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. 2007 Aug;81(16):8838-42.
doi: 10.1128/JVI.02663-06. Epub 2007 May 30.

Low immune activation despite high levels of pathogenic human immunodeficiency virus type 1 results in long-term asymptomatic disease

Shailesh K Choudhary  1 , Nienke Vrisekoop, Christine A Jansen, Sigrid A Otto, Hanneke Schuitemaker, Frank Miedema, David Camerini
Affiliations

Low immune activation despite high levels of pathogenic human immunodeficiency virus type 1 results in long-term asymptomatic disease

Shailesh K Choudhary et al. J Virol. 2007 Aug.

Abstract

Long-term asymptomatic human immunodeficiency virus (HIV)-infected individuals (LTA) usually have low viral load and low immune activation. To discern whether viral load or immune activation is dominant in determining progression to AIDS, we studied three exceptional LTA with high viral loads. HIV type 1 isolates from these LTA were as pathogenic as viruses from progressors in organ culture. Despite high viral loads, these LTA had low levels of proliferating and activated T cells compared to progressors, like other LTA. In contrast to those in progressors, HIV-specific CD4(+) T-cell responses in these LTA were maintained. Thus, low immune activation despite a high viral load preserved HIV-specific T-cell responses and resulted in a long-term asymptomatic phenotype.

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Figures

FIG. 1.
FIG. 1.
Longitudinal analysis of CD4+ T-cell numbers in blood and HIV-1 RNA copies in plasma of the patients used in this study. Plasma viral RNA copies per ml (left axes; large symbols and dashed lines) and CD4+ T cells per μl blood (right axes; small symbols and solid lines) against time in years after seroconversion or after seropositive entry into the cohort are shown. The horizontal dashed lines represent the detection limit of 1,000 RNA copies/ml. Gray arrows along the x axes indicate the times of isolation of the HIV-1 clones used for Fig. 2 and 3, while black arrows with letters refer to time points of T-cell isolation for analyses shown in Fig. 4.
FIG. 2.
FIG. 2.
R5-HIV-1 clones from LTA-HVL replicated to high levels and depleted CD4+ thymocytes in FTOC. FTOCs were infected with the indicated HIV-1 clones. (A) The bars represent average percentages of CD4+ thymocytes (CD4SP and -DP) in FTOC, with error bars indicating standard deviations. The numbers of samples used to obtain data on day 14 and day 21 postinfection, respectively, are as follows: n = 9 for mock in five experiments; n = 4 for NL4-3 in two experiments; n = 8 for ACH 142*E11 in five experiments; n = 3 for ACH 337.40.1a1 in two experiments; and n = 5 for ACH 337.40.1c1, ACH 68.39.D11, ACH 68.39.H4, ACH 750.34.1e2, and ACH 583.38.1a5 in three experiments. (B) Viral replication was quantified by measuring HIV-1 capsid antigen (p24) concentration in FTOC medium on days 4, 6, 8, 10, 14, 16, 18, and 20 postinfection with a commercial enzyme-linked immunosorbent assay kit (NEN Life Science Products). Each dot represents the medium from an individual FTOC.
FIG. 3.
FIG. 3.
Depletion of CD4+ cells in human spleen histoculture infected ex vivo with HIV-1. Spleen histocultures were infected with the indicated HIV-1 clones. (A) Depletion of CD4+ lymphocytes measured by change in the ratio of CD4+ to CD8+ cells. (B) Depletion of CD4+ CXCR4+ T lymphocytes. (C) Depletion of CD4+ CCR5+ T lymphocytes. Data shown are representative of two experiments done in duplicate, with error bars indicating standard deviations.
FIG. 4.
FIG. 4.
LTA-HVL had low immune activation and preserved HIV-specific responses. (A) Percentages of activated (CD38+ HLA-DR+) and proliferating (Ki67+) CD4+ and CD8+ T cells. (B) Absolute numbers of HIV-specific IL-2-producing (upper panel) and IFN-γ-producing (lower panel) CD4+ T cells. Time points in panels A and B correspond to the black arrows in Fig. 1. Black symbols depict progressors, white symbols depict LTA with low viral loads, and gray symbols depict LTA with high viral loads. Asterisks indicate significant differences between LTA or LTA-HVL compared to progressors at time point B (P < 0.01 for LTA and LTA-HVL Ki67+ CD4+ cells, P < 0.01 for LTA Ki67+ CD8+ cells, P < 0.05 for LTA-HVL CD8+ cells, and P < 0.05 for LTA-HVL IFN-γ+ CD4+ cells).
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