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Journal of Virology, January 2007, p. 893-902, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01635-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Loss of Naïve Cells Accompanies Memory CD4⁺ T-Cell Depletion during Long-Term Progression to AIDS in Simian Immunodeficiency Virus-Infected Macaques

Yoshiaki Nishimura,¹ Tatsuhiko Igarashi,¹ Alicia Buckler-White,¹ Charles Buckler,¹ Hiromi Imamichi,³ Robert M. Goeken,¹ Wendy R. Lee,¹ Bernard A. P. Lafont,¹ Russ Byrum,⁴ H. Clifford Lane,² Vanessa M. Hirsch,¹ and Malcolm A. Martin^1*

Laboratory of Molecular Microbiology,¹ Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,² Science Applications International Corporation—Frederick, Inc., Frederick, Maryland 21702,³ Bioqual, Rockville, Maryland 20850⁴

Received 31 July 2006/ Accepted 24 October 2006

Top Abstract Introduction Materials and Methods Results Discussion References

 
Human immunodeficiency virus and simian immunodeficiency virus (SIV) induce a slow progressive disease, characterized by the massive loss of memory CD4⁺ T cells during the acute infection followed by a recovery phase in which virus replication is partially controlled. However, because the initial injury is so severe and virus production persists, the immune system eventually collapses and a symptomatic fatal disease invariably occurs. We have assessed CD4⁺ T-cell dynamics and disease progression in 12 SIV-infected rhesus monkeys for nearly 2 years. Three macaques exhibiting a rapid progressor phenotype experienced rapid and irreversible loss of memory, but not naïve, CD4⁺ T lymphocytes from peripheral blood and secondary lymphoid tissues and died within the first 6 months of virus inoculation. In contrast, SIV-infected conventional progressor animals sustained marked but incomplete depletions of memory CD4⁺ T cells and continuous activation/proliferation of this T-lymphocyte subset. This was associated with a profound loss of naïve CD4⁺ T cells from peripheral blood and secondary lymphoid tissues, which declined at rates that correlated with disease progression. These data suggest that the persistent loss of memory CD4⁺T cells, which are being eliminated by direct virus killing and activation-induced cell death, requires the continuous differentiation of naïve into memory CD4⁺ T cells. This unrelenting replenishment process eventually leads to the exhaustion of the naïve CD4⁺T-cell pool and the development of disease.

Top Abstract Introduction Materials and Methods Results Discussion References

 
It is now appreciated that during acute human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) infections of humans and macaques, respectively, large numbers of memory CD4⁺ T lymphocytes residing in mucosal tissues, such as the gastrointestinal tract, are killed (4, 26, 28, 29, 49). In most cases, a vigorous cell-mediated immune response is mounted, which partially controls, but does not eliminate, the virus produced during the primary infection. For HIV-1, an asymptomatic clinical course lasting approximately 10 years commonly occurs, characterized by relatively low levels of circulating infected mononuclear cells (0.01 to 1%) and large numbers of hyperactivated uninfected T and B lymphocytes (3, 25, 31, 42, 44, 45). In a significant fraction of HIV-1-infected individuals, the onset of symptomatic disease is heralded by the emergence of CXCR4 (X4)-tropic syncytium-inducing viral variants whose appearance is associated with accelerated depletion of CD4⁺ T cells and more rapid progression to AIDS (2, 23, 47).

Because the host range of HIV-1 is limited (humans and chimpanzees) and chimpanzees only rarely progress to symptomatic disease, a number of nonhuman primate models have been used to elucidate the pathogenic mechanisms leading to immunodeficiency. Unlike the highly pathogenic SIV/HIV chimeric viruses (SHIVs), which exclusively use the X4 chemokine receptor and cause a systemic and irreversible loss of CD4⁺ T lymphocytes within weeks of infection of macaque monkeys, SIVs only utilize the CCR5 (R5) coreceptor and therefore replicate in and kill memory CD4⁺ T cells in vitro and in vivo (34). In this regard, SIV is similar to HIV-1 in that R5-using, and not X4-using, HIV-1 strains are commonly recovered following the control of the acute infection and remain the dominant virus for several years (6, 46). SIV usually induces a slow progressive disease in Asian macaques, characterized by a gradual loss of circulating CD4⁺ T lymphocytes with a median survival of 1 to 2 years (22, 35). Many of these conventional progressor (CP) animals develop strong cellular immune responses against the virus but eventually succumb to opportunistic infections during the symptomatic phase of their infections (15, 22, 40).

Approximately 20 to 25% of SIV-infected rhesus monkeys rapidly progress to disease within the first 6 months of infection (18, 27, 35). Such rapid progressors (RPs) experience persistently high levels of plasma viremia/p27 antigenemia, undetectable or transient anti-SIV antibody responses that wane within 3 to 4 weeks of virus inoculation, and the early onset of clinical disease characterized by marked weight loss, chronic diarrhea, and cachexia (16, 37). SIV preferentially targets the elimination of the memory CD4⁺ T-cell subset residing in effector sites during the primary infection, since these lymphocytes express the highest levels of CCR5 (10). In most infected macaques, the initial burst of virus production and associated cell killing induces a robust proliferation of memory CD4⁺ T lymphocytes in secondary lymphoid tissues, from which they migrate to effector sites where SIV replication continues unabatedly (28, 34, 37). In RPs, however, the severe injury sustained by the immune system during the acute infection impairs this proliferative response, the effector memory T-cell population is not replenished, and the animals rapidly develop immunodeficiency (37).

In this study, we have monitored CD4⁺ T-cell dynamics and disease course in 12 SIV-infected rhesus monkeys for 2 years. Early, rapid, and irreversible loss of memory but not naïve CD4⁺ T lymphocytes characterized disease progression for the three RP macaques in our cohort. SIV-infected CP animals sustained more modest yet unrelenting depletion of their memory CD4⁺ T cells during their infections that was accompanied by the continuous activation/proliferation of this T-lymphocyte subset. In contrast to RP monkeys, a profound loss of naïve CD4⁺ T cells occurred in all of the chronically infected CP animals; the rate of their depletion correlated inversely with survivability. At the time of death, naïve CD4⁺ T cells represented the minority population in lymphoid tissues compared to the memory subset, and virtually no memory CD4⁺ T lymphocytes were present at effector sites. This scenario presumably reflects the exhaustion of the naive CD4⁺ T-cell supply, which had been sustaining immune function by continuously differentiating into and replacing memory CD4⁺ cells that were lost during long-term SIV infections.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Virus and animal experiments. The origin and preparation of the tissue culture-derived SIV_sm543-3 (13) and SIV_mac239 stocks (21, 32) from molecular clones have been previously described. Rhesus macaques (Macaca mulatta) were maintained in accordance with the guidelines of the Committee on Care and Use of Laboratory Animals (5) and were housed in a biosafety level 2 facility; biosafety level 3 practices were followed. Phlebotomies, intravenous virus inoculations (2,000 50% tissue culture infectious doses [TCID₅₀] of SIV_sm543-3 and 10,000 TCID₅₀ of SIV_mac239), euthanasia, and tissue sample collections were performed as previously described (11, 19). Bronchoalveolar lavage (BAL) lymphocytes were prepared from uninfected donor animals and SIV-infected animals by using a pediatric bronchoscope (BF3C40; Olympus America, Inc., Melville, N.Y.), as previously described (21).

Assays for SIV-specific antibodies and p27 antigenemia. Serology for SIV antibodies was performed by Western blot analysis, as previously described (13, 17). SIV p27 antigenemia was detected by employing a SIV antigen capture kit (Coulter Corp., Hialeah, Fla.), as previously reported (14).

Plasma viral RNA quantitation. Viral RNA levels in plasma were determined by real-time reverse transcription-PCR (ABI Prism 7700 sequence detection system; Applied Biosystems, Foster City, Calif.) as previously reported (11).

