HIV infection-associated immune activation occurs by two distinct pathways that differentially affect CD4 and CD8 T cells - PubMed (original) (raw)

. 2008 Dec 16;105(50):19851-6.

doi: 10.1073/pnas.0810032105. Epub 2008 Dec 5.

Michele Di Mascio, Zonghui Hu, Sharat Srinivasula, Vishakha Thaker, Joseph Adelsberger, Adam Rupert, Michael Baseler, Yutaka Tagaya, Gregg Roby, Catherine Rehm, Dean Follmann, H Clifford Lane

Affiliations

HIV infection-associated immune activation occurs by two distinct pathways that differentially affect CD4 and CD8 T cells

Marta Catalfamo et al. Proc Natl Acad Sci U S A. 2008.

Abstract

HIV infection is characterized by a brisk immune activation that plays an important role in the CD4 depletion and immune dysfunction of patients with AIDS. The mechanism underlying this activation is poorly understood. In the current study, we tested the hypothesis that this activation is the net product of two distinct pathways: the inflammatory response to HIV infection and the homeostatic response to CD4 T cell depletion. Using ex vivo BrdU incorporation of PBMCs from 284 patients with different stages of HIV infection, we found that CD4 proliferation was better predicted by the combination of CD4 depletion and HIV viral load (R(2) = 0.375, P < 0.001) than by either parameter alone (CD4 T cell counts, R(2) = 0.202, P < 0.001; HIV viremia, R(2) = 0.302, P < 0.001). Interestingly, CD8 T cell proliferation could be predicted by HIV RNA levels alone (R(2) = 0.334, P < 0.001) and this predictive value increased only slightly (R(2) = 0.346, P < 0.001) when CD4 T cell depletion was taken into account. Consistent with the hypothesis that CD4 T cell proliferation is driven by IL-7 as a homeostatic response to CD4 T cell depletion, levels of phosphorylated STAT-5 were found to be elevated in naive subsets of CD4 and CD8 T cells from patients with HIV infection and in the central memory subset of CD4 T cells. Taken together these data demonstrate that at least two different pathways lead to immune activation of T cells in patients with HIV infection and these pathways differentially influence CD4 and CD8 T cell subsets.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

CD4 T cell proliferation is driven by homeostatic response to CD4 T cell depletion in HIV infected individuals and normal volunteers, while CD8 T cell proliferation is driven by the viral load. (A) Ex vivo BrdU labeling of PBMCs in a cohort of 284 HIV positive individuals. T cells were analyzed by flow cytometry gating in CD3+CD4+ and CD3+CD8+ T cells. The groups of patients were divided based upon low (LCD4: <300 cells per microliter) and high (HCD4: >800 cells per microliter) CD4 T cells with high (HVL: >10,000 copies per milliliter) and with low (LVL: <50 copies per milliliter) viral loads. (_B_) Ex vivo BrdU labeling of PBMCs from normal volunteers (_n_ = 373) as above. The normal volunteers were divided into individuals with low (LCD4: <500 cells per microliter) and high (HCD4: >800 cells per microliter) CD4 T cell counts. Values for CD4 T cell counts and viral load are expressed as Mean (SD) across randomizations. The P values represent the differences between CD4 and CD8 T cell proliferation.

Fig. 2.

Fig. 2.

Modeling of CD4 and CD8 T cell proliferation in response to viral load and CD4 T cell depletion. (A) The relationship between CD4 T cell count and CD4 (CD4 BrdU+ T cells) or CD8 (CD8 BrdU+ T cells) proliferation was studied in the subgroup of HIV infected patients with HIV RNA <50 copies per milliliter and normal volunteers. Linear regressions of T cell proliferation vs. CD4 T cell count are depicted in the solid lines with the 95% confidence interval bands indicated by the dotted lines. Data from the patients are depicted in red; data for the normal volunteers are depicted in blue. The P values indicate the differences between the slopes (ANCOVA type analysis). (B) The relationships between CD4 T cell counts (cells per microliter), HIV RNA levels (log10 viral load) and CD4 (Red curve) or CD8 (Blue curve) T cell proliferation depicted from two different views.

Fig. 3.

Fig. 3.

Effect of CD4 T cell counts and viral load on IL-7 serum levels. (A) One hundred two serum samples from the 4 groups of HIV positive patients were tested by ELISA for IL-7 (red symbols) and IL-15 (blue symbols). Values for CD4 T cell counts and viral load are expressed as means (SD). Median values for the IL-7 levels are noted inside the plot. (B) Linear regression of IL-7 vs. CD4 T cell counts in patients with viral loads >10,000 (solid red line) or <50 (solid blue line) copies per milliliter. Dotted lines represent the 95% confidence interval bands.

Fig. 4.

Fig. 4.

Phosphorylated STAT-5 expression in HIV positive individuals and normal volunteers. (A)Whole blood was stained by flow cytometry for pSTAT-5 in normal volunteers and HIV positive individuals. (B) Results from HIV positive (red) and normal volunteers (blue) are shown. Each dot represents an individual subject (34 HIV positive and 18 normal individuals). The mean (SD) CD4 counts for the patients and controls were 415 (264) and 704 (323); the mean (SD) CD8 counts for the patients and controls were 870 (518) and 376 (237); and the mean(SD) HIV RNA level for the patients was 35,861 (90, 228).

Fig. 5.

Fig. 5.

Phosphorylated STAT-5 expression in CD4 and CD8 T cell subsets from HIV positive individuals and normal volunteers. (A) Whole blood was stained by flow cytometry for pSTAT-5 in normal volunteers and HIV positive individuals, using CD45RA and CD62L as markers of naive, central memory, effector memory, and terminal effector memory CD4 or CD8 T cells. (B) Results from HIV positive (red) and normal volunteers (blue) are shown. Each dot represents an individual subject (16 HIV positive and 16 normal individuals).

References

    1. Hazenberg MD, Hamann D, Schuitemaker H, Miedema F. T cell depletion in HIV-1 infection: How CD4+ T cells go out of stock. Nat Immunol. 2000;1:285–289. - PubMed
    1. Ho HN, et al. Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens. J Immunol. 1993;150:3070–3079. - PubMed
    1. Kestens LG, et al. Selective increase of activation antigens HLA-DR and CD38 on CD4+ CD45RO+ T lymphocytes during HIV-1 infection. Clin Exp Immunol. 1994;95:436–441. - PMC - PubMed
    1. Mahalingam M, et al. T cell activation and disease severity in HIV infection. Clin Exp Immunol. 1993;93:337–343. - PMC - PubMed
    1. Giorgi JV, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis. 1999;179:859–870. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources