So AIDS Is Not About Losing Helper Cells …
… as it appears in three related papers, providing new insights into the complexity of HIV/AIDS.
Don Sodora, Ph.D., a principal investigator in SBRI’s Viral Vaccines Program who recently joined SBRI from the University of Texas, Southwestern Medical Center, is senior author on one of three papers that collectively show CD4 T-cell depletion, a critical symptom of AIDS, is likely a part of a multifaceted scenario that triggers disease rather than the only cause.
In an HIV-infected person, CD4 T-cells (white blood cells that play a central role in creating immunity) decline and, at a certain point, the person gets sick and dies. This rapid and dramatic loss of CD4 T-cells is considered to be a key determinant of AIDS disease. However, in natural hosts, like the sooty mangabey (an African monkey species), simian immunodeficiency virus (SIV) induced CD4 T-cell depletion can be comparable to that in humans, but the monkeys do not show clinical signs of AIDS. “Our assessment of these natural hosts like mangabeys offers insight into the disease and shows us that progression to AIDS likely results from the cumulative effects of HIV/SIV replication, CD4 T-cell depletion, generalized immune activation and non-CD4 T-cells depletion or dysfunction,” said Sodora.
Sodora’s paper provides evidence, using the sooty mangabey SIV natural host, that virally induced CD4 T-cell depletion, by itself, is not sufficient to induce AIDS in a natural host. “When we first observed the dramatic CD4 depletion in all the tissues we examined in these monkeys, we were concerned that they might begin to exhibit clinical signs of AIDS,” said Jeffrey Milush, Ph.D., lead author on the paper. “But after more than six years, we are sure that CD4 depletion by itself does not necessarily result in progression to AIDS”.
Sodora contributed to a second paper, with senior author Guido Silvestri, M.D., of the University of Pennsylvania. In a study of disease free SIV–infected sooty mangabeys, Silvestri proposes that these African monkeys preserve immune function despite a major loss of mucosal CD4 T-cells as a result of an evolutionary adaptation to reduce immune activation in response to virus replication.
The third of the three papers published this week in The Journal of Immunology, with Ivona Pandrea, M.D., Ph.D., and Cristian Apetrei, M.D., Ph.D., from Tulane University as lead authors, shows that a severe loss of intestinal CD4 T-cells in another natural host, the African green monkey, is also not predictive of SIV virulence.
“These three papers published together indicate that CD4 T-cell depletion is one part of a more complex scenario that results in the clinical signs identified as AIDS,” Sodora said. “We hope that studies in these natural host models will lead to improved HIV vaccines or new therapeutics that might someday make HIV-infected people more like these disease-resistant sooty mangabeys.”
J Immunol. 2007 Sep 1;179(5):3047-56.
Virally Induced CD4+ T Cell Depletion Is Not Sufficient to Induce AIDS in a Natural Host.
University of Texas Southwestern Medical Center, Dallas, TX 75390.
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/mul 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.
J Immunol. 2007 Sep 1;179(5):3026-34.
Severe Depletion of Mucosal CD4+ T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys.
Gordon SN, Klatt NR, Bosinger SE, Brenchley JM, Milush JM, Engram JC, Dunham RM, Paiardini M, Klucking S, Danesh A, Strobert EA, Apetrei C, Pandrea IV, Kelvin D, Douek DC, Staprans SI, Sodora DL, Silvestri G.
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
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.
J Immunol. 2007 Sep 1;179(5):3035-46.
Acute Loss of Intestinal CD4+ T Cells Is Not Predictive of Simian Immunodeficiency Virus Virulence.
Divisions of Comparative Pathology and Microbiology, Tulane National Primate Research Center, Covington, LA 70433.
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.
J Exp Med. 2007 Sep 3;204(9):2171-85. Epub 2007 Aug 27.
Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection.
Okoye A, Meier-Schellersheim M, Brenchley JM, Hagen SI, Walker JM, Rohankhedkar M, Lum R, Edgar JB, Planer SL, Legasse A, Sylwester AW, Piatak M Jr, Lifson JD, Maino VC, Sodora DL, Douek DC, Axthelm MK, Grossman Z, Picker LJ.
Vaccine and Gene Therapy Institute, Department of Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006.
Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4(+) CCR5(+) effector-memory T (T(EM)) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4(+) memory T cell proliferation appears to prevent collapse of effector site CD4(+) T(EM) cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4(+) T(EM) cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors. The instability of effector site CD4(+) T(EM) cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5(-) CD4(+) T(CM) cells. These data suggest that although CD4(+) T(EM) cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4(+) T(CM) cells.