|
|
|
|
Gladstone Study Yields New Insight Into HIV
|
|
Dendritic cells (DCs) can transmit HIV-1 to T cells via two distinct pathways. In the classical pathway, DCs are actively infected with HIV-1, leading to the budding and spread of new virions to neighboring CD4 T cells. In the trans pathway, intact HIV-1 virions are captured and transferred to neighboring CD4 T cells. The capture step involves alternative HIV-1 receptors, the C-type lectins, which bind virions through the envelope protein, but without triggering fusion. Although these receptors can mediate the rapid internalization of the virions in vesicles, only virions that remain outside of the DCs are transmitted. LTR, long-terminal repeat.
|
|
|
Achilles Heel
of the Trojan
Horse Model of
HIV Infection
|
For some time, the transmission of HIV-1 from dendritic cells (DCs) to T cells was assumed to involve viral particles within vesicles. Virions were thought to be captured and internalized into vesicles in DC and then released to infect T cells. This mechanism is known as the “Trojan Horse” model of HIV infection.
However, a new study indicates that the transferred virions originate primarily from the surface of the DCs rather than from internalized vesicles. In other words, the Greeks are not hiding inside the Trojan Horse but rather sitting in the saddle.
“Early studies had proposed that HIV virions had to be internalized to mediate trans-infection and compared DCs to Trojan Horses
|
|
|
loaded with virus,” said Marielle Cavrois, lead author of the study and Gladstone staff research scientist. “But in fact we found that internalization is generally a dead-end path for HIV virions. Only surface-bound virions are efficiently transmitted from DCs to T cells.”
DCs are an integral part of the immune defense system, particularly in peripheral mucosal sites, such as the lining of the intestinal tract and the vagina. They capture and degrade pathogens into small protein fragments called peptides. These antigenic peptides are then presented at the DC surface to initiate an immune response in T cells.
During sexual transmission, DCs are probably among the first cells that HIV encounters at mucosal sites. These cells express the HIV receptor CD4 and the coreceptor CCR5, which enable the virus to enter and infect the cells directly. After new virions are produced, they “bud” from the surface of the infected DC and then infect other cells, including CD4 T cells that are deeper in the mucosa or in the draining lymph nodes.
The Gladstone researchers showed that DCs support extremely high levels of fusion of some strains of HIV; other strains, however, did not fuse efficiently. Viruses that don't fuse efficiently can still take advantage of the DCs and be captured and transported to areas rich in T cells (deep in the mucosa or in lymph nodes). HIV-1 is captured by DCs through an interaction with special receptors that don't trigger fusion. The captured virions are then presented in trans to infect T cells that naturally interact with the DCs.
|
|
The team selectively neutralized surface-bound virions with antibodies or with fragments of the protein CD4, which prevents HIV from binding to cell-surface CD4 receptors, and followed the reaction with a fluorescence assay and cell sorting. Selective neutralization of surface-bound HIV virions virtually eliminated trans-infection. Treatment of the cell surface with pronase also eliminated trans-infection. In a separate assay with fluorescently labeled HIV, internalized virus was not transmitted.
“We are intrigued by these findings,” said Warner C. Greene, director of GIVI and senior author of the study. “They suggest that the prevailing model for HIV trans-infection requires modification. Perhaps more importantly, they indicate that attachment inhibitors could prevent trans-infection of T cells by DCs in vivo and may represent a new approach for an anti-HIV therapy.”
|
|
Study authors Marielle Cavrois, Jason Neidleman, & Warner Greene.
|
|
Cavrois M, Neidleman J, Kreisberg JF, Fenard D, Callebaut C, Greene WC (2006) HIV fusion to dendritic cells declines as cells mature. J. Virol. 80:1992–1999.
Cavrois M, Neidleman J, Kreisberg JF, Greene WC (2007) In vitro derived dendritic cells trans-infect CD4 T cells primarily with surface-bound HIV-1 virions. PLoS Pathogens 3:e4.
TOP
|
|
|
