CD4 Receptors and the Immune Response to HIV

Researchers recently found that Human Immunodeficiency Virus-1 (HIV) virions move similarly to influenza within cells, and that CD4-HIV interactions may mediate type I interferon (IFN) production. The study, conducted by Meagan O’Brien of the Division of Infectious Diseases in the Department of Medicine at the Icahn School of Medicine at Mount Sinai in New York, and colleagues, and was published in PLOS Pathogens on April 15, 2016.

IFN contributes to viral replication in HIV and also plays a part in disease progression by “activating target cells for infections, decreasing antiviral gene expression, enabling infection with increased reservoir size, and accelerating CD4 T-cell loss,” according to the researchers. Additionally, plasmacytoid dendritic cells (pDC) may play a role in IFN responses.

The researchers add “pDC can act as antigen-presenting cells (APC) to activate T-cell-mediated adaptive immune responses,” but for that to happen, specific signals, which are different from those that bring about large amounts of IFN, must be sent. Previous studies suggest that “the functional response of pDC to pathogens is flexible,” say the researchers. They hypothesized, “that HIV envelope protein interactions with cell surface CD4 determine the intracellular trafficking of HIV and the resultant signaling in pDC, based on the spatiotemporal model of TLR signaling.”

In order to test their hypothesis, the researchers replaced the HIV envelope protein with “envelope protein from a virus that activates pDC to differentiate into mature pDC, namely influenza virus,” they report. “We pseudotyped HIV virions with influenza hemagglutinin glycoprotein envelope (HA-HIV),” they said.

The researchers then investigated to see whether HA-HIV traffics in the same way that influenza does in pDC. They report finding, “HA-HIV, similarly to influenza and unlike HIV itself, rapidly trafficked to lysosomes by 30 minutes as evidenced by co-localization with Lysotracker, a dye that traffics to these organelles.” After 18 hours HIV had trafficked to early endosomal compartments, as the researchers had expected. They say, “Thus, the nature of the viral envelope seems crucial to determining trafficking of virions in pDC, and for the downstream signaling pathways activated in different intracellular compartments.”

“Using purified human pDCs and viruses, we demonstrate that HIV trafficking in pDC at early timepoints is determined by the initial envelope-receptor (CD4) interaction and is regulated by receptor target motifs,” conclude the researchers. They add that more studies will be necessary to determine if that is still true in the case of cell-associated virus.