Mamu-A*01 allele-mediated attenuation of disease progression in simian-human immunodeficiency virus infection - PubMed (original) (raw)

. 2002 Dec;76(24):12845-54.

doi: 10.1128/jvi.76.24.12845-12854.2002.

Tong-Ming Fu, Danilo R Casimiro, Mary-Ellen Davies, Xiaoping Liang, William A Schleif, Larry Handt, Lynda Tussey, Minchun Chen, Aimin Tang, Keith A Wilson, Wendy L Trigona, Daniel C Freed, Charles Y Tan, Melanie Horton, Emilio A Emini, John W Shiver

Affiliations

Mamu-A*01 allele-mediated attenuation of disease progression in simian-human immunodeficiency virus infection

Zhi-Qiang Zhang et al. J Virol. 2002 Dec.

Abstract

Expression of several major histocompatibility complex (MHC) class I alleles is associated with a protective effect against disease progression in both human immunodeficiency virus type 1 and simian immunodeficiency virus infection. To understand the mechanism underlying this effect, we investigated the expression of the MHC class I allele Mamu-A*01 in simian-human immunodeficiency virus (SHIV) infection, one of the major models for evaluation of AIDS vaccine candidates. We found that disease progression was significantly delayed in Mamu-A*01-positive rhesus monkeys infected with the highly pathogenic SHIV 89.6P. The delay corresponded not only to a noted Mamu-A*01-restricted dominant cytotoxic T-lymphocyte (CTL) response but also to a lower viral load in lymph nodes (LN) and, importantly, to minimal destruction of LN structure during early infection. In contrast, Mamu-A*01-negative monkeys exhibited massive destruction of LN structure with accompanying rapid disease progression. These data indicate that MHC class I allele-restricted CTL responses may play an important role in preservation of lymphoid tissue structure, thereby resulting in attenuation of disease progression in immunodeficiency virus infection.

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Figures

FIG. 1.

FIG. 1.

Survival curves of Mamu-A∗01+ and _Mamu-A∗01_− monkeys following intravenous challenge with SHIV 89.6P.

FIG. 2.

FIG. 2.

Postchallenge viremia and CD4+ cell count profiles. Plasma viral levels were determined by use of a branched-DNA amplification assay with a detection limit of 500 vRNA copies/ml (Bayer Diagnostics). For CD4+ cell counts, total lymphocyte numbers were determined by the percent CD3+/CD4+ lymphocyte staining based on flow cytometry and reported as the number of cells per microliter of whole blood. The thick black line in each figure represents the average curve.

FIG. 3.

FIG. 3.

ISH of SHIV RNA (A) and staining of CD4+ cells (B) in LNs. The frequency of vRNA+ cells and the amount of vRNA deposited on the FDC network in the GC are shown for two representative monkeys, AW9C (Mamu-A∗01+) and C6CF (_Mamu-A∗01_−), at days 12, 20, 40, and 100 postchallenge. In the day 12 panels, the frequency of vRNA+ cells is significantly lower in AW9C than in C6CF (magnification, ×160; original magnification, ×200). In the day 20 panels, at a higher magnification (×320; original magnification, ×400), the level of vRNA in GCs is also significantly lower in AW9C than in C6CF. By days 40 and 100, there is no significant difference in either the frequency of vRNA+ cells or the amount of vRNA in GCs between these two monkeys. CD4 T-cell staining shows a higher density of CD4+ cells in the paracortical region (T-cell zone) in AW9C than in C6CF (magnification, ×160; original magnification, ×200). From day 20 to day 100, most CD4+ cells were depleted in both animals.

FIG. 3.

FIG. 3.

ISH of SHIV RNA (A) and staining of CD4+ cells (B) in LNs. The frequency of vRNA+ cells and the amount of vRNA deposited on the FDC network in the GC are shown for two representative monkeys, AW9C (Mamu-A∗01+) and C6CF (_Mamu-A∗01_−), at days 12, 20, 40, and 100 postchallenge. In the day 12 panels, the frequency of vRNA+ cells is significantly lower in AW9C than in C6CF (magnification, ×160; original magnification, ×200). In the day 20 panels, at a higher magnification (×320; original magnification, ×400), the level of vRNA in GCs is also significantly lower in AW9C than in C6CF. By days 40 and 100, there is no significant difference in either the frequency of vRNA+ cells or the amount of vRNA in GCs between these two monkeys. CD4 T-cell staining shows a higher density of CD4+ cells in the paracortical region (T-cell zone) in AW9C than in C6CF (magnification, ×160; original magnification, ×200). From day 20 to day 100, most CD4+ cells were depleted in both animals.

FIG. 4.

FIG. 4.

Staining of FDC network (A) and proliferating B cells in GCs (B) in LNs. (A) The normal morphology of the FDC network is shown in day 12 panels for both monkeys, AW9C (Mamu-A∗01+) and C6CF (_Mamu-A∗01_−). In day 20 panels, the processes appear to be fragmented in C6CF but not in AW9C. At days 40 and 100, staining of the FDC network is completely absent in C6CF but obvious in AW9C. (B) Ki67+ cells and CD20+ cells are shown in brown and purple, respectively. The long arrow points to proliferating B cells (Ki67+ CD20+) locating in GCs. The short arrow points to the follicular mantle area, which is packed with nonproliferating CD20+ B cells. Proliferating B cells in GCs were observed in both monkeys at day 12. However, from day 20, there were no proliferating B cells in GCs in C6CF (shown as a blank, nonstaining GC area). GCs gradually became smaller and were almost invisible at day 100 in C6CF, indicating complete destruction of GCs. Magnification, ×160; original magnification, ×200.

FIG. 4.

FIG. 4.

Staining of FDC network (A) and proliferating B cells in GCs (B) in LNs. (A) The normal morphology of the FDC network is shown in day 12 panels for both monkeys, AW9C (Mamu-A∗01+) and C6CF (_Mamu-A∗01_−). In day 20 panels, the processes appear to be fragmented in C6CF but not in AW9C. At days 40 and 100, staining of the FDC network is completely absent in C6CF but obvious in AW9C. (B) Ki67+ cells and CD20+ cells are shown in brown and purple, respectively. The long arrow points to proliferating B cells (Ki67+ CD20+) locating in GCs. The short arrow points to the follicular mantle area, which is packed with nonproliferating CD20+ B cells. Proliferating B cells in GCs were observed in both monkeys at day 12. However, from day 20, there were no proliferating B cells in GCs in C6CF (shown as a blank, nonstaining GC area). GCs gradually became smaller and were almost invisible at day 100 in C6CF, indicating complete destruction of GCs. Magnification, ×160; original magnification, ×200.

FIG. 5.

FIG. 5.

Kinetics of CD8+ T-cell responses detected by tetramer staining following intravenous challenge with SHIV 89.6P. The percentage of CD3+ CD8+ cells indicates the levels of circulating p11CM-specific CD8+ T cells for Mamu-A∗01-expressing monkeys. The cutoff value was 0.1%. Two animals (designations marked with asterisks) were Mamu-A∗01 negative (CC6F and CC6P).

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