Flt3 ligand enhances thymic-dependent and thymic-independent immune reconstitution

Blood ◽  
2004 ◽  
Vol 104 (9) ◽  
pp. 2794-2800 ◽  
Author(s):  
Terry J. Fry ◽  
Manoj Sinha ◽  
Matthew Milliron ◽  
Yu-Waye Chu ◽  
Veena Kapoor ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Cell Receptor ◽  
Cell Depletion ◽  
Athymic Mice ◽  
Flt3 Ligand ◽  
T Cell Depletion

Abstract Despite recent progress in our understanding of the biology of T-cell homeostasis, clinically available therapies to substantially improve immune reconstitution in patients sustaining T-cell depletion are lacking. T cells are regenerated via a dynamic interplay between thymopoiesis and thymic-independent homeostatic peripheral expansion (HPE). Using athymic mice subjected to T-cell depletion, we observed that HPE is critically dependent on dendritic cells (DCs) for presentation of antigen, raising the possibility that the availability of DCs might be limiting in vivo for HPE to occur efficiently. Indeed, flt3 ligand (flt3L) treatment of athymic mice subjected to T-cell depletion (without DC depletion) substantially enhanced HPE and improved immune competence. Following bone marrow transplantation (BMT) in athymic hosts, both dendritic cells and T cells were profoundly depleted and flt3L therapy restored DC numbers and enhanced HPE. In addition, thymus-bearing BMT recipients treated with flt3L regenerated increased numbers of thymic-dependent progeny with increased numbers of T-cell receptor excision circle (TREC)-positive T cells, indicating increased thymopoiesis. Therefore, flt3L is a potent immunorestorative agent that enhances both thymic-dependent and thymic-independent pathways of T-cell regeneration. (Blood. 2004;104:2794-2800)

scholarly journals Impact of Different T Cell Depletion Protocols on Immune Reconstitution Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Amandine Pradier ◽  
Adrien Petitpas ◽  
Anne-Claire Mamez ◽  
Federica Giannotti ◽  
Sarah Morin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
The Impact

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic modality for a variety of hematological malignancies and congenital disorders. One of the major complications of the procedure is graft-versus-host-disease (GVHD) initiated by T cells co-administered with the graft. Removal of donor T cells from the graft is a widely employed and effective strategy to prevent GVHD, although its impact on post-transplant immune reconstitution might significantly affect anti-tumor and anti-infectious responses. Several approaches of T cell depletion (TCD) exist, including in vivo depletion using anti-thymocyte globulin (ATG) and/or post-transplant cyclophosphamide (PTCy) as well as in vitro manipulation of the graft. In this work, we analyzed the impact of different T cell depletion strategies on immune reconstitution after allogeneic HSCT. Methods We retrospectively analysed data from 168 patients transplanted between 2015 and 2019 at Geneva University Hospitals. In our center, several methods for TCD are being used, alone or in combination: 1) In vivo T cell depletion using ATG (ATG-Thymoglobulin 7.5 mg/kg or ATG-Fresenius 25 mg/kg); 2) in vitro partial T cell depletion (pTCD) of the graft obtained through in vitro incubation with alemtuzumab (Campath [Genzyme Corporation, Cambridge, MA]), washed before infusion and administered at day 0, followed on day +1 by an add-back of unmanipulated grafts containing about 100 × 106/kg donor T cells. The procedure is followed by donor lymphocyte infusions at incremental doses starting with 1 × 106 CD3/kg at 3 months to all patients who had received pTCD grafts with RIC in the absence of GVHD; 3) post-transplant cyclophosphamide (PTCy; 50 mg/kg) on days 3 and 4 post-HSCT. Absolute counts of CD3, CD4, CD8, CD19 and NK cells measured by flow cytometry during the first year after allogeneic HSCT were analyzed. Measures obtained from patients with mixed donor chimerism or after therapeutic DLI were excluded from the analysis. Cell numbers during time were compared using mixed-effects linear models depending on the TCD. Multivariable analysis was performed taking into account the impact of clinical factors differing between patients groups (patient's age, donor type and conditioning). Results ATG was administered to 77 (46%) patients, 15 (9%) patients received a pTCD graft and 26 (15%) patients received a combination of both ATG and pTCD graft. 24 (14%) patients were treated with PTCy and 26 (15%) patients received a T replete graft. 60% of patients had a reduced intensity conditioning (RIC). 48 (29%) patients received grafts from a sibling identical donor, 94 (56%) from a matched unrelated donor, 13 (8%) from mismatched unrelated donor and 13 (8%) received haploidentical grafts. TCD protocols had no significant impact on CD3 or CD8 T cell reconstitution during the first year post-HSCT (Figure 1). Conversely, CD4 T cells recovery was affected by the ATG/pTCD combination (coefficient ± SE: -67±28, p=0.019) when compared to the T cell replete group (Figure 1). Analysis of data censored for acute or chronic GVHD requiring treatment or relapse revealed a delay of CD4 T cell reconstitution in the ATG and/or pTCD treated groups on (ATG:-79±27, p=0.004; pTCD:-100±43, p=0.022; ATG/pTCD:-110±33, p<0.001). Interestingly, pTCD alone or in combination with ATG resulted in a better reconstitution of NK cells compared to T replete group (pTCD: 152±45, p<0.001; ATG/pTCD: 94±36, p=0.009; Figure 1). A similar effect of pTCD was also observed for B cells (pTCD: 170±48, p<.001; ATG/pTCD: 127±38, p<.001). The effect of pTCD on NK was confirmed when data were censored for GVHD and relapse (pTCD: 132±60, p=0.028; ATG/pTCD: 106±47, p=0.023) while only ATG/pTCD retained a significant impact on B cells (102±49, p=0.037). The use of PTCy did not affect T, NK or B cell reconstitution when compared to the T cell replete group. Conclusion Our results indicate that all TCD protocols with the only exception of PTCy are associated with a delayed recovery of CD4 T cells whereas pTCD of the graft, alone or in combination with ATG, significantly improves NK and B cell reconstitution. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Priming of T cells to Fas-mediated proliferative signals by interleukin-7

