The integrin α ₄ β ₇ forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1

Abstract

Both activated and resting CD4 ؉ T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. HIV-1 gp120 binds to integrin ␣4␤7 (␣4␤7), the gut mucosal homing receptor. We find that ␣4␤7 high CD4 ؉ T cells are more susceptible to productive infection than are ␣4␤7 low-neg CD4 ؉ T cells in part because this cellular subset is enriched with metabolically active CD4 ؉ T cells. ␣4␤7 high CD4 ؉ T cells are CCR5 high and CXCR4 low ; on these cells, ␣4␤7 appears in a complex with CD4. The specific affinity of gp120 for ␣4␤7 provides a mechanism for HIV-1 to target activated cells that are critical for efficient virus propagation and dissemination following sexual transmission.integrin receptor ͉ transmission ͉ gut-associated lymphoid tissues (GALT)

Preferential loss of gut-homing α4β7 CD4+ T cells and their circulating functional subsets in acute HIV-1 infection

“…However, mean absolute numbers of CD8 1 T cells were similar between these two groups. The mean HIV-1 viral load of 10 AHIs was 70 623 copies mL 21 . Two of these 10 AHIs were hepatitis B virus (HBV) positive.…”

“…Peripheral blood mononuclear cells (PBMCs) (1 3 10 6 cells mL 21 ) were stimulated with PMA (50 ng mL 21 ) and ionomycin (1 mg mL 21 ) in the presence of brefeldin A (10 mg mL 21 ) for 5 h at 37uC in 5% CO 2 . Surfaces were stained with the appropriate conjugated antibodies, and intracellular staining was performed using anti-IL-17A-PE and IFN-c-PE (BD Biosciences) and the BD cytofix/cytoperm fixation/permeabilization solution kit according to the manufacturer's protocols (BD Biosciences).…”

“…18,19 The binding of integrin a4b7 and HIV-1 gp120 facilitates selective infection and replication in a4b7 CD4 1 T cells, which results in HIV-1 cell-to-cell spreading. 20,21 A loss of peripheral blood a4b7 CD4 1 T cells occurs in HIV/SIV infection. 22,23 Therefore, deficient recruitment of gut-homing a4b7 CD4 1 T cells from peripheral blood to gut mucosa may underlie the incomplete restoration of gut CD4 1 T cells in HIV-1 patients.…”

The Thai Phase III HIV Type 1 Vaccine Trial (RV144) Regimen Induces Antibodies That Target Conserved Regions Within the V2 Loop of gp120

“…Epitopes found in the second variable (V2) loop have been associated with HIV-1 Env functions that are important in infectivity, CD4 receptor and CCR5/CXCR4 coreceptor usage, escape from antibody neutralization, the formation of Env trimers, and the protection of the coreceptor binding site. [22][23][24][25][26][27][28] Sequence variation within the V1/V2 loops alters neutralization resistance and viral escape is associated with V2 loop mutations. [29][30][31][32][33] Compared to viruses circulating in chronically infected persons, transmitted viruses (subtypes A and C) appear to have shorter V1/V2 regions and fewer N-linked glycosylation sites.…”

Designing a Soluble Near Full-length HIV-1 gp41 Trimer

“…HIV-1 entry involves a series of initial interactions between the virus and host cell receptors. The virus is first captured through relatively weak interactions between gp120 and surface molecules, such as ␣ 4 ␤ 7 integrin and DC-SIGN (11)(12)(13), which then leads to high affinity interactions with CD4, the primary receptor on CD4 ϩ T cell (14). A conformational change in gp120 exposes the binding site for the chemokine co-receptor, CCR5 or CXCR4 (15).…”