Abstract
Human and chimpanzee CD4+ T cells differ markedly in expression of the inhibitory receptor Siglec-5, which contributes towards differential responses to activating stimuli. While CD4+ T cells from both species are equally susceptible to HIV-1 infection, chimpanzee cells survive better, suggesting a cell-intrinsic difference. We hypothesized that Siglec-5 expression protects T cells from activation-induced and HIV-1-induced cell death. Transduction of human CEM T cells with Siglec-5 decreased cell responses to stimulation. Following HIV-1 infection, a higher percentage of Siglec-5-positive cells survived, suggesting relative resistance to virus-induced cell death. Consistent with this, we observed an increase in percentage of Siglec-5-positive cells surviving in mixed infected cultures. Siglec-5-transduced cells also showed decreased expression of apoptosis-related proteins following infection and reduced susceptibility to Fas-mediated cell death. Similar Siglec-5-dependent differences were seen when comparing infection outcomes in primary CD4+ T cells from humans and chimpanzees. A protective effect of Siglec-5 was further supported by observing greater proportions of circulating CD4+ T cells expressing Siglec-5 in acutely infected HIV-1 patients, compared to controls. Taken together, our results suggest that Siglec-5 expression protects T cells from HIV-1- and apoptosis-induced cell death and contributes to the different outcomes of HIV-1 infection in humans and chimpanzees.
Highlights
Nonhuman primate models have contributed greatly to our understanding of HIV-1 pathogenesis and have been invaluable for testing the efficacy of experimental vaccines and drug regimens [1, 2]
Our results suggest that Siglec-5 expression protects T cells from HIV-1- and apoptosis-induced cell death and contributes to the different outcomes of HIV-1 infection in humans and chimpanzees
CEM cells expressing Siglec-5 survive better in HIV-1infected cultures We have previously shown that human and chimpanzee cells differ in expression levels of Siglec-5 and that higher expression correlates with decreased response to activating stimuli [14]
Summary
Nonhuman primate models have contributed greatly to our understanding of HIV-1 pathogenesis and have been invaluable for testing the efficacy of experimental vaccines and drug regimens [1, 2]. There are, surprising differences in outcomes of HIV-1 infection between humans and captive chimpanzees. The major circulating clade of HIV-1 arose via crossspecies transfer of a chimpanzee SIVcpz and resulted in rapid progression to AIDS in the great majority of untreated infected humans [3]. Endemic SIVcpz infection in wild chimpanzees can cause a less severe AIDS-like syndrome, with CD4+ T cell depletion, lymphatic tissue destruction, and premature death [4]. Several explanations have been put forward, including a lack of CD4+ T cell bystander apoptosis, a relative resistance of chimpanzee monocyte macrophages to infection with primary isolates, low HIV-1-specific cytotoxic T lymphocyte responses, low immune activation, and preservation of CD4+ T helper function (reviewed in [6])
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