Lymphocyte immunophenotyping and data analysis. EDTA-treated blood samples, BAL lymphocytes, and mesenteric lymph node cell suspensions were stained for flow cytometric analysis as described previously (33, 34) using combinations of the following fluorochrome-conjugated monoclonal antibodies (MAbs): CD3 (fluorescein isothiocyanate [FITC] or phycoerythrin [PE]), CD4 (PE, peridinin chlorophyll protein-Cy5.5 [PerCP-Cy5.5], or allophycocyanin [APC]), CD8 (PerCP or APC), CD28 (FITC or PE), CD95 (APC), and Ki-67 (FITC or PE). All antibodies were obtained from BD Biosciences (San Diego, CA), and samples were analyzed by four-color flow cytometry (FACSCalibur; BD Biosciences Immunocytometry Systems). Data analysis was performed using CellQuest Pro (BD Biosciences) and FlowJo (TreeStar, Inc, San Carlos). For Ki-67 staining, cells were fixed with fluorescence-activated cell sorting (FACS) lysing solution (Becton Dickinson), treated with FACS permeabilization buffer (Becton Dickinson), and stained with Ki-67 MAb or a control isotype immunoglobulin G1 (IgG1). In this study, naïve CD4⁺ T cells were identified by their CD95^low CD28^high phenotype, whereas memory CD4⁺ T cells were CD95^high CD28^high or CD95^high CD28^low in the CD4⁺ small lymphocyte gate (34, 38). The statistical analysis was performed by using STATVIEW software (Abacus Concepts, Berkeley, CA). The significance of differences between paired groups was analyzed with the Mann-Whitney U test.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Acute infection (weeks 0 to 5) of rhesus monkeys with SIV. Twelve Indian rhesus monkeys were inoculated intravenously with SIV_sm543 (n = 10) or SIV_mac239 (n = 2) as described in Materials and Methods. Three animals (RhCK2K, RhCK2F, and Rh95D139) experienced an extremely rapid clinical disease course characterized by persistent antigenemia detectable at week 4 postinoculation (p.i.), high levels of plasma viral RNA, no measurable SIV-specific antibody responses, and death from immunodeficiency between weeks 15 and 31 (Table 1). These animals were designated RPs. Two other macaques (RhCK7E and RhCK61) also generated high levels of circulating SIV p27, produced anti-SIV Env antibodies by week 8 p.i. (but no anti-Gag antibodies after week 12 p.i.), and developed disease that required euthanasia at weeks 39 and 56, respectively. In this study, these two animals were designated "intermediate progressors" (IPs). The RP and IP monkeys all produced high levels (6.7 x 10⁷ to 1.7 x 10⁸ viral RNA copies/ml plasma) of viremia that peaked at day 10 p.i. (Fig. 1a). The remaining seven monkeys generated high plasma viral loads which peaked between days 10 and 17 days p.i. and produced SIV-specific antibodies detectable at week 4 p.i. (Table 1). These latter macaques were designated CPs. At week 4 p.i., the RP and IP animals had mean plasma viral RNA levels of 2.1 x 10⁷ RNA copies/ml, whereas the CP monkeys had significantly lower levels (P = 0.0105) of plasma viremia (1.1 x 10⁶ RNA copies/ml) (Fig. 1a).

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TABLE 1. SIV-infected macaques exhibited three different disease phenotypes

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FIG. 1. Levels of plasma viremia and CD4+ T cells during acute SIV infection. Rhesus macaques were inoculated intravenously with 2,000 TCID50 of SIVsmE543. RP, IP, and CP were distinguished based on levels of p27 antigenemia at 4 weeks postinoculation and anti-SIV-specific antibody production at weeks 4 and 8 as shown in Table 1. Plasma viral loads (a), absolute numbers of CD4+ T cells (b), the percentage of memory CD4+ T cells (c), and the percentage of CD4+ T cells expressing CCR5 (d) are shown. The significance of differences between paired groups at 4 weeks p.i. was analyzed by using the Mann-Whitney U test and is presented in a panel to the right of each graph. One CP macaque (RhH677) had higher percentages of memory and CCR5-positive CD4+ T cells (50% and 15%, respectively) during acute infection; these data are not plotted in panel c or d.

Although a transient decline of the absolute number of circulating CD4⁺ T lymphocytes was observed at week 1 in nearly all of the SIV-infected monkeys, their levels fluctuated widely over the next several weeks; by week 5 p.i., the number of total CD4⁺ T cells in the blood was similar to that measured prior to virus inoculation in most of the animals (Fig. 1b). Nonetheless, the mean percentage (11.9) of circulating CD95^high CD28^high/low memory CD4⁺ T lymphocytes in the RP and IP macaques was statistically lower (P = 0.0105) compared to the CP animals (37.0%) by week 4 p.i. (Fig. 1c). Similarly, the mean percentage of CCR5⁺ CD4⁺ T cells in the circulation had declined markedly in the RP and IP groups (0.3%) compared to the CP macaques (6.0%) (Fig. 1d). Thus, by week 4 p.i., the SIV-infected RP and IP monkeys could be distinguished from the CP animals on the basis of both their viral loads and loss of circulating CCR5⁺ memory CD4 cells.

Disease progression in SIV RPs is characterized by the continuous depletion of circulating memory but not naïve CD4⁺ T cells. The plasma viral RNA levels continued to rise in the RP macaques and were accompanied by the sustained depletion of memory CD4⁺ T lymphocytes (Fig. 2). In two representative RP animals, the absolute number of circulating memory CD4⁺ T cells had declined to 32 (monkey RhCK2K) and 23 (monkey RhCK2F) cells/µl blood at the time of euthanasia (weeks 15 and 31, respectively). This contrasted with the number of naïve CD4⁺ T cells in the blood, which remained unchanged or increased in these two animals during the course of their relatively short infections (Fig. 2b and c). At the time of death, naïve CD4⁺ T cells comprised more than 90% of the total circulating CD4⁺ T-lymphocyte population in the RP monkeys (Fig. 2d). Taken together, these results show that SIV-induced disease in rapidly progressing rhesus monkeys is characterized by extremely high levels of plasma viremia and the unremitting elimination of circulating memory CD4⁺ T lymphocytes; the levels of naïve CD4⁺ T cells tended to increase during the course of these infections.

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FIG. 2. The depletion of peripheral blood memory CD4+ T lymphocytes in RP macaques is rapid and irreversible. Plasma viral RNA levels (a) and peripheral blood memory and naïve CD4+ T-cell numbers were measured at the indicated times from representative RP animals RhCK2K (b) and RhCK2F (c). The preinfection levels of the memory and naïve CD4+ T cells for each animal were determined from three independent time points prior to virus inoculation. (d) Memory/naïve CD4+ T-cell ratios calculated from the absolute numbers of these subsets in macaques RhCK2K and RhCK2F at the indicated times.

CD4⁺ memory T lymphocytes are activated and depleted during long-term SIV infections. As noted earlier, the two SIV-infected IP macaques sustained a profound loss of circulating memory CD4⁺ T cells during the acute infection (Fig. 1c). However, in contrast to the RP animals, the percent memory CD4⁺ T lymphocytes in the blood of IP monkeys gradually increased between weeks 4 and 20 (data not shown), and the absolute number of this T-cell subset subsequently stabilized in the range of 100 to 125 cells/µl blood (Fig. 3a). In CP macaques, the absolute number of circulating memory CD4⁺ T lymphocytes gradually declined; by week 20 p.i., five of the seven animals had experienced a major loss of this T-cell subset (Fig. 3a). One of the exceptions, monkey RhCJ6C, rapidly and durably controlled its post-peak plasma viremia in the range of 1 x 10³ to 7 x 10³ RNA copies/ml from week 10 onward (Fig. 3b). The absolute number of circulating memory CD4⁺ T lymphocytes in macaque RhCJ6C increased during this period. A less dramatic correlation between suppression of post-peak plasma viremia and long-term preservation of the memory subset was also observed for macaque RhH682. It is also noteworthy that the delayed loss of memory CD4⁺ T cells in macaque RhH677 was associated with relatively low levels of peak (4 x 10⁶ RNA copies/ml) and week 4 (2.9 x 10⁵ RNA copies/ml) plasma viremia. However, memory CD4⁺ T lymphocytes did decline between weeks 10 and 20 in RhH677 as the level of viral RNA climbed above 1 x 10⁷ RNA copies/ml in the plasma (Fig. 3a and b). These associations notwithstanding, the overall pattern observed in this long-term cohort of two IP and seven CP animals was that of continuous depletion of circulating memory CD4⁺ T cells in eight of the nine SIV-infected monkeys.

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FIG. 3. Memory CD4+ T lymphocytes are lost during long-term SIV infection in IP and CP macaques. The absolute number of memory CD4+ T cells in the peripheral blood (a) and plasma viral RNA levels (b) in two IP and seven CP macaques through 100 weeks of infection are shown.

