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. 2000 Mar;74(6):2943-8.
doi: 10.1128/jvi.74.6.2943-2948.2000.

Functional reconstitution of thymopoiesis after human immunodeficiency virus infection

S G Kitchen  1 , S Killian, J V Giorgi, J A Zack
Affiliations

Functional reconstitution of thymopoiesis after human immunodeficiency virus infection

S G Kitchen et al. J Virol. 2000 Mar.

Abstract

We have utilized combination antiretroviral therapy following human immunodeficiency virus type 1-induced human CD4(+) thymocyte depletion in the SCID-hu mouse to examine the immune competence of reconstituting thymocytes which appear following administration of combination therapy. These cells express a normal distribution of T-cell receptor variable gene families and are responsive to costimulatory signals. These results suggest that normal thymic function may be restored following antiretroviral treatment.

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Figures

FIG. 1
FIG. 1
Effects of HAART on thymocytes. SCID-hu mice were constructed, as described previously, at the University of California–Los Angeles (1, 12). Thy/Liv implants were infected with HIV-1NL4-3, and biopsies were taken at 8 weeks (A) and 11 weeks (B) postinfection and analyzed by flow cytometry. Immediately following the biopsies 8 weeks postinfection, mice were administered a daily combination of AZT, ddI and indinavir for the remainder of the experiment. Cells at each time point were stained with antibodies specific for CCR5 (FITC), CXCR4 (PE), CD4 (Red613), and CD8 (APC). The panels show flow cytometry profiles of a representative mock-infected animal (animal no. 175-28, top row) and the flow cytometry profiles of an HIV-1NL4-3-infected animal (animal no. 175-29, lower row). Percentages of cells within each relevant quadrant are provided.
FIG. 2
FIG. 2
TCRVβ distribution in CD4-CD8 DP thymocytes following HAART. The top panel and bottom panel are two separate experiments involving tissue donors 175 and 179, respectively. SCID-hu mice were either infected with HIVNL4-3 or mock infected and biopsied 8 weeks postinfection to establish that depletion of the CD4-CD8 DP population had occurred (not shown). Mice with total CD4-CD8 DP-cell depletion were administered HAART for 3 weeks. Following therapy, mice were biopsied and analyzed by flow cytometry for CD4 (APC), CD8 (PerCP), and TCRVβ distribution. CD4-CD8 DP cells were gated and analyzed for positive staining of each Vβ receptor. The percentages of each Vβ subtype recognized in the CD4-CD8 DP population were summed to determine the total T-cell Vβ population. The relative abundance of each Vβ subtype was then calculated as a percentage of that total. The top panel represents data from three HIV-infected mice and two mock-infected mice. The bottom panel represents data from four HIV-infected mice and two mock-infected mice. Differences between percentages of each Vβ subtype of HIV- and mock-infected mice were not statistically significant by the Wilcoxon rank sum test (P > 0.4) (performed with SAS software; SAS Institute, Inc., Cary, N.C.).
FIG. 3
FIG. 3
Functional response of the reconstituting thymocyte population. HIV-infected or mock-infected (not shown) thymic implants were biopsied 8 weeks postinfection and analyzed by flow cytometry for CD4 (biotin-Red613) and CD8 (APC) (upper left panel). HAART was initiated at this time, and CD34+/HLA-A2+ cells were injected into the implants at 8.5 weeks postinfection. A second biopsy was performed at 12 weeks postinfection, at which time cells were examined by flow cytometry (upper right panel) and cultured in the presence or absence of costimulation. Three days following costimulation, cells derived from implants not receiving HLA-A2+ cells (grey histogram) and those receiving HLA-A2+ CD34+ cells (black histogram) were analyzed for HLA-A2 (FITC) expression (lower left panel). HLA-A2+ cells in the implant, which in this mouse (animal no. 179-28) constituted the majority of cells, were gated and analyzed for CD25 (interleukin-2 receptor) (PE) expression (lower right panel) (black histogram). Unstimulated cells were cultured and analyzed in parallel (grey histogram). At this time, 92% of costimulated cells and 1% of unstimulated cells expressed CD25. CD25 expression was less than 1% in freshly isolated thymocytes prior to stimulation (not shown). Similar expression of CD25 was seen following costimulation of thymocytes from two mock-infected and six HIV-infected mice.
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