Severe CD4⁺T-Cell Depletion in Gut Lymphoid Tissue during Primary Human Immunodeficiency Virus Type 1 Infection and Substantial Delay in Restoration following Highly Active Antiretroviral Therapy

Abstract

Gut-associated lymphoid tissue (GALT) harbors the majority of T lymphocytes in the body

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…However, Li et al, using in situ hybridization to detect SIV RNA, concluded that only ϳ7% of mucosal CD4 ϩ cells were productively infected by SIV during acute infection, thus supporting the hypothesis that apoptosis-mediated death is a pivotal mechanism sustaining mucosal T-lymphocyte depletion (77). Similar data have also been obtained by serial gastrointestinal tract sampling in HIV-infected individuals during early stages of infection, although the depletion of intestinal CD4 ϩ CCR5 ϩ T cells appeared to be somewhat less dramatic than in the SIVmac infection model (34,35,71). Following the acute phase of infection, CD4 ϩ T-cell depletion in the intestinal mucosa has been shown to continue throughout chronic disease to a much greater extent than in the peripheral blood and lymph nodes.…”

“…Such severe CD4 ϩ T-cell impairment has been shown to preferentially involve gut-residing memory-activated CD4 ϩ CCR5 ϩ T cells, reflecting the well-known prevalence of CCR5-tropic viruses in the early phases of infection. Almost concomitantly, Veazey et al and Kewenig et al showed that more than 70% of intestinal CD4 ϩ cells were depleted as early as 21 days post-SIVmac239 infection (72,73), and several subsequent studies then confirmed these findings and shed further light onto the mechanistic pathways underlying CD4 ϩ T-cell depletion (34,(74)(75)(76). Among those studies, Mattapallil et al were able to demonstrate the presence of SIV DNA in up to 60% of intestinal CD4 ϩ T cells as early as 10 days after experimental SIVmac251 infection, therefore emphasizing the role of direct virus-mediated killing of CD4 ϩ T cells as a mechanism causing the observed depletion (70).…”

“…Several months later, those authors reported significantly increased levels of circulating LPS in both chronically HIV-infected individuals and SIV-infected rhesus macaques (RM) that positively correlated with measures of innate and adaptive immune activation (33). After that initial report, numerous studies have confirmed that HIV infection is associated with a substantial loss of CD4 ϩ T cells residing in the gut, in turn leading to microbial translocation (34,35).…”

“…Collectively, these alterations may result in the increased passage of gut microflora and microbial products into the systemic circulation. Interestingly, several aspects of HIVassociated mucosal immune dysfunction were described prior to the original formulation of the microbial translocation hypothesis, including the presence of a rapid and severe loss of CD4 ϩ T cells in the gastrointestinal tract of SIV-infected macaques and HIV-infected humans (34,35,(70)(71)(72).…”

Understanding the Failure of CD8+T-Cell Vaccination against Simian/Human Immunodeficiency Virus

“…During the early expansion phase, massive numbers of CCR5 ϩ CD4 ϩ memory T cells in the gut mucosa become infected and disappear (38,55,62,93), and such a severe depletion of target cells is expected to slow down viral replication (75). Despite equal initial replication rates, the peak viral loads that are obtained in vaccinated monkeys can be 10-fold lower than those in naive monkeys (12,21,22,32,86).…”