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HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV.

Cicala C, Arthos J, Fauci AS - J Transl Med (2011)

Bottom Line: The receptor switch occurs in ~ 40% of the infected individuals and is associated with faster disease progression.On CD4(+)/CCR5(high)/ α4β7(high) T cells, α₄β₇ is closely associated with CD4 and CCR5.Although many details remain unresolved, we hypothesize that gp120-α₄β₇ interactions play an important role in the very early events following sexual transmission of HIV and may have important implication in the design of vaccine strategies for the prevention of acquisition of HIV infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Immunoregulation National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. CCICALA@niaid.nih.gov

ABSTRACT
It is well established that HIV-1 infection typically involves an interaction between the viral envelope protein gp120/41 and the CD4 molecule followed by a second interaction with a chemokine receptor, usually CCR5 or CXCR4. In the early stages of an HIV-1 infection CCR5 using viruses (R5 viruses) predominate. In some viral subtypes there is a propensity to switch to CXCR4 usage (X4 viruses). The receptor switch occurs in ~ 40% of the infected individuals and is associated with faster disease progression. This holds for subtypes B and D, but occurs less frequently in subtypes A and C. There are several hypotheses to explain the preferential transmission of R5 viruses and the mechanisms that lead to switching of co-receptor usage; however, there is no definitive explanation for either. One important consideration regarding transmission is that signaling by R5 gp120 may facilitate transmission of R5 viruses by inducing a permissive environment for HIV replication. In the case of sexual transmission, infection by HIV requires the virus to breach the mucosal barrier to gain access to the immune cell targets that it infects; however, the immediate events that follow HIV exposure at genital mucosal sites are not well understood. Upon transmission, the HIV quasispecies that is replicating in an infected donor contracts through a "genetic bottleneck", and often infection results from a single infectious event. Many details surrounding this initial infection remain unresolved. In mucosal tissues, CD4(+) T cells express high levels of CCR5, and a subset of these CD4(+)/CCR5(high) cells express the integrin α₄β₇, the gut homing receptor. CD4(+)/CCR5(high)/ α4β7(high) T cells are highly susceptible to infection by HIV-1 and are ideal targets for an efficient productive infection at the point of transmission. In this context we have demonstrated that the HIV-1 envelope protein gp120 binds to α₄β₇ on CD4(+) T cells. On CD4(+)/CCR5(high)/ α4β7(high) T cells, α₄β₇ is closely associated with CD4 and CCR5. Furthermore, α₄β₇ is ~3 times the size of CD4 on the cell surface, that makes it a prominent receptor for an efficient virus capture. gp120-α₄β₇ interactions mediate the activation of the adhesion-associated integrin LFA-1. LFA-1 facilitates the formation of virological synapses and cell-to-cell spread of HIV-1. gp120 binding to α₄β₇ is mediated by a tripeptide located in the V1/V2 domain of gp120. Of note, the V1/V2 domain of gp120 has been linked to variations in transmission fitness among viral isolates raising the intriguing possibility that gp120-α₄β₇ interactions may be linked to transmission fitness. Although many details remain unresolved, we hypothesize that gp120-α₄β₇ interactions play an important role in the very early events following sexual transmission of HIV and may have important implication in the design of vaccine strategies for the prevention of acquisition of HIV infection.

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A schematic depicting approximate sizes of α4β7, CD4, and a gp160 trimer.
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Figure 2: A schematic depicting approximate sizes of α4β7, CD4, and a gp160 trimer.

Mentions: α4β7 is upregulated on activated CD4+ T cells localized within mucosal tissues that are highly relevant to HIV-1 pathogenesis: Peyer’s patches, mesenteric lymph nodes, lamina propria, and genital mucosa [15,16,19,27,28]. These cells also express high levels of CCR5, and therefore represent an ideal target population for productive infection. On these cells α4β7 is closely associated with both CD4, the HIV-1 entry receptor [16] (Fig. 1) and CCR5, the predominant fusion coreceptor. Of note, these cells express relatively low levels of CXCR4 [16]. Transmission of R5 viruses is strongly favored over X4 viruses; however, the underlying basis for the selection of R5 viruses is unknown. The marked coexpression of CCR5 and α4β7 along with the close physical association of these two surface markers with CD4, on cells that are highly susceptible to productive infection, may provide at least in part an explanation for the strong bias toward R5 virus transmission across mucosal surfaces. It is important to note that, despite the high level expression of CCR5 on this cellular subset, CCR5 is effectively hidden from HIV-1 before engaging the CD4 receptor. In contrast, α4β7 is a prominent receptor (~3 times the size of CD4) (Fig 2) that gp120 can engage independently of CD4 [14,16]. Unlike CD4, which is expressed uniformly on both resting and activated CD4+ T cells, α4β7 is expressed at high levels primarily on activated cells. In this manner α4β7 provides a structural mechanism for HIV-1 to target activated cells that express high levels of CCR5. Of note, analysis of subtype C gp120s derived from early transmitted isolates indicates that these gp120s require high levels of CCR5 and CD4 [29]. Thus, the structural prominence of α4β7 and its CD4-independent engagement of gp120, combined with its selective expression on metabolically activated [16] CCR5high CD4+ T cells provides a rational basis for the HIV-1 envelope to have evolved a specific affinity for α4β7.


HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV.

