By Richard Jefferys
One of the main sources of pessimism about prospects for an effective HIV vaccine has been the generally poor results obtained in animal models. In particular, a stringent system involving rhesus macaque monkeys challenged with highly pathogenic simian cousins of HIV (SIVmac239 or SIVmac251) has proven too stern a test for many vaccines—even those once considered promising like Merck’s now-discontinued candidate. To date, only a live attenuated SIV (simian immunodefiency virus) vaccine has demonstrated significant efficacy against these challenge viruses, and this approach is too dangerous to be adapted for use in humans.
It is against this backdrop that a recent flurry of media stories celebrated the results of a new vaccine experiment published in the venerable science journal Nature. Conducted by Louis Picker and colleagues from the Vaccine and Gene Therapy Institute (VGTI), the study used cytomegalovirus (CMV) as a vaccine vector, altering its genetic makeup so that it produced SIV proteins in addition to its own protein payload. Rhesus macaques were immunized with the vaccine and challenged with SIVmac239 a little over a year afterward. The excitement about Picker’s study stems from the unprecedented degree of long-term control of SIV replication observed in 12 out of 24 macaques that received the CMV vector; after transient postinfection peaks ranging from 60 to 10,000,000 copies, there were only occasional blips above the limit of detection that diminished over time. In four of these animals that were euthanized after 52 weeks of follow-up and had multiple tissues analyzed, replication-competent virus could not be found and viral RNA and DNA levels were extremely low, leading to the suggestion that SIV was being progressively cleared. Although