New findings by researchers at the Gladstone Institute of Virology at the University of California at San Francisco (UCSF) have upended how we understand the pathogenesis of the acquired immunodeficiency syndrome (AIDS).

Within weeks of initial infection with the human immunodeficiency virus (HIV), up to 90 percent of the CD4+ T cells residing in the lining of the gut die, and rarely recover fully even after effective HIV therapy. In parallel, blood CD4+ T cell numbers dip precipitously after initial HIV infection and only rebound partially before beginning a steady and inexorable decline. This death of CD4+ T cells over the ensuing years leads to progressive immune deficiency, and thus AIDS.

In AIDS, the loss of CD4+ T cells – and the immunological disarray this creates – renders people with HIV susceptible to opportunistic infections otherwise unknown in those with healthy immunity. Without treatment, a third of AIDS patients develop pneumonia from a ubiquitous fungus called Pneumocystis. The virus cytomegalovirus leads to the development of blind spots and then complete blindness in one eye before savaging the sight of the other eye. Inflamed pockets of brain infection by the cat parasite Toxoplasma gondii cause focal weakness and other neurological defects.

These and other cardinal manifestations of AIDS have been known since 1981 when doctors first reported new and perplexing cases of opportunistic infections among gay men in the coastal United States. What has eluded full explication until recently is how HIV infection causes this progressive death of CD4+ T cells.

One reasonable assumption early on would have been that HIV caused the death of CD4+ T cells via direct infection of CD4+ T cells. Many viruses like influenza and poliovirus cause lysis of their human host cells either through direct viral toxicity or mediated by vigorous host immune efforts to kill infected cells.

Yet a conundrum emerged early in the effort to understand AIDS pathogenesis: only a minority of CD4+ T cells are actively infected by HIV – usually fewer than five percent – so why did so many CD4+ T cells die if so few were actively infected?

Until recently, the best explanation for this paradoxical finding was that chronic immune activation associated with HIV infection was killing CD4+ T cells. It was already known that unquenched HIV infection is accompanied by chronic immune activation in which an unending flurry of cytokine release stimulates cellular proliferation and antibody production. During this process, wave after wave of immune cells are recruited to fight HIV, but all fail. Instead HIV rages on in lymph nodes and in the blood, calling forth still further waves of immune cells in an ultimately futile and ever-weaker attempt to contain HIV infection. The perpetual recruitment of immune cells into an ultimately futile fight against a ravaging virus – augmented by bloodstream leakage of pro-inflammatory bacterial products past the damaged gut immunological barrier – came with a huge cost: wave after wave of CD4+ T cell death.

The massive losses of vital CD4+ T cell defenders against the HIV invasion appeared, at least early on, to result from a coopted normal immunological housekeeping mechanism: apoptosis. Apoptosis is programmed death of cells whose utility has waned. Imagine contracting an upper respiratory tract infection from a rhinovirus or some other cause of the common cold. Neutrophils, lymphocytes and other immune cells migrate to the mucosal lining of the sinuses and other airway tissues to eliminate this rhinoviral invader, getting killed in the process of pitched immunological battle and as a result being extruded from the body in the form of snot. In a few days, the rhinoviral invader has been repelled, and the utility of these cellular defenders comes to an end unless a lifelong runny nose is desired. The most expeditious way to extinguish the immunological fire, then, is via activation-induced cell death, in which responder immune cells are preprogrammed to undergo apoptosis, thus clearing the mucosal battlefield and making way for good health to return. AIDS pathogenesis was felt to hijack this normal process because wave after wave of ineffectual CD4+ T cell responses to HIV infection would lead to CD4+ T cell apoptosis followed by recruitment of new CD4+ T cells which in turn would die, and so on.

Enter Warner Greene, a dapper white-haired professor of medicine at UCSF and its Gladstone Institute of Virology. In a feat of scientific hutzpah sure to trigger fits of envy among other scientific heavy-hitters, Greene shattered the existing model of AIDS pathogenesis in two simultaneous groundbreaking articles in the prestigious journals Science and Nature in late December 2013.

Greene’s team made multiple seminal observations. Their key findings were:

  1. Abortive infection of CD4+ T cells by HIV virions – in which HIV enters the CD4+ T cell cytosol but then accumulates incomplete viral transcripts which cannot establish a productive replication cycle – is detected by a host DNA sensor called interferon-gamma-inducible protein 16, or IFI16;
  2. IFI16 (and potentially other sensors of abortive HIV infection) triggers an intense inflammatory process of programmed cell death distinct from apoptosis, known as pyroptosis;
  3. Pyroptosis leads to release of intracellular contents as well as inflammatory cytokines into the extracellular milieu thus plausibly contributing to chronic immune activation;
  4. The pyroptosis caused by widespread abortive HIV infection of CD4+ T cells is mediated in part by the intracellular enzyme caspase-1; and,
  5. Pharmaceutical blockade of caspase-1 safely precluded HIV-mediated pyroptosis of CD4+ T cells.

And thus our model of AIDS pathogenesis is revised once again. While clearly chronic immune activation contributes to the loss of CD4+ T cells and AIDS pathogenesis, Greene and colleagues explain this process in an entirely novel way. Instead of chronic immune activation serving in a leading role during AIDS pathogenesis, chronic immune activation is recast in a supporting role, becoming itself a bystander to the real culprit, abortive HIV infection of CD4+ T cells.

These findings topple our conception of how HIV causes death among millions each year. They also have concrete clinical import. By demonstrating that caspase-1 inhibitors can block pyroptosis and thus a critical step in AIDS pathogenesis, Greene and colleagues breathe new life into the global effort to fight AIDS. Modern anti-HIV therapy has restored decades of life to the millions who can access it, but despite these successes current anti-HIV treatments do not wholly rectify chronic immune activation, restore full immunological function nor stave off all of the non-infectious risks of HIV infection such as cancer. Greene and collaborators recently announced a phase II human clinical trial testing the safety and potency of caspase-1 inhibitors in precluding HIV-associated pyroptosis. If safe, targeting capsase-1 mediated CD4+ T cell pyroptosis could help delay expensive anti-HIV therapy and/or augment anti-HIV therapy-mediated protection from the clinical manifestations of HIV and AIDS.

Nearly 33 years after clinicians first reported AIDS, we are still learning how HIV kills. The novel identification of a major role of pyroptosis in AIDS pathogenesis suggests novel therapeutic pathways and thus new hope in the fight against HIV.

Photo credit: Gross L (2006) Reconfirming the Traditional Model of HIV Particle Assembly. PLoS Biol 4(12): e445. doi:10.1371/journal.pbio.0040445 via Wikimedia Commons.