Acute Loss of Intestinal CD4+ T Cells Is Not Predictive of Simian Immunodeficiency Virus Virulence

Abstract

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.

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].…”

“…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]. Finally, it has been argued that because CCR5-expressing effector memory CD4 + T cells are produced by differentiation of central memory CD4 + T cells and have limited regenerative capacity [34,35], loss of these cells in HIV infection might be relatively unimportant in disease progression [35].…”

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).…”