The extent and importance of direct, HIV-mediated killing of CD4 T cells in AIDS pathogenesis has long been a subject of contentious debate. Many early pathogenesis theories were based on the reasonable assumption that there was a direct connection between the virus-induced CD4 T cell death observed in lab dishes and the decline of peripheral blood CD4 T cell counts in people with HIV infection. In one famous formulation, HIV was portrayed as Pac Man, vigorously gobbling up CD4 T cells until they were gone. However, over time – and particularly over recent years – the role of virus-induced immune activation in indirectly depleting CD4 T cells (and draining other important immune system reserves such as naïve CD8 T cells) has come to prominence as new data has been published and presented. Two new papers in J. Virology underscore this shift in the understanding of AIDS pathogenesis by reporting data on the dynamics of SIV-infected CD4 T cells in two different monkey species in which SIV is typically benign: sooty mangabeys and African green monkeys (AGMs).
The researchers (one group led by Shari Gordon, the other by Ivona Pandrea, with considerable overlap between the two) set out to address whether SIV-infected CD4 T cells live longer in these monkey species, potentially explaining the absence of virus-induced disease. In both studies, antiretroviral therapy (emitricitabine and tenofovir) was administered and SIV viral load measured very frequently in order to establish the decay of the infected cell population. The results echo those reported for humans and SIV-infected rhesus macaques: there was a rapid initial phase of viral load decline (albeit with a blip on day 2 in the AGMs) with the vast majority of infected cells (>90%) disappearing in a week. Accordingly, mathematical modeling showed the vast majority of infected cells had a very short half-life of ~1.1 days in sooty mangabeys and ~9.5 hours in AGMs. In most mangabeys, a second phase decay involving cells with a longer half-life (~15 days) was also observed but in AGMs the rapid decline of viral load to undetectable levels (<100 copies) meant that no second phase decay was measurable.
Interestingly, in both monkey species, viral load rebounded after ART and settled at a steady state setpoint in a manner akin to that seen in HIV infection (although the setpoint SIV viral load levels were much higher). The establishment of the post-ART setpoint was associated with a significant increase in CD4 and CD8 T cell proliferation in both studies, which may offer support for Amitinder Kaur’s longstanding contention that SIV-specific immune responses do exert some control over SIV replication in non-pathogenic infections.
In discussing the broader implications of their work, the authors note that it establishes there are no significant differences in the death rates of infected cells in non-pathogenic vs. pathogenic SIV infections, presenting a stern challenge to the notion that the cytopathic effects of the virus play a key role in the development of disease. They also emphasize that their findings buttress the view that it is not viral replication per se that is important in driving pathogenesis, but the way the host copes with the virus.
JVI Accepts, published online ahead of print on 23 January 2008
J. Virol. doi:10.1128/JVI.02408-07
Shari N. Gordon, Richard M. Dunham, Jessica C. Engram, Jacob Estes, Zichun Wang, Nichole R. Klatt, Mirko Paiardini, Ivona V. Pandrea, Cristian Apetrei, Donald L. Sodora, Ha Youn Lee, Ashley T. Haase, Michael D. Miller, Amitinder Kaur, Silvija I. Staprans, Alan S. Perelson, Mark. B. Feinberg, and Guido Silvestri*
Department of Pathology, University of Pennsylvania, Philadelphia, PA; Emory Vaccine Center and Yerkes National Primate Research Center, Atlanta, GA; Department of Microbiology, University of Minnesota, Minneapolis, MN; New England Primate Research Center, Harvard Medical School, Southborough, MA; Tulane National Primate Research Center, Covington, LA; Seattle Biomedical Research Institute, Seattle, WA; Los Alamos National Laboratory, Los Alamos, NM; University of Rochester, Rochester, NY; Gilead Sciences, Inc., Foster City, CA; Merck Vaccine Division, Merck & Co., Inc. West Point, PA
Abstract
Naturally SIV-infected sooty mangabeys (SMs) do not develop AIDS despite high levels of virus replication. At present, the mechanisms underlying this disease-resistance are poorly understood. Here we tested the hypothesis that SIV-infected SMs avoid immunodeficiency as a result of virus replication occurring in infected cells that live significantly longer than HIV-infected human cells. To this end, we treated six SIV-infected SMs with potent antiretroviral therapy (ART) and longitudinally measured the decline in plasma viremia. We applied the same mathematical models used in HIV-infected individuals, and observed that naturally SIV-infected SMs also present a two-phase decay of viremia following ART, with the bulk (92-99%) of virus replication sustained by short-lived cells (average lifespan 1.06 days) and only 1-8% occurring in longer-lived cells. In addition, we observed that ART had a limited impact on CD4+ T cells and the prevailing level of T cell activation and proliferation in SIV-infected SMs. Collectively, these results suggest that in SIV-infected SMs, similar to HIV-1-infected humans, short-lived activated CD4+ T cells, rather than macrophages, are the main source of virus production. These findings indicate that a short in vivo lifespan of infected cells is a common feature of both pathogenic and non-pathogenic primate lentivirus infections, and support a model for AIDS pathogenesis whereby the direct killing of infected cells by HIV is not the main determinant of disease progression.
JVI Accepts, published online ahead of print on 23 January 2008
J. Virol. doi:10.1128/JVI.02402-07
SIVagm Dynamics in African Green Monkeys
Ivona Pandrea*, Ruy M. Ribeiro, Rajeev Gautam, Thaidra Gaufin, Melissa Pattison, Mary Barnes, Christopher Monjure, Crystal Stoulig, Jason Dufour, Wayne Cyprian, Guido Silvestri, Michael D. Miller, Alan S. Perelson, and Cristian Apetrei
Divisions of Comparative Pathology, Microbiology, and Veterinary Medicine Tulane National Primate Research Center, Covington Louisiana 70433, USA; Department of Pathology, School of Medicine, Tulane University, New Orleans, Louisiana 70112, USA; Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA; Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19107, USA; Gilead Sciences, Inc, Foster City, California 94404, USA; Department of Tropical Medicine, School of Public Health, Tulane University, New Orleans, Louisiana 70112, USA
Abstract
The mechanisms underlying the lack of disease progression in natural SIV hosts are still poorly understood. To test the hypothesis that SIV-infected AGMs avoid AIDS due to virus replication occurring in long-lived infected cells, we infected six animals with SIVagm and treated them with potent antiretroviral therapy [ART: (PMPA, tenofovir) and (FTC, emtricitabine)]. All AGMs showed a rapid decay of plasma viremia that became undetectable 36 hours after ART initiation. Significant decrease of viral load was observed in PBMCs and intestine. Mathematical modeling of viremia decay post-ART indicates a half-life of productively infected cells ranging from 4 to 9.5 h, i.e., faster than previously reported for HIV and SIV. ART induced a slight but significant increase in peripheral CD4+ T-cell counts but no significant changes in CD4+ T-cell levels in LNs and intestine. Similarly, ART did not significantly change the levels of cell proliferation, activation and apoptosis, already low in chronically SIVagm-infected AGMs. Collectively, these results indicate that, in SIVagm-infected AGMs, the bulk of virus replication is sustained by short-lived cells; therefore, differences in disease outcome between SIVmac infection of macaques and SIVagm infection of AGMs are unlikely due to intrinsic differences of the in vivo cytopathicity between the two viruses.
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