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1195-1204 ◽  
Author(s):  
Bence Rethi ◽  
Nancy Vivar ◽  
Stefano Sammicheli ◽  
Caroline Fluur ◽  
Nicolas Ruffin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Cell Receptor ◽  
Cell Depletion ◽  
Activated T Cells ◽  
T Cell Depletion ◽  
Interleukin 7 ◽  
Costimulatory Signals ◽  
Opposing Effects

Abstract T-cell depletion associated with HIV infection or cytoreductive therapies triggers potential T-cell regenerative mechanisms such as peripheral T-lymphocyte expansion to weak antigenic stimuli and the increased availability of interleukin-7 (IL-7), a cytokine with potent antiapoptotic and proliferative activities. Deleterious mechanisms also associated with lymphopenia, such as increased Fas expression and apoptosis of T cell, however, may result in opposing effects. In this study, we show that Fas molecules, primarily associated with T-cell depletion in lymphopenic settings, may also contribute to compensatory T-cell expansion through transmitting costimulatory signals to suboptimally activated T cells. Proliferation of T lymphocytes in response to concomitant Fas and T-cell receptor (TCR) triggering was shown to be increased in HIV-infected individuals compared with noninfected controls. As IL-7 levels are often elevated in lymphopenic individuals in association with increased Fas expression, we analyzed whether IL-7 would influence Fas-mediated proliferative signals in T cells. We show that IL-7 is able to increase the efficacy of Fas to induce proliferation of suboptimally activated T cells. Thus, high IL-7 levels associated with lymphopenic conditions may simultaneously induce sensitivity to Fas-mediated apoptosis in nonactivated T cells and increase Fas-induced costimulatory signals in T cells recognizing low-affinity antigens.

Reconstitution of CD52-Negative CD4 T Cells after Alemtuzumab-Based T Cell Depleted Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1182-1182
Author(s):  
Eva M Wagner ◽  
Aline N Lay ◽  
Sina Wenzel ◽  
Timo Schmitt ◽  
Julia Hemmerling ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Lymphocytic Leukemia ◽  
Cell Depletion ◽  
Down Regulation ◽  
T Cell Depletion ◽  
Hematopoietic Stem

