Severe Depletion of Mucosal CD4+ T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys

Abstract

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.

Activated CD4 + CCR5 + T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

“…PBMCs were isolated by gradient centrifugation. Procedures for lymph node biopsy, RBs, and isolation of lymphocytes from the obtained samples were performed as previously described (24,35).…”

Do most lymphocytes in humans really reside in the gut?

“…The importance of massive depletion of LP CD4 + T lymphocytes for disease progression has been questioned in several recent studies. SIV infection of sooty mangabeys (SMs) and african green monkeys (AGMs), which are natural hosts of SIVsm and SIVagm, respectively, also leads to a dramatic depletion of LP CD4 + T lymphocytes [32,33]. However, infected animals remain typically healthy throughout life, despite a chronically high viral load [32,33].…”

“…LPS accumulation in blood might result from a translocation (leakage) of bacterial products from the gut [38]. Of note, no increase in LPS levels in the blood occurs in SMs and AGMs infected with their natural viruses, SIVsm and SIVagm, respectively [32,33]. The detrimental effects of SIV infection in macaques and HIV infection in humans might, therefore, not be directly due to depletion of CD4 + T cells from the gut LP, but indirectly owing to translocation of microbial products from the gut to the blood, leading to chronic immune activation [38] (see Box 3).…”

“…SIV infection of sooty mangabeys (SMs) and african green monkeys (AGMs), which are natural hosts of SIVsm and SIVagm, respectively, also leads to a dramatic depletion of LP CD4 + T lymphocytes [32,33]. However, infected animals remain typically healthy throughout life, despite a chronically high viral load [32,33]. Furthermore, infection of rhesus macaques (RMs) with SIVagm leads to a dramatic depletion of LP CD4 + T lymphocytes as well, but these animals survive the infection and clear the virus [33].…”

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…Interestingly, studies of nonpathogenic SIV infection in the natural hosts of SIV, e.g., sooty mangabeys (SM) and African green monkeys (AGM), have also shown severe CD4 ϩ T-cell depletion in mucosal tissues during acute infection (78,79). However, this depletion is not accompanied by sustained microbial translocation and chronic mucosal immune activation, and in fact, in contrast to pathogenic SIV and HIV infections, the early mucosal CD4 ϩ T-cell loss does not seem to progress further in SM and is even followed by a partial recovery in AGM (80).…”