CD4+ T Cells Can Control Viral Load by Directly Killing HIV-infected Cells

CD4+ T cells are central players in the body’s immune response. Often called “helper” cells, they orchestrate the assault on invading pathogens: They stimulate the development of antibodies in B cells, and send signals to CD8+ T cells, which detect and kill other infected cells, to make them better killers and to form memory cells. But CD4+ T cells are also the primary targets of HIV, which is why they are not believed to play a leading role in controlling infection by that virus. Instead, CD8+ T cells are thought to be the primary agents of HIV suppression, deploying so-called “death” molecules such as perforin, which pops open infected cells, and granzyme B, which forces them to commit suicide. 

But helper T cells have recently also been found to play a somewhat more violent part in controlling infections by other viruses, such as influenza. Far from being solely coordinators and assistants, helper T cells participate directly in the killing of infected cells in such cases. 

This made Ragon Institute researcher Hendrik Streeck and his colleagues curious about whether some CD4+ T cells might be similarly disposed in HIV-infected people. In a paper recently published in Science Translational Medicine, they report that the answer, at least in some cases, appears to be yes (Sci. Transl. Med. 4, 123ra25, 2012). 

Streeck and his colleagues looked at blood samples from 11 volunteers, starting at the time when they had just been infected with HIV. All of them had roughly the same viral load until about two months after they contracted the infection. But four months after that, six of the patients suppressed their set point viral load at a level 10-times lower than that of the other five. 

Two months after infection—before one group developed a lower set point viral load—the CD8+ T-cell responses were virtually identical in the two groups, but the researchers already found distinct differences in the HIV-specific CD4+ T-cell responses of the people who would later control their infections more effectively. These people had a much larger fraction of HIV-specific CD4+ T cells that carried granules containing granzyme A, a death molecule related to granzyme B, which CD8+ T cells use to kill infected cells. What’s more, high granzyme A levels in HIV-specific CD4+ T cells correlated with about a one year delay in the onset of disease progression. 

This suggested that, like CD8+ T cells, CD4+ T cells can kill HIV-infected cells. And in subsequent experiments, the researchers found that indeed, HIV-specific CD4+ T cells taken from the people who better controlled the virus recognized and killed HIV-infected macrophages in vitro.  

Streeck says these results are consistent with unpublished results that were presented at the 18th Conference on Retroviruses and Opportunistic Infections last year. Those findings suggest that in the RV144 HIV vaccine trial—the only one so far that has provided evidence of efficacy—the modest protection observed in vaccinated volunteers was in part associated with HIV-specific CD4+ T cells that expressed certain molecular markers that indicate that they were able to kill infected cells. Together with his recent study, Streeck says, this suggests that the induction of a CD4+ T cell response by a vaccine might translate into viral load control and also into protection from infection.  

Nichole Klatt, a research fellow in Jason Brenchley’s laboratory at the National Institute of Allergy and Infectious Diseases, who co-wrote a commentary on the study in the same issue of Science Translational Medicine, calls the findings “very important” in the context that measuring HIV-specific cytolytic CD4+ T cells during acute infection could be valuable to determine disease progression, adding that such cells may also be a valuable target for vaccination strategies. She notes, however, that because CD4+ T cells are also HIV’s primary target, any vaccine that induces their proliferation could also serve up more host cells for the virus. “Further studies should be performed in the SIV model,” says Klatt, to assess the safety of expanding HIV-specific CD4+ T cells to ensure that there are no “increased infection rates due to increased targets.”