The dynamics of memory CD4⁺ T-cell depletion in the blood of SIV-infected animals was compared to that occurring at an extralymphoid effector site by analyzing the fraction of CD4⁺ T lymphocytes recovered from the lung by BAL, as previously described by Picker and colleagues (37). In uninfected animals, approximately 40% of T cells obtained in BAL samples were CD4⁺ T lymphocytes in 11 uninfected Indian origin rhesus monkeys examined (Fig. 4a, upper panel). A similarly analyzed BAL specimen from a representative SIV-infected RP macaque (Rh95D139) revealed a nearly complete absence of CD4⁺ T cells by week 4 p.i. (Fig. 4b, top). The massive depletion of CD4 lymphocytes from the lung of this monkey persisted during the entire 13-week course of its SIV infection. In contrast, a representative CP animal (RhH589) experienced a marked but incomplete loss of CD4⁺ T cells from the pulmonary interstitial space at week 4 p.i. (Fig. 4b, bottom). This lymphocyte subset was partially replenished in the lung over the ensuing several weeks. It is always possible, but unlikely based on other reports (28, 37), that the decrease in the percentage of CD4⁺ T cells in BAL specimens may reflect an expansion of CD8⁺ T lymphocytes at this effector site. Thus, the marked loss of circulating memory CD4⁺ T lymphocytes in SIV-infected CP macaques shown in Fig. 3a was also reflected in the changes observed for this subset at a nonlymphoid effector site.

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FIG. 4. CD4+ T cells are rapidly and irreversibly lost in BAL specimens recovered from SIV-infected RP monkeys. BAL specimens were collected from uninfected rhesus macaques (n = 11), including the representative uninfected animal RhDA1X (a), or from representative RP (Rh95D139) and CP (RhH589) monkeys during the first 13 weeks of infection (b), gated on CD3+ T lymphocytes, and analyzed for expression of CD8 and CD4. The percentage of total cells within each gate is indicated.

Memory CD4⁺ T-cell regenerative capacity in IP and CP animals was assessed by determining the fraction expressing the Ki-67 proliferation marker, an indicator of recent passage through the S phase of the cell cycle. Not unexpectedly, an initial increase in memory CD4⁺ T-cell turnover was observed in most of the SIV-infected IP and CP cohort by week 4 p.i. and was particularly prominent in some monkeys (e.g., RhCK7E, RhH679, and RhXGE) experiencing higher levels of peak viremia and marked losses of the circulating memory cell population during the acute infection (Fig. 5a). When peak viremia was relatively low and memory CD4⁺ T lymphocytes were spared (e.g., macaque Rh677), increased proliferation was delayed and more gradual. By week 20 p.i., eight of nine IP/CP animals were exhibiting high levels (approximately 30%) of memory CD4⁺ T-lymphocyte proliferation (Fig. 5a). The exception, again, was monkey RhCJ6C, which had potently suppressed its plasma viremia and had experienced no loss of circulating memory CD4⁺ T lymphocytes (Fig. 3a). Nonetheless, the results obtained for the entire cohort of monkeys clearly indicate that sustained high levels of virus replication drives CD4⁺ T-cell proliferation. The overall pattern of Ki-67 expression presented in Fig. 5b shows that in contrast to the three RP macaques, which exhibited no proliferation of memory CD4⁺ T cells, six of the seven CP animals exhibited striking increases in memory CD4⁺ T-cell turnover. In addition, Fig. 5b shows that the IP monkeys can be distinguished from the RP animals by the capacity of their memory CD4⁺ T lymphocytes to proliferate during the first 20 weeks of infection.

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FIG. 5. Memory CD4+ T-lymphocyte turnover increases during long-term SIV infection. (a) The percentages of Ki-67-positive memory CD4+ T cells in two IP and seven CP macaques during 100 weeks of SIV infection are shown. (b) The fractions of Ki-67-positive memory T cells at weeks 0 and 20 p.i. are shown for three RP, two IP, and seven CP animals. The asterisk denotes the single CP animal, RhCJ6C, which experienced no loss of memory CD4+ T cells and no increase in Ki-67 expression.

