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Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection.

ABSTRACT: Human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infections are believed to infect minimally activated CD4(+) T cells after viral entry. Not much is known about why SIV selectively targets these cells. Here we show that CD4(+) T cells that express high levels of the alpha4beta7 heterodimer are preferentially infected very early during the course of SIV infection. At days 2-4 post infection, alpha4(+)beta7(hi)CD4(+) T cells had approximately 5x more SIV-gag DNA than beta7(-)CD4(+) T cells. alpha4(+)beta7(hi)CD4(+) T cells displayed a predominantly central memory (CD45RA(-)CD28(+)CCR7(+)) and a resting (CD25(-)CD69(-)HLA-DR(-)Ki-67(-)) phenotype. Although the expression of detectable CCR5 was variable on alpha4(+)beta7(hi) and beta7(-)CD4(+) T cells, both CCR5(+) and CCR5(-) subsets of alpha4(+)beta7(hi) and beta7(-)CD4(+) T cells were found to express sufficient levels of CCR5 mRNA, suggesting that both these subsets could be efficiently infected by SIV. In line with this, we found similar levels of SIV infection in beta7(-)CD4(+)CCR5(+) and beta7(-)CD4(+)CCR5(-) T cells. alpha4beta7(hi)CD4(+) T cells were found to harbor most T helper (Th)-17 cells that were significantly depleted during acute SIV infection. Taken together, our results show that resting memory alpha4(+)beta7(hi)CD4(+) T cells in the blood are preferentially infected and depleted during acute SIV infection, and the loss of these cells alters the balance between Th-17 and Th-1 responses, thereby contributing to disease pathogenesis.

SUBMITTER: Kader M

PROVIDER: S-EPMC2763371 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection.

Kader M M Wang X X Piatak M M Lifson J J Roederer M M Veazey R R Mattapallil J J JJ

Mucosal immunology 20090701 5

Human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infections are believed to infect minimally activated CD4(+) T cells after viral entry. Not much is known about why SIV selectively targets these cells. Here we show that CD4(+) T cells that express high levels of the alpha4beta7 heterodimer are preferentially infected very early during the course of SIV infection. At days 2-4 post infection, alpha4(+)beta7(hi)CD4(+) T cells had approximately 5x more SIV-gag DNA than beta7(-)CD ...[more]

PMID: 19571800

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Project description:BackgroundChemokine receptors (CKRs), the primordial receptors for primate lentiviruses, are sufficient to mediate virus-cell fusion. Several different fusogenic CKRs and related receptors provide a broad potential host cell range, presumably advantageous for viral spread within a given infected individual, and across species. By contrast, the additional constraint of obligatory CD4 binding, just prior to CKR engagement, radically restricts potential host cells within an individual (or lymph node microenvironment), and might also limit xenotransmission, as CD4 sequences vary among primates. In spite of these potential drawbacks, CD4 dependent entry for SIV and HIV is the rule rather than the exception, and is generally thought to have evolved by selection for 1) stabilization of virus-cell surface interactions, and 2) conformational shielding of readily neutralized CKR binding epitopes. CD4 binding residues of SIV and HIV envelope are recessed, (relatively hidden from immune detection) and may exhibit a strong degree of automimicry, thus benefitting from self tolerance.Documented evolution, within individual macaques, of neutralization-resistant CD4-dependent SIV, derived from CD4-independent inocula, supports these ideas, but does not explain CD4's exclusive role as the penultimate receptor-even more striking, given the wide diversity of CKRs and other surface molecules that can serve as actual fusion receptors for SIV. We, therefore, explored the additional, non-exclusive, hypothesis that surface CD4 on leukocytes is a marker of a more favorable host cell environment, as compared to CD8, NK, or B cell surface markers.ResultsWe demonstrate progressive in vitro evolution of two SIV strains to CD4-dependence (and CXCR4 tropism) in normal human PBMCs (hPBMCs). The two CD4-independent strains of SIV tested developed nearly complete CD4 dependence over several months of serial passage in hPBMCs, correlating with a limited number of non-synonymous env region mutations, some previously reported to be determinants of CD4-dependency. The initial ability of SIV stocks to grow to significant (albeit, relatively low) levels in CD4(-), CD14(-) cells was also lost with long term passage. Rapid emergence and subsequent prominence of G → A and A → G mutations within env regions associated with CD4 dependence was seen.ConclusionsProgressive acquisition of strict CD4 tropism, independent of immunoselection, supports the idea that surface CD4 identifies optimal host cells having intracellular environments most favorable to viral replication. The prominence of mutations involving G to A, or A to G, suggests that APOBEC 3 mediated infidelity may facilitate rapid switching of cell surface receptor usage within SIV swarms encountering fluctuating availability of optimal CD4+CKR+ targets. These observations of non-immune selection are compatible with, and may accelerate, simultaneous selection for previously described CD4-dependent neutralization resistance in vivo.

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Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection.

Publications

Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection.

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