus at 27 dpi (Fig. 3A, panel c). In the mesenteric LN of uninfected monkeys, CD4+ cells were found in the paracortical region (Fig. 3A, panel d). KS661 depleted CD4+ cells in this area (Fig. 3A, panel e). Unlike KS661, #64 did not reduce the level of CD4+ cells (Fig. 3A, panel f). The jejunum samples from uninfected animals contained CD4+ cells in the lamina propria and follicles of gut-associated lymphatic tissues (Fig. 3 A, panel g). KS661 depleted CD4+ cells in these tissues, too (Fig. 3A, panel h). Interestingly, #64 caused CD4+ cell depletion in the small intestine comparable to that caused by KS661 (Fig. 3A, panel i). To confirm the observed cell reduction in the jejunum samples, we randomly selected a total of 40 fields on the tissue sections from each animal for viewing at a total magnification of x400, counted CD4+ cells, and averaged the numbers (Fig. 3B). The CD4+ cell densities in the jejunum samples from the #64-infected monkeys were significantly lower than those in the samples from uninfected animals (P < 0.001). This gut-specific CD4+ cell depletion caused by #64 prompted us to analyze the frequencies of CD4+ T cells (including CD4 and CD8 doubly positive cells) in a variety of tissues by flow cytometry (Fig. 3C). KS661 caused systemic CD4+ T-lymphocyte depletion by 27 dpi (Fig. 3C). In agreement with the immunohistochemistry results, #64 significantly depleted CD4+ T cells only in the jejunum intraepithelial lymphocytes and LPL (P = 0.01 and 0.003, respectively) (Fig. 3C) by 27 dpi, although we examined only two #64-infected monkeys at 27 dpi. In conclusion, the CD4+ T-cell depletion patterns caused by KS661 and #64 were distinct, and the small intestine was the only site in which CD4+ T cells were significantly depleted by the moderately pathogenic #64.


Figure 3
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  		FIG. 3. Profiles of CD4+ T cells in systemic lymphoid tissues during acute infection. (A) Immunohistochemical staining for CD4 molecules (stained brown) in the thymus, mesenteric (mes.) LN, and jejunum tissues of KS661- or #64-infected monkeys at 27 dpi, in addition to those of uninfected monkeys. Black scale bars, 100 µm; white scale bars in insets of panels g, h, and i, 50 µm. (B) Comparison of CD4+ cell frequencies in the jejunum LPL of uninfected and #64-infected monkeys at 27 dpi. A total of forty randomly selected fields (total magnification, x400) of at least four tissue sections per animal were used for the analysis of jejunum LPL. P values (determined by Student's t test with 95% confidence intervals) are for comparisons of each #64-infected monkey with uninfected monkeys. (C) Percentages of CD4+ T cells among total lymphocytes from KS661- and #64-infected monkeys. In each graph, data for 0 dpi (time points postinfection are shown along the x axis) are averages of percentages for seven uninfected control monkeys. Percentages of CD4+ T cells (including CD4 and CD8 doubly positive cells) were obtained by first gating lymphocytes and then CD3+ T cells with a flow cytometer. PBMC, peripheral blood mononuclear cells; Ing., inguinal; Jej., jejunum; iEL, intraepithelial lymphocytes; BM, bone marrow; Col., colon; *, P < 0.05 (percentage at 0 dpi versus that at 27 dpi; Student's t test with a 95% confidence interval).

 
Taken together, our results show that #64 disseminated more slowly and replicated less than KS661 in systemic lymphoid tissues, as well as in peripheral blood, during the acute phase of infection. We believe that because of its low rate and low levels of replication, #64 could not cause irreversible injury before the host mounted an immune reaction. As a result, CD4+ T cells were not completely depleted in all the tissues examined, except in the small intestine. These results suggest that the small intestine is the tissue most sensitive to virus-induced CD4+ T-cell depletion during the acute phase of infection. Recent reports revealed that severe acute depletions of mucosal CD4+ T cells have been observed in simian immunodeficiency virus-infected monkeys (11, 12, 24, 25) and human immunodeficiency virus-infected humans (2, 5, 13). The acute depletion of mucosal CD4+ T cells and the disease outcome are correlated (1, 3, 21, 26). However, a decrease of mucosal CD4+ T cells has also been observed in the early phases of natural host infections, such as SIVagm infection in African green monkeys and SIVsmm infection in sooty mangabeys, which typically do not progress to AIDS (4, 14, 19). In addition, the levels of apoptosis and immune activation and the degrees of CD4+ T-cell restoration differ between progressors and nonprogressors in simian immunodeficiency virus models (4, 14, 19). Taken together, these results raise the possibility that the severe acute depletion of mucosal CD4+ T cells is not sufficient to induce AIDS. The restoration of CD4+ T cells and normal immune function after the severe acute depletion may define the eventual disease outcome (20). The abilities of KS661- and #64-infected monkeys to restore the immune system may be different, because KS661, but not #64, impairs thymic T-cell differentiation (18). Currently, we are focusing on the restoration of CD4+ T cells and the functional aspect of the immune cells in the small intestines of animals infected with KS661 and #64 to further clarify the determinant(s) of the disease outcome.


   ACKNOWLEDGMENTS
 
We are grateful to James Raymond for English editing of the manuscript and to Takahito Kazama for technical support.

This work was supported, in part, by Research on Human Immunodeficiency Virus/AIDS in Health and Labor Sciences research grants from the Ministry of Health, Labor and Welfare, Japan, a grant-in-aid for scientific research from the Ministry of Education and Science, Japan, a research grant for health sciences focusing on drug innovation for AIDS from the Japan Health Sciences Foundation, and a grant from the Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) of Japan.


   FOOTNOTES
 
* Corresponding author. Mailing address: Laboratory of Primate Model, Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, 53 Shogoinkawaramachi, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-3984. Fax: 81-75-761-9335. E-mail: tmiura{at}virus.kyoto-u.ac.jp Back

{triangledown} Published ahead of print on 9 April 2007. Back

{dagger} These authors contributed equally to this work. Back


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Journal of Virology, June 2008, p. 6039-6044, Vol. 82, No. 12
0022-538X/08/$08.00+0     doi:10.1128/JVI.02753-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.




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