Abstract The human CD52 molecule is the target of the monoclonal antibody Alemtuzumab, which is used for treating patients with chemo-refractory chronic lymphocytic leukemia as well as for T cell depletion (TCD) in the context of allogeneic hematopoietic stem cell transplantation (HSCT). The molecule is expressed on the surface of lymphocytes, dendritic cells and to a lesser extent on blood-derived monocytes. Previously, investigators have demonstrated that the surface expression of CD52 on T cells is down-regulated after in vitro incubation with Alemtuzumab. By treating purified human CD4 T cells over 4 hours with 10 μg/mL Alemtuzumab in medium supplemented with 10% human AB serum in vitro, we observed a strong decrease of CD52 expression by flow cytometry with a maximum 3–7 days after incubation. The CD52 down-regulation was also found at weaker intensity on CD8 T cells. From previous studies in chronic lymphocytic leukemia patients, it is known that Alemtuzumab treatment also leads to a down-regulation of CD52 on T cells in vivo. However, similar experiments have not been performed in allogeneic HSCT patients receiving Alemtuzumab in vivo for T cell depletion. We therefore analyzed the expression of CD52 on human peripheral blood mononuclear cells isolated at repeated time points from 22 allogeneic HSCT patients after reduced-intensity conditioning with fludarabine and melphalan and in vivo T cell depletion with Alemtuzumab (100 mg). Half of the patients received prophylactic CD8-depleted donor lymphocyte infusions (DLI) to promote immune reconstitution. By flow cytometry, we observed that the CD52 expression on monocytes, B cells, and natural killer cells remained unaltered after transplantation and was not influenced by the application of DLI. In contrast, the majority of CD4 T cells were CD52-negative (median, 72%) after transplantation and they remained CD52-negative in patients who did not receive DLI throughout the first year after HSCT. The permanent lack of CD52 expression could not be explained by a continuous effect of Alemtuzumab, because earlier studies have shown that the antibody is not present in active plasma concentrations beyond day +60 after HSCT. In contrast, patients receiving CD8-depleted DLI demonstrated a significant increase in the proportion of CD52-positive CD4 T cells. In three of our patients (DLI: n=2, non-DLI: n=1) we analyzed the donor chimerism of CD52-positive and CD52-negative CD4 T cells sorted with high purity by flow cytometry. Three months after HSCT (before DLI), the proportion of donor T cells was clearly higher among the CD52-negative compared to the small proportion of CD52-positive cells in all patients (44% vs. 10%, 83% vs. 0%, and 100% vs. 40%). In the patient who did not receive DLI, the donor T cell chimerism remained mixed in the CD52-negative and CD52-positive fractions on days 200 (CD52-negative: 95%; CD52-positive: 15%) and 350 (CD52-negative: 92%; CD52-positive: 65%). In contrast, the two patients receiving CD8-depleted DLI showed a strong increase in the proportion of CD52-positive CD4 T cells that were of complete donor origin. Altogether, CD52 is permanently down-regulated in reconstituting CD4 T cells following HSCT with an Alemtuzumab-based TCD regimen unless DLI are applied. Our data support the idea of an active mechanism for CD52 down-regulation in CD4 T cells that is not related to B cells and natural killer cells and that appears to differently affect donor and host T cells, respectively.

Pentostatin Is Advantageous Relative to Fludarabine for in Vivo Murine T Cell Depletion, Suppression of T Cell Cytokine Secretion, and Inhibition of HVGR

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3483-3483
Author(s):  
Jacopo Mariotti ◽  
Jason Foley ◽  
Kaitlyn Ryan ◽  
Nicole Buxhoeveden ◽  
Daniel Fowler
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytokine Secretion ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
T Cell Suppression ◽  
Ifn Γ ◽  
Cell Suppression

