Back in March 2006, this blog covered some of the diverging views of researchers regarding the importance of depletion of CD4 T cells from the gut in HIV and SIV infections. Two reviews had been published, one by Jason Brenchley and Daniel Douek arguing that HIV pathogenesis may be a consequence of the early depletion of memory CD4 T cells from the gut (or "fallout from a mucosal catastrophe") and another by Zvi Grossman, Martin Meier-Schellersheim, William Paul and Louis Picker suggesting that this phenomenon may be less important than the persistent immune activation that follows.
Three new papers in the September 1 issue of J. Immunology may shed significant light on this debate. One research team, led by Shari Gordon, reports that sooty mangabeys - a monkey species that naturally hosts SIV and rarely develops immune deficiency as a result - also show an early and significant loss of CD4 T cells from the lamina propria of the gut. The researchers conclude that gut CD4 T cell depletion alone is insufficient to cause systemic immune activation and progression to AIDS.
Similarly, Ivona Pandrea and colleagues show that African green monkeys (AGMs) - another natural SIV host that is resistant to immune deficiency - display a profound loss of CD4 T cells from the gut, again with no obvious consequences. The same held true for rhesus macaques infected with a non-pathogenic SIV isolate derived from AGMs. Pandrea et al also conclude that immune activation - not gut CD4 T cell depletion - appears to be the key factor distinguishing pathogenic from non-pathogenic SIV infections.
Jason Brenchley and Daniel Douek also contribute to these papers, showing that these animals do not show any evidence of sustained translocation of bacteria across the mucosa (although two animals show transient indications of microbial translocation during acute infection). The authors suggest that these results show that early loss of CD4 T cells may only briefly compromise the integrity of the mucosal barrier or, alternatively, that both of these phenomena result from the early peak of SIV replication in the gut which - for reasons as yet unknown - only transiently impacts mucosal integrity.
A third paper led by Mike Milush reports that even peripheral blood CD4 T cell counts may be less important than immune activation when it comes to AIDS pathogenesis. Milush describes two sooty mangabeys with long term asymptomatic SIV infection who display low peripheral blood CD4 T cell numbers without any signs of immune activation such as lymph node disruption and fibrosis.
The Journal of Immunology, 2007, 179: 3026-3034.
Shari N. Gordon, Nichole R. Klatt, Steven E. Bosinger, Jason M. Brenchley, Jeffrey M. Milush, Jessica C. Engram, Richard M. Dunham, Mirko Paiardini, Sara Klucking, Ali Danesh, Elizabeth A. Strobert, Cristian Apetrei, Ivona V. Pandrea, David Kelvin, Daniel C. Douek, Silvija I. Staprans, Donald L. Sodora and Guido Silvestri
HIV-infected humans and SIV-infected rhesus macaques experience a rapid and dramatic loss of mucosal CD4+ T cells that is considered to be a key determinant of AIDS pathogenesis. In this study, we show that nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species for SIV, is also associated with an early, severe, and persistent depletion of memory CD4+ T cells from the intestinal and respiratory mucosa. Importantly, the kinetics of the loss of mucosal CD4+ T cells in SMs is similar to that of SIVmac239-infected rhesus macaques. Although the nonpathogenic SIV infection of SMs induces the same pattern of mucosal target cell depletion observed during pathogenic HIV/SIV infections, the depletion in SMs occurs in the context of limited local and systemic immune activation and can be reverted if virus replication is suppressed by antiretroviral treatment. These results indicate that a profound depletion of mucosal CD4+ T cells is not sufficient per se to induce loss of mucosal immunity and disease progression during a primate lentiviral infection. We propose that, in the disease-resistant SIV-infected SMs, evolutionary adaptation to both preserve immune function with fewer mucosal CD4+ T cells and attenuate the immune activation that follows acute viral infection protect these animals from progressing to AIDS.
The Journal of Immunology, 2007, 179: 3035-3046.
Ivona V. Pandrea Rajeev Gautam*, Ruy M. Ribeiro, Jason M. Brenchley||, Isolde F. Butler, Melissa Pattison, Terri Rasmussen, Preston A. Marx, Guido Silvestri, Andrew A. Lackner, Alan S. Perelson, Daniel C. Douek, Ronald S. Veazey, and Cristian Apetrei
The predictive value of acute gut-associated lymphoid tissue (GALT) CD4+ T cell depletion in lentiviral infections was assessed by comparing three animal models illustrative of the outcomes of SIV infection: pathogenic infection (SIVsmm infection of rhesus macaques (Rh)), persistent nonprogressive infection (SIVagm infection of African green monkeys (AGM)), and transient, controlled infection (SIVagm infection of Rh). Massive acute depletion of GALT CD4+ T cells was a common feature of acute SIV infection in all three models. The outcome of this mucosal CD4+ T cell depletion, however, differed substantially between the three models: in SIVsmm-infected Rh, the acute GALT CD4+ T cell depletion was persistent and continued with disease progression; in SIVagm, intestinal CD4+ T cells were partially restored during chronic infection in the context of normal levels of apoptosis and immune activation and absence of damage to the mucosal immunologic barrier; in SIVagm-infected Rh, complete control of viral replication resulted in restoration of the mucosal barrier and immune restoration. Therefore, our data support a revised paradigm wherein severe GALT CD4+ T cell depletion during acute pathogenic HIV and SIV infections of humans and Rh is necessary but neither sufficient nor predictive of disease progression, with levels of immune activation, proliferation and apoptosis being key factors involved in determining progression to AIDS.
The Journal of Immunology, 2007, 179: 3047-3056.
Jeffrey M. Milush, Jacqueline D. Reeves, Shari N. Gordon, Dejiang Zhou, Alagar Muthukumar, David A. Kosub, Elizabeth Chacko, Luis D. Giavedoni, Chris C. Ibegbu, Kelly S. Cole, John L. Miamidian Mirko Paiardini, Ashley P. Barry, Silvija I. Staprans, Guido Silvestri and Donald L. Sodora
Peripheral blood CD4+ T cell counts are a key measure for assessing disease progression and need for antiretroviral therapy in HIV-infected patients. More recently, studies have demonstrated a dramatic depletion of mucosal CD4+ T cells during acute infection that is maintained during chronic pathogenic HIV as well as SIV infection. A different clinical disease course is observed during the infection of natural hosts of SIV infection, such as sooty mangabeys (Cercocebus atys), which typically do not progress to AIDS. Previous studies have determined that SIV+ mangabeys generally maintain healthy levels of CD4+ T cells despite having viral replication comparable to HIV-infected patients. In this study, we identify the emergence of a multitropic (R5/X4/R8-using) SIV infection after 43 or 71 wk postinfection in two mangabeys that is associated with an extreme, persistent (>5.5 years), and generalized loss of CD4+ T cells (5–80 cells/µl of blood) in the absence of clinical signs of AIDS. This study demonstrates that generalized CD4+ T cell depletion from the blood and mucosal tissues is not sufficient to induce AIDS in this natural host species. Rather, AIDS pathogenesis appears to be the cumulative result of multiple aberrant immunologic parameters that include CD4+ T cell depletion, generalized immune activation, and depletion/dysfunction of non-CD4+ T cells. Therefore, these data provide a rationale for investigating multifaceted therapeutic strategies to prevent progression to AIDS, even following dramatic CD4 depletion, such that HIV+ humans can survive normal life spans analogous to what occurs naturally in SIV+ mangabeys.