Understanding the Immune Response to HIV

Published August 4, 2011

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HIV infection may not be the death sentence it once was, but it remains an undeniably serious condition that requires aggressive, life-long treatment and entails the ever-present threat of severe immunological impairment. Consequently, medical researchers continue to investigate the mechanisms by which HIV infection evades detection by the body’s normal immune responses. In the August 3, 2011, issue of Nature (opens in new tab), investigators from the Ragon Institute of MGH, MIT, and Harvard (opens in new tab); Imperial College London (opens in new tab); the National Cancer Institute (opens in new tab); and Microsoft Research (opens in new tab) have shed light on the interactions of HIV and the immune system’s natural killer (NK) cells. Our paper is the first to show that NK cells play a direct role in fighting HIV. This knowledge opens a new path of research into ways to beat the virus.

Scientists have long known that NK cells play an important role in the control of viral infections, mounting short-lived but highly toxic assaults on infected cells. NK cells bind to virus-infected cells, releasing proteins that destroy the target cells. To regulate this cytotoxic potential, the membranes of NK cells are studded with activating receptors, which unleash the cell-killing response, and inhibitory receptors, which keep it in check.

It’s logical to expect that NK cells would play a role in the control of HIV infections, and, in fact, various in-vitro and epidemiological studies suggest that NK cells do just that. For example, research has shown that the population of NK cells increases during the earliest phase of HIV infection and that NK cells can suppress HIV replication in cultured tissues. Moreover, epidemiological evidence indicates that infected individuals who have particular versions of the genes that code for a class of NK cell receptors called KIRs (killer immunoglobulin-like receptors) are better able to control HIV levels. However, it remained unknown whether NK cells directly mediate anti-HIV immune pressure inside the human body.

We wanted to test the hypothesis that mutations in the HIV proteins that are recognized by KIRs could allow the virus to escape NK cell activity. Proving this hypothesis would support a role for NK cells in HIV control. After analyzing the sequences of both HIV proteins and the genes encoding KIR molecules from 91 infected individuals, we found that particular variants in viral proteins were associated with specific KIR genes. This finding suggested that the virus mutates in response to NK cell activity. In particular, we found individuals whose NK cells included an inhibitory receptor called KIR2DL2 were more likely to have variant forms of HIV that enhance viral interaction with that receptor. Those results suggest that the HIV mutates into a form that interacts with the inhibitory receptor, thereby preventing NK cells from attacking HIV-infected cells.

Microsoft Research was intensely involved in this study. The first tell-tale signs that NK cells were affecting HIV were found by using a sophisticated software tool that was developed at Microsoft Research. The tool used almost a CPU-year of computation to sift through millions of possible clues as to how our immune system interacts with this deadly virus.

Our study provides hope that a greater appreciation of the NK-cell-mediated immune responses to HIV can lead to therapies that interrupt the virus’s evasive processes, thereby giving physicians another weapon in their long-running battle with HIV and AIDS.

—David Heckerman (opens in new tab), Distinguished Scientist, Microsoft Research

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