A Dichotomy in Cortical Actin and Chemotactic Actin Activity between Human Memory and Naive T Cells Contributes to Their Differential Susceptibility to HIV-1 Infection

Abstract

Human memory and naive CD4 T cells can mainly be identified by the reciprocal expression of the CD45RO or CD45RA isoforms. In HIV-1 infection, blood CD45RO memory CD4 T cells are preferentially infected and serve as a major viral reservoir. The molecular mechanism dictating this differential susceptibility to HIV-1 remains largely obscure. Here, we report that the different susceptibility of memory and naive T cells to HIV is not determined by restriction factors such as Apobec3G or BST2. However, we observed a phenotypic distinction between human CD45RO and CD45RA resting CD4 T cells in their cortical actin density and actin dynamics. CD45RO CD4 T cells possess a higher cortical actin density and can be distinguished as CD45RO+Actinhigh. In contrast, CD45RA T cells are phenotypically CD45RA+Actinlow. In addition, the cortical actin in CD45RO memory CD4 T cells is more dynamic and can respond to low dosages of chemotactic induction by SDF-1, whereas that of naive cells cannot, despite a similar level of the chemokine receptor CXCR4 present on both cells. We further demonstrate that this difference in the cortical actin contributes to their differential susceptibility to HIV-1; resting memory but not naive T cells are highly responsive to HIV-mediated actin dynamics that promote higher levels of viral entry and early DNA synthesis in resting memory CD4 T cells. Furthermore, transient induction of actin dynamics in resting naive T cells rescues HIV latent infection following CD3/CD28 stimulation. These results suggest a key role of chemotactic actin activity in facilitating HIV-1 latent infection of these T cell subsets.

Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4+T CellsIn Vitro

“…While our data show a critical role for F-actin density in the ability of HIV-1 to infect resting CD4 ϩ T cells (Fig. 4) and suggest that T N cells may be less susceptible to HIV-1 infection than T CM cells due to a lower F-actin density, as reported previously (46,47), our comprehensive imaging and flow cytometry data do not support a role for CCL19 in increasing F-actin density in either cell type (Fig. 5).…”

“…The actin cytoskeleton is known to be a key regulator in many early events of HIV-1 infection, including viral entry, reverse transcription, intracellular trafficking, and integration (45)(46)(47)(48). In resting CD4 ϩ T cells, cortical actin is static and is restrictive to HIV-1 infection due to actin and its regulators being in an inactive state.…”

Quantitation of Replication-Competent HIV-1 in Populations of Resting CD4 + T Cells

“…We also detected replication-competent HIV in naive CD4 ϩ T cells from four patients with poor initial immune control of viremia during AHI, suggesting that innate immune responses in early infection may play a critical role in limiting the establishment of latent infection (26)(27)(28). Also, these results imply that other mechanisms such as rapid innate immune responses, more potent HIV-specific CD8 responses, or expression of specific protective alleles, such as HLA-B27/B57 (29), may, at least partially, determine the size of the reservoir of replication-competent HIV.…”

HIV-1 Triggers WAVE2 Phosphorylation in Primary CD4 T Cells and Macrophages, Mediating Arp2/3-dependent Nuclear Migration

“…Signaling from both G␣ i and G␣ q has been known to be involved in HIV infection (7,8,27,28). Given that HIV triggers higher levels of actin activity to promote latent infection of resting memory CD4 T cells (9) (Fig. 1, C and D), we treated resting memory CD4 T cells with HIV-1.…”