Cicala C, Arthos J, Fauci AS - J Transl Med (2011)

A schematic depicting approximate sizes of α4β7, CD4, and a gp160 trimer.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105502&req=5

Figure 2: A schematic depicting approximate sizes of α4β7, CD4, and a gp160 trimer.
Mentions: α4β7 is upregulated on activated CD4+ T cells localized within mucosal tissues that are highly relevant to HIV-1 pathogenesis: Peyer’s patches, mesenteric lymph nodes, lamina propria, and genital mucosa [15,16,19,27,28]. These cells also express high levels of CCR5, and therefore represent an ideal target population for productive infection. On these cells α4β7 is closely associated with both CD4, the HIV-1 entry receptor [16] (Fig. 1) and CCR5, the predominant fusion coreceptor. Of note, these cells express relatively low levels of CXCR4 [16]. Transmission of R5 viruses is strongly favored over X4 viruses; however, the underlying basis for the selection of R5 viruses is unknown. The marked coexpression of CCR5 and α4β7 along with the close physical association of these two surface markers with CD4, on cells that are highly susceptible to productive infection, may provide at least in part an explanation for the strong bias toward R5 virus transmission across mucosal surfaces. It is important to note that, despite the high level expression of CCR5 on this cellular subset, CCR5 is effectively hidden from HIV-1 before engaging the CD4 receptor. In contrast, α4β7 is a prominent receptor (~3 times the size of CD4) (Fig 2) that gp120 can engage independently of CD4 [14,16]. Unlike CD4, which is expressed uniformly on both resting and activated CD4+ T cells, α4β7 is expressed at high levels primarily on activated cells. In this manner α4β7 provides a structural mechanism for HIV-1 to target activated cells that express high levels of CCR5. Of note, analysis of subtype C gp120s derived from early transmitted isolates indicates that these gp120s require high levels of CCR5 and CD4 [29]. Thus, the structural prominence of α4β7 and its CD4-independent engagement of gp120, combined with its selective expression on metabolically activated [16] CCR5high CD4+ T cells provides a rational basis for the HIV-1 envelope to have evolved a specific affinity for α4β7.

Bottom Line: The receptor switch occurs in ~ 40% of the infected individuals and is associated with faster disease progression.On CD4(+)/CCR5(high)/ α4β7(high) T cells, α₄β₇ is closely associated with CD4 and CCR5.Although many details remain unresolved, we hypothesize that gp120-α₄β₇ interactions play an important role in the very early events following sexual transmission of HIV and may have important implication in the design of vaccine strategies for the prevention of acquisition of HIV infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Immunoregulation National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. CCICALA@niaid.nih.gov

ABSTRACT
It is well established that HIV-1 infection typically involves an interaction between the viral envelope protein gp120/41 and the CD4 molecule followed by a second interaction with a chemokine receptor, usually CCR5 or CXCR4. In the early stages of an HIV-1 infection CCR5 using viruses (R5 viruses) predominate. In some viral subtypes there is a propensity to switch to CXCR4 usage (X4 viruses). The receptor switch occurs in ~ 40% of the infected individuals and is associated with faster disease progression. This holds for subtypes B and D, but occurs less frequently in subtypes A and C. There are several hypotheses to explain the preferential transmission of R5 viruses and the mechanisms that lead to switching of co-receptor usage; however, there is no definitive explanation for either. One important consideration regarding transmission is that signaling by R5 gp120 may facilitate transmission of R5 viruses by inducing a permissive environment for HIV replication. In the case of sexual transmission, infection by HIV requires the virus to breach the mucosal barrier to gain access to the immune cell targets that it infects; however, the immediate events that follow HIV exposure at genital mucosal sites are not well understood. Upon transmission, the HIV quasispecies that is replicating in an infected donor contracts through a "genetic bottleneck", and often infection results from a single infectious event. Many details surrounding this initial infection remain unresolved. In mucosal tissues, CD4(+) T cells express high levels of CCR5, and a subset of these CD4(+)/CCR5(high) cells express the integrin α₄β₇, the gut homing receptor. CD4(+)/CCR5(high)/ α4β7(high) T cells are highly susceptible to infection by HIV-1 and are ideal targets for an efficient productive infection at the point of transmission. In this context we have demonstrated that the HIV-1 envelope protein gp120 binds to α₄β₇ on CD4(+) T cells. On CD4(+)/CCR5(high)/ α4β7(high) T cells, α₄β₇ is closely associated with CD4 and CCR5. Furthermore, α₄β₇ is ~3 times the size of CD4 on the cell surface, that makes it a prominent receptor for an efficient virus capture. gp120-α₄β₇ interactions mediate the activation of the adhesion-associated integrin LFA-1. LFA-1 facilitates the formation of virological synapses and cell-to-cell spread of HIV-1. gp120 binding to α₄β₇ is mediated by a tripeptide located in the V1/V2 domain of gp120. Of note, the V1/V2 domain of gp120 has been linked to variations in transmission fitness among viral isolates raising the intriguing possibility that gp120-α₄β₇ interactions may be linked to transmission fitness. Although many details remain unresolved, we hypothesize that gp120-α₄β₇ interactions play an important role in the very early events following sexual transmission of HIV and may have important implication in the design of vaccine strategies for the prevention of acquisition of HIV infection.

Show MeSH
Related in: MedlinePlus