Abstract Although fludarabine and pentostatin are variably utilized for conditioning prior to clinical allogeneic transplantation, limited data exists with respect to their relative efficacy in terms of host immune T cell depletion and T cell suppression. To directly compare these agents in vivo in a murine model, we compared a regimen of fludarabine plus cyclophosphamide (FC) similar to one that we previously developed (Petrus et al, BBMT, 2000) to a new regimen of pentostatin plus cyclophosphamide (PC). Cohorts of mice (n=5–10) received a three-day regimen consisting of P alone (1 mg/kg/d), F alone (100 mg/kg/d), C alone (50 mg/kg/d), or combination PC or FC. Similar to our previous data, administration of P, F, or C alone yielded minimal host T cell depletion (as measured by enumeration of splenic CD4+ and CD8+ T cells) and minimal T cell suppression (as determined by CD3, CD28 co-stimulation of a constant number of remaining splenic T cells and measuring resultant cytokine secretion by multi-analyte assay). The PC and FC regimens were similar in terms of myeloid suppression (p=.2). However, the PC regimen was more potent in terms of depleting host CD4+ T cells (remaining host CD4 number [× 10^6/spleen], 2.1±0.3 [PC] vs. 4.4±0.6 [FC], p<0.01) and CD8+ T cells (remaining host CD8 number, 1.7±0.2 [PC] vs. 2.4±0.5 [FC], p<0.01). Moreover, the PC regimen yielded greater T cell immune suppression than the FC regimen (cytokine values are pg/ml/0.5×10^6 cells/ml; all comparisons p<0.05) with respect to capacity to secrete IFN-γ (13±5 [PC] vs. 48±12 [FC]), IL-2 (59±44 [PC] vs. 258±32 [FC]), IL-4 (34±10 [PC] vs. 104±12 [FC]), and IL-10 (15±3 [PC] vs. 34±5 [FC]). In light of this differential in both immune T cell depletion and suppression of T cell effector function, we hypothesized that T cells from PC-treated recipients would have reduced capacity to mediate a host-versus-graft rejection response (HVGR) relative to FC-treated recipients. To directly test this hypothesis, we utilized a host T cell add-back model of rejection whereby BALB/c hosts were lethally irradiated (1050 cGy; day -2), reconstituted with host-type T cells from PC- or FC-treated recipients (day -1; 0.1 × 10^6 T cells transferred), and finally challenged with fully MHC-disparate transplantation (B6 donor bone marrow cells, 10 × 10^6 cells; day 0). In vivo HVGR was quantified by the following method at day 7 post-BMT: harvest of splenic T cells, stimulation with host- or donor-type dendritic cells, and use of six-color flow cytometry to detect host T cells, CD4 and CD8 subsets, and cytokine secretion by capture method. Consistent with our hypothesis, PC-treated cells acquired greatly reduced alloreactivity in vivo relative to FC-treated cells: the percentage of host CD4+ T cells secreting IFN-γ in an allospecific manner was 2.3±0.8% in recipients of PC-treated T cells and 62.7±13.4% in recipients of FC-treated cells (p<0.001). Similarly, the percentage of host CD8+ T cells secreting IFN-γ in an allospecific manner was 8.6±2.8% in recipients of PC-treated T cells and 92.7±4.1% in recipients of FC-treated T cells (p<0.001). We therefore conclude that at similar levels of myeloid suppression, the PC regimen is superior to the FC regimen in terms of murine T cell depletion, suppression of global T cell cytokine secretion, and inhibition of in vivo capacity to acquire allospecificity in response to fully genetically disparate marrow allografts. These data provide a rationale to develop PC regimens as an alternative to currently utilized FC regimens.

scholarly journals Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells

2003 ◽  
Vol 198 (2) ◽  
pp. 235-247 ◽  
Author(s):  
Sayuri Yamazaki ◽  
Tomonori Iyoda ◽  
Kristin Tarbell ◽  
Kara Olson ◽  
Klara Velinzon ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Antigen Processing ◽  
Specific Antigen ◽  
Cell Receptor ◽  
Cd4 T Cell

An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25− autoimmune disease–inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25− CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25− CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC–T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25− CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses.

scholarly journals Identifying the Target Cell in Primary Simian Immunodeficiency Virus (SIV) Infection: Highly Activated Memory CD4+ T Cells Are Rapidly Eliminated in Early SIV Infection In Vivo

2000 ◽  
Vol 74 (1) ◽  
pp. 57-64 ◽  
Author(s):  
Ronald S. Veazey ◽  
Irene C. Tham ◽  
Keith G. Mansfield ◽  
MaryAnn DeMaria ◽  
Amy E. Forand ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Cell Depletion ◽  
Cell Type ◽  
T Cell Depletion ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT It has recently been shown that rapid and profound CD4+T-cell depletion occurs almost exclusively within the intestinal tract of simian immunodeficiency virus (SIV)-infected macaques within days of infection. Here we demonstrate (by three- and four-color flow cytometry) that this depletion is specific to a definable subset of CD4+ T cells, namely, those having both a highly and/or acutely activated (CD69+ CD38+HLA-DR+) and memory (CD45RA−Leu8−) phenotype. Moreover, we demonstrate that this subset of helper T cells is found primarily within the intestinal lamina propria. Viral tropism for this particular cell type (which has been previously suggested by various studies in vitro) could explain why profound CD4+ T-cell depletion occurs in the intestine and not in peripheral lymphoid tissues in early SIV infection. Furthermore, we demonstrate that an acute loss of this specific subset of activated memory CD4+ T cells may also be detected in peripheral blood and lymph nodes in early SIV infection. However, since this particular cell type is present in such small numbers in circulation, its loss does not significantly affect total CD4+ T cell counts. This finding suggests that SIV and, presumably, human immunodeficiency virus specifically infect, replicate in, and eliminate definable subsets of CD4+ T cells in vivo.

scholarly journals Evaluation of CD8+ T-cell and antibody responses following transient increased viraemia in rhesus macaques infected with live, attenuated simian immunodeficiency virus

2005 ◽  
Vol 86 (12) ◽  
pp. 3375-3384 ◽  
Author(s):  
Karin J. Metzner ◽  
Walter J. Moretto ◽  
Sean M. Donahoe ◽  
Xia Jin ◽  
Agegnehu Gettie ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
Immunodeficiency Virus ◽  
Transient Period ◽  
Antibody Titres

In vivo depletion of CD8+ T cells results in an increase in viral load in macaques chronically infected with simian immunodeficiency virus (SIVmac239Δnef). Here, the cellular and humoral immune responses associated with this transient period of enhanced viraemia in macaques infected with SIVmac239Δnef were characterized. Fourteen days after in vivo CD8+ T-cell depletion, two of six macaques experienced a 1–2 log10 increase in anti-gp130 and p27 antibody titres and a three- to fivefold increase in gamma interferon-secreting SIV-specific CD8+ T cells. Three other macaques had modest or no increase in anti-gp130 antibodies and significantly lower titres of anti-p27 antibodies, with minimal induction of functional CD8+ T cells. Four of the five CD8-depleted macaques experienced an increase in neutralizing antibody titres to SIVmac239. Induction of SIV-specific immune responses was associated with increases in CD8+ T-cell proliferation and fluctuations in the levels of signal-joint T-cell receptor excision circles in peripheral blood cells. Five months after CD8+ T-cell depletion, only the two high-responding macaques were protected from intravenous challenge with pathogenic SIV, whilst the remaining animals were unable to control replication of the challenge virus. Together, these findings suggest that a transient period of enhanced antigenaemia during chronic SIV infection may serve to augment virus-specific immunity in some, but not all, macaques. These findings have relevance for induction of human immunodeficiency virus (HIV)-specific immune responses during prophylactic and therapeutic vaccination and for immunological evaluation of structured treatment interruptions in patients chronically infected with HIV-1.

scholarly journals On the Death Rate of Abortively Infected Cells: Estimation from Simian-Human Immunodeficiency Virus Infection

2017 ◽  
Vol 91 (18) ◽  
Author(s):  
Ruian Ke ◽  
Mian-er Cong ◽  
David Li ◽  
J. Gerardo García-Lerma ◽  
Alan S. Perelson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Loss ◽  
Cell Depletion ◽  
Abortive Infection ◽  
T Cell Depletion ◽  
Human Immunodeficiency Viruses ◽  
Quantitative Understanding ◽  
Infected Cells

ABSTRACT Progressive T cell depletion during chronic human immunodeficiency virus type 1 (HIV) infection is a key mechanism that leads to the development of AIDS. Recent studies have suggested that most T cells in the tissue die through pyroptosis triggered by abortive infection, i.e., infection of resting T cells in which HIV failed to complete reverse transcription. However, the contribution of abortive infection to T cell loss and how quickly abortively infected cells die in vivo, key parameters for a quantitative understanding of T cell population dynamics, are not clear. Here, we infected rhesus macaques with simian-human immunodeficiency viruses (SHIV) and followed the dynamics of both plasma SHIV RNA and total cell-associated SHIV DNA. Fitting mathematical models to the data, we estimate that upon infection a majority of CD4+ T cells (approximately 65%, on average) become abortively infected and die at a relatively high rate of 0.27 day−1 (half-life, 2.6 days). This confirms the importance of abortive infection in driving T cell depletion. Further, we find evidence suggesting that an immune response may be restricting viral infection 1 to 3 weeks after infection. Our study serves as a step forward toward a quantitative understanding of the mechanisms driving T cell depletion during HIV infection. IMPORTANCE In HIV-infected patients, progressive CD4+ T cell loss ultimately leads to the development of AIDS. The mechanisms underlying this T cell loss are not clear. Recent experimental data suggest that the majority of CD4+ T cells in tissue die through abortive infection, where the accumulation of incomplete HIV transcripts triggers cell death. To investigate the role of abortive infection in driving CD4+ T cell loss in vivo, we infected macaques with simian-human immunodeficiency viruses (SHIV) and followed the viral kinetics of both plasma RNA and cell-associated DNA during infection. Fitting mathematical models, we estimated that a large fraction of infected cells dies through abortive infection and has a half-life of approximately 2.6 days. Our results provide the first in vivo quantitative estimates of parameters characterizing abortive infection and support the notion that abortive infection represents an important mechanism underlying progressive CD4+ T cell depletion in vivo.

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