Naïve CD4⁺ T lymphocytes are markedly depleted during long-term SIV infections of rhesus monkeys. Recent reports describing the massive depletion of memory CD4⁺ T cells at effector sites by pathogenic SIV strains during acute infections are consistent with other studies showing that memory, not naïve, CD4⁺ T lymphocytes express surface CCR5, the chemokine receptor utilized by virtually all SIV isolates for cell entry (26, 28, 34, 37). We were therefore surprised to find that by week 20 p.i., several of the CP monkeys had also experienced a profound loss of naïve CD4⁺ T cells (Fig. 6). The depletion of the naïve subset was progressive and irreversible, eventually affecting all of the CP animals except for RhCJ6C, which paradoxically responded to the SIV infection by increasing the absolute number of its circulating naïve CD4⁺ T lymphocytes. The decline of circulating naïve CD4⁺ T lymphocytes to very low levels in the CP macaques is in striking contrast to the dynamics of this T-cell subset observed during infections of RP monkeys, which experienced little if any changes affecting the naïve CD4⁺ cell population (compare with Fig. 2).

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FIG. 6. Marked depletion of naïve CD4+ T lymphocytes characterizes long-term SIV infection. Absolute numbers of naïve CD4+ T cells from two IP and seven CP macaques during 100 weeks of SIV infection are shown.

Disease development and clinical outcome in SIV-infected macaques. As indicated in Table 2, five of the nine long-term IP and CP SIV-infected animals died during the course of this study. Two IP macaques were euthanized at weeks 39 and 56, and three CP monkeys were sacrificed at weeks 60, 73, and 77 because of anorexia, intractable diarrhea, and marked weight loss. Not unexpectedly, this group of five animals sustained a substantial loss of circulating memory CD4⁺ T cells compared to the absolute number of this subset at the time of virus inoculation (Table 2). Although substantially reduced, the levels of memory CD4⁺ T lymphocytes in both the blood and lymph nodes of CP monkeys at the time of death were considerably higher than those observed for RP animals (Fig. 7a and b; Table 2). Memory cells were also severely depleted at nonlymphoid effector sites, as monitored by BAL for four representative IP and CP macaques at the time of sacrifice (Fig. 7c). It should be noted that three of the four CP animals remaining alive at week 100 had also sustained marked depletions of absolute numbers of memory CD4⁺ T cells (Table 2). The exception, again, was macaque RhCJ6C, which had also maintained control of its plasma viremia (3,400 viral RNA copies/ml) for nearly 2 years. Depletion of circulating memory CD4⁺ T cells in the IP/CP cohort was also analyzed as percent change from the time of virus inoculation. Using this approach, a significant inverse correlation was observed between the percent decline of the CD4⁺ memory subset at week 4 p.i. and survivability beyond 100 weeks p.i. (Fig. 7d). When assessing events occurring during this period of the acute infection, we also found a significant correlation (P = 0.0272) between the levels of plasma viral RNA at week 4 and subsequent disease induction (data not shown).

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TABLE 2. CD4+ T-cell subpopulations in SIV-infected macaques at the time of euthanasia

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FIG. 7. Loss of CD4+ T-cell subpopulations in peripheral blood, secondary lymph nodes, and effector sites at the time of death in SIV-infected macaques. EDTA-treated blood samples or mesenteric lymph node cell suspensions, collected at the time of necropsy from two RP macaques (RhCK2K and RhCK2F) (a) and two CP macaques (RhXGE and RhH679) (b) were gated on CD4+ T cells and analyzed for the indicated surface markers that distinguish naïve and memory cells. The percentages for each CD4+ T-cell subset are indicated. (c) BAL samples, collected at necropsy from two IP and two CP SIV-infected animals at weeks 56 (RhCK61), 39 (RhCK7E), 73 (RhH679), and 60 (RhH589) were gated on CD3+ T lymphocytes and analyzed for expression of CD8 and CD4. The percentage of total cells within each gate is indicated. (d) The percent decline of memory CD4+ T cells at week 4 p.i. in eight dead and four live SIV-infected animals is shown. The significance of difference between the groups at 4 weeks p.i. was analyzed using the Mann-Whitney U test.

As noted earlier, profound depletion of naïve CD4⁺ T lymphocytes was a prominent feature observed during all long-term SIV infections in IP and CP animals (Fig. 6). In the group of the two IP and three CP monkeys that had to be euthanized during the course of this study, the CP macaques sustained a much greater loss of circulating naïve CD4⁺ T cells than the IP monkeys (Table 2). Because of the highly variable absolute number of naïve CD4⁺ T cells circulating in each animal at the start of this experiment, we plotted the dynamics of this T-lymphocyte subset as the percent change from the time of virus inoculation (Fig. 8a). With one exception, naive CD4⁺ T cells in the blood were lost at a more rapid rate in the three CP monkeys that died than in the four CP animals that were still alive. This finding is reflected in the significant difference (P = 0.0339) between these two groups of CP macaques when the percent loss of naïve CD4⁺ T lymphocytes is compared at the time of death or week 80 p.i. (for live animals) (Fig. 8b). Not unexpectedly, the percent decline of naïve CD4⁺ T cells at the time of death in RP versus CP monkeys is also statistically different.

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FIG. 8. The extent of naïve CD4+ T-cell loss during chronic SIV infection correlates with clinical outcome. (a) The percent change of the naïve CD4+ T-cell subset from preinfection is indicated for two IP and seven CP SIV-infected monkeys. (b) The percent decline of naïve CD4+ T cells in RP, IP, and CP macaques is shown at the time of death or at 80 weeks p.i. The significance of differences between the indicated paired groups was analyzed using the Mann-Whitney U test.

Top Abstract Introduction Materials and Methods Results Discussion References

 
The results of this study show that (i) SIV induces a continuum of disease syndromes (RP to IP to CP), with distinguishing clinical and immunologic features that most likely reflect the severity of the acute infection, and (ii) a profound loss of naïve CD4⁺ T cells occurs during chronic SIV infections in IP and CP macaques, which correlated with disease progression. The depletion of the naïve subset may reflect their continuous differentiation into memory CD4⁺ T lymphocytes in combination with their intrinsically slow rate of renewal.

The rapid progression phenotype represents one extreme of the clinical outcomes experienced by SIV-infected monkeys. In RP animals, the injury to the immune system, as exemplified by targeted destruction of memory CD4⁺ T cells in mucosal effector sites, is apparently so severe during the primary infection that this subset is rapidly and irreversibly eliminated with little or no evidence of its regeneration. The uncontrolled replication of virus in RP monkeys occurs in the absence of sustained antiviral antibody production or significant memory CD4⁺ T-lymphocyte replacement. Our results are consistent with those previously reported by Picker and colleagues, who described the compromised production/turnover and inadequate transport of memory CD4⁺ T cells to nonlymphoid effector tissues in SIV-infected RP macaques (37). We also observed impaired proliferation of memory CD4⁺ lymphocytes in RP animals as monitored by Ki-67 staining (Fig. 5b). In contrast to events occurring in the longer-lived and healthier IP and CP animals, the naïve CD4⁺ T-lymphocyte population in RPs escaped relatively unscathed.

At week 4 p.i., the virologic and immunologic statuses of SIV-infected RP and IP monkeys were nearly indistinguishable: both generated extremely high plasma viral loads, and both had experienced marked losses of their memory CD4⁺ T cells (Fig. 1). The IP macaques, however, subsequently generated humoral immune responses against some of the viral proteins, exhibited high and sustained levels of memory CD4⁺ T-cell turnover as measured by Ki-67 expression, and maintained low but sufficient numbers of memory CD4⁺ T lymphocytes to delay the onset of immunodeficiency for several additional months. Furthermore, unlike the RP animals, the IP monkeys sustained significant depletions of naïve CD4⁺ T cells, which at the time of necropsy were not as low as that measured in CP macaques (Fig. 6).

In CP monkeys, the depletion of memory CD4⁺ cells was not as severe, and post-peak levels of plasma viremia were lower during the acute infection. Nonetheless, we observed a statistically significant inverse correlation between the percent decline of the CD4⁺ memory subset at week 4 p.i. and survivability (Fig. 7d). This correlation most likely reflects better control of viremia at week 4 in those monkeys remaining alive at week 100. Following the acute infection, the CP monkeys all experienced falling numbers of circulating memory CD4⁺ T cells despite high levels of Ki-67 expression (20 to 50%). The persistent memory CD4⁺ T-cell proliferation-induced/virus-induced cell killing in chronically SIV-infected CP macaques requires that naïve cells continuously differentiate into memory CD4⁺ lymphocytes. This unrelenting replenishment of memory cells eventually results in a marked reduction in the size of the naïve cell pool, a failure to generate the numbers of memory cells needed to suppress virus replication, and the ultimate collapse of the immune system.

SIV exclusively utilizes CCR5 as a coreceptor to establish infections in vitro and in vivo (34). Based solely on coreceptor expression, loss of naïve CD4⁺ T lymphocytes, which display CXCR4, not CCR5, at the cell surface, seems paradoxical if cell depletion is simply a consequence of virus replication and direct cell killing. Our results, in fact, demonstrate that disease progression in CP animals correlates with the loss of the naïve CD4⁺ T-cell subset. In this regard, several studies have reported that progressive depletion of naïve CD4⁺ T cells is a common feature of long-term HIV-1 infections (7, 9, 41). It is now believed that the activation-induced proliferation of memory CD4⁺ T lymphocytes and their subsequent death drives a diminishing pool of naive CD4 cells to differentiate into memory cells in HIV-1-infected persons. As shown in the present study, this appears to be the case for SIV-infected CP monkeys. Because naïve CD4⁺ T-cell replacement is slow and dependent on thymic output, a continuous drain on this T-lymphocyte subset cannot be readily sustained (1, 12, 48). In this regard, treatment of patients with Hodgkin's disease by external radiation frequently results in profound depletions of naïve CD4⁺ T lymphocytes that may last up to 30 years (50). In mice, the maintenance of naïve CD4⁺ T cells has been reported to require their trafficking through secondary lymphoid tissues (8). The fibrotic changes and/or destruction of lymph node architecture that usually accompanies chronic HIV-1 and SIV infections (36, 39, 43) would have additional deleterious effects on the maintenance of the naïve CD4⁺ T-cell pool and contribute to their dwindling numbers.

Although no current animal model system fully recapitulates the pathogenic and clinical features associated with a particular human disease, the SIV-infected IP and CP monkeys more accurately represent the tempo and characteristics of immunodeficiency induced by HIV-1 than the SIV-inoculated RP macaques. Rapid progression to disease has also been reported for a small fraction of HIV-1-infected adults, but clinical symptoms generally appear in a 1- to 2-year time frame rather than within a few months, as seen in the SIV RP animals. For HIV-1, CXCR4-utilizing strains, which target and rapidly eliminate both naïve and memory CD4⁺ T cells, are frequently recovered from human rapid progressors (24, 30), in contrast to R5-tropic viral isolates, which replicate exclusively in CD4 memory cells and are the predominant strains detected in the majority of patients experiencing a "normal" disease course (6, 46). Another feature of the SIV RP syndrome rarely observed in HIV-1-infected individuals is the systemic and unrestricted infection of tissue macrophages that sustains high levels of viremia in infected macaques following the destruction and elimination of the memory CD4⁺ T-lymphocyte population (16). The latter is reminiscent of macaques infected with highly pathogenic SHIVs in which virus production is also maintained by tissue macrophages following the rapid and irreversible depletion of CD4⁺ T-cell targets (20). It is presently unclear how the acute infection in SIV RP macaques quickly and irreversibly incapacitates the immune system. Is the transient and inadequate proliferation of memory CD4⁺ T lymphocytes in RP monkeys due to a dysfunctional immunologic response or simply a reflection of overwhelming and continuous cell destruction that masks the ongoing turnover of this subset? Why has the capacity of naïve CD4⁺ T cells in SIV-infected RP animals to differentiate into memory cells been lost? Although these questions pertain to unique aspects of the rapid progressing syndrome in SIV-infected macaques, their answers could provide critical information for understanding events occurring during primary lentiviral infections that dictate subsequent clinical outcomes.

 
We are indebted to Liz Scanlon, Frances Banks, Wilbur Fish, Sekou Savane, Wes Thornton, and Liza Murray for their diligence and assistance in the care and maintenance of our animals, Christopher Erb and Ranjini Iyengar for determining viral RNA levels, and Michael Eckhaus for interpreting histopathological specimens.

 
* Corresponding author. Mailing address: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD 20892. Phone: (301) 496-4012. Fax: (301) 402-0226. E-mail: malm{at}nih.gov.

Published ahead of print on 8 November 2006.

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Journal of Virology, January 2007, p. 893-902, Vol. 81, No. 2
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