It has been appreciated for some time that naturally SIV-infected sooty mangabey monkeys rarely develop immunodeficiency, even though they typically have high viral loads. This contrasts with non-progressive infection in humans, which is associated with the low levels of HIV replication. However, there are few studies that have directly addressed whether long term non progressive infection can occur in humans despite relatively high viral loads. A new paper in J. Virology now reports on three individuals from the Amsterdam HIV Cohort with long term asymptomatic infection with viral loads comparable to typical progressors (in the 10,000-100,000 range). The researchers found that the lack of disease progression in these individuals was associated with the maintenance of low levels of immune activation (as measured by HLA-DR and CD38 expression on CD4 and CD8 T cells) out to ten years of follow-up. Levels of immune activation were comparable to long-term non-progressors with low viral loads and significantly lower than those seen in individuals with progressing disease. As the study authors note, these findings are similar to those reported for sooty mangabeys who maintain low levels of immune activation despite their high SIV viral loads.
The researchers also looked at HIV-specific CD4 T cell responses and found that study participants with long term asympomatic infection – including the three with high viral loads - maintained Gag-specific CD4 T cells capable of making IL-2 and interferon gamma while these responses decreased over time in progressors. The authors state that this finding suggests the loss of functional HIV-specific CD4 T cells is related to the combination of immune activation and high viral load, not just high viral load alone.
Two additional papers in the new Journal of Immunology attempt to shed further light on asymptomatic SIV infection in sooty mangabeys. Researchers from Emory University have previously reported that CD4 T cells from mangabeys are resistant to the induction of anergy (unresponsiveness) and do not show the same cell cycle perturbations seen in progressing SIV and HIV infections. The latest finding of this research group is that an enhanced ability of CD4 T cells to synthesize IL-2 may contribute to the disease-resistance of the sooty mangabeys.
A controversial question among sooty mangabey researchers is the extent to which SIV-specific CD4 and CD8 T cell responses contribute to the prevention of SIV-induced immunodeficiency. SIV-specific T cell responses can be detected in mangabeys but are typically much lower than those seen in disease-susceptible rhesus macaques. This has led one research group, led by Mark Feinberg, to propose that sooty mangabeys do not mount a vigorous immune response against SIV and this lack of an immune response may be protective. In their new paper, Feinberg and colleagues attempt to support this hypothesis by depleting SIV-infected mangabeys of CD8 T cells and measuring the impact on viral loads. While the SIV viral loads clearly increased in CD8-depleted animals, the authors suggest that these increases were relatively minor and argue that SIV-specific CD8 T cell responses do not play a role in controlling SIV replication in sooty mangabeys. A similar study by Amitinder Kaur’s group, which has yet to be published, drew different conclusions. Kaur found that viral load increases in SIV-infected mangabeys depleted of CD8 T cell did appear to be linked with the loss SIV-specific T cells and that viral load declined as SIV-specific T cell responses returned. Kaur’s results suggest that perhaps SIV-specific T cell responses do play a role in maintaining the health of infected sooty mangabeys, even though they only partially suppress viral load. Further studies will likely be needed to definitively resolve this question.
JVI Accepts, published online ahead of print on 30 May 2007
J. Virol. doi:10.1128/JVI.02663-06
Shailesh K. Choudhary, Nienke Vrisekoop, Christine A. Jansen, Sigrid A. Otto, Hanneke Schuitemaker, Frank Miedema, and David Camerini
Long-term asymptomatic 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 load. HIV-1 isolates from these LTA were as pathogenic as viruses from progressors in organ culture. Despite high viral load, these LTA had low levels of proliferating and activated T cells compared to progressors, like other LTA. In contrast to progressors, HIV-specific CD4+ T cell responses in these LTA were maintained. Thus, low immune activation despite high viral load preserves HIV specific T cell responses and resulted in a long-term asymptomatic phenotype.
The Journal of Immunology, 2007, 178: 7720-7729
Pavel Bostik2, Erika S. Noble, Susan T. Stephenson, Francois Villinger and Aftab A. Ansari
IL-2 is an important cytokine required for the physiological function of CD4+ T cells. Immunological unresponsiveness—anergy— of CD4+ T cells is characterized by the inability of these cells to synthesize IL-2. Both progressive HIV infection leading to AIDS in humans and SIV infection in rhesus macaques (RM) are associated with dysregulation of IL-2 synthesis. In certain nonhuman primate species, such as sooty mangabeys (SM), SIV infection does not lead to AIDS. We have shown that this is associated with the resistance of the CD4+ T cells from SM to undergo anergy in vitro. In this study, we show that CD4+ T cells from SM spontaneously synthesize 2- to 3-fold higher levels of IL-2 than corresponding cells from RM. Proximal IL-2 promoter constructs derived from SM show significantly higher activity than the RM-derived constructs in primary CD4+ T cells, which is associated with an element at approximately nt –200. Activity of both constructs was up-regulated by p300 and down-regulated by CREB to a similar degree. Chromatin immunoprecipitation analysis showed significantly higher binding of p300 and lower binding of CREB to the SM promoter in vivo. Two single nucleotide substitutions present in the SM sequence around position –200 and –180 seem to increase the affinity of these sites for the binding of transcription factors, one of which was identified as Oct-1. These unique characteristics of the proximal IL-2 promoter in SM therefore can represent one of the mechanisms contributing to the resistance of these cells to undergo anergy.
The Journal of Immunology, 2007, 178: 8002-8012.
Ashley P. Barry, Guido Silvestri, Jeffrey T. Safrit, Beth Sumpter, Natalia Kozyr, Harold M. McClure, Silvija I. Staprans, and Mark B. Feinberg
SIV infection of sooty mangabeys (SMs), a natural host species, does not cause AIDS despite high-level virus replication. In contrast, SIV infection of nonnatural hosts such as rhesus macaques (RMs) induces an AIDS-like disease. The depletion of CD8+ T cells during SIV infection of RMs results in marked increases in plasma viremia, suggesting a key role for CD8+ T cells in controlling levels of SIV replication. To assess the role that CD8+ T cells play in determining the virologic and immunologic features of nonpathogenic SIV infection in SMs, we transiently depleted CD8+ T cells in SIV-infected and uninfected SMs using a CD8{alpha}-specific Ab (OKT8F) previously used in studies of SIV-infected RMs. Treatment of SMs with the OKT8F Ab resulted in the prompt and profound depletion of CD8+ T cells. However, in contrast to CD8+ cell depleted, SIV-infected RMs, only minor changes in the levels of plasma viremia were observed in most SIV-infected SMs during the period of CD8+ cell deficiency. Those SMs demonstrating greater increases in SIV replication following CD8+ cell depletion also displayed higher levels of CD4+ T cell activation and/or evidence of CMV reactivation, suggesting that an expanded target cell pool rather than the absence of CD8+ T cell control may have been primarily responsible for transient increases in viremia. These data indicate that CD8+ T cells exert a limited influence in determining the levels of SIV replication in SMs and provide additional evidence demonstrating that the absence of AIDS in SIV-infected SMs is not due to the effective control of viral replication by cellular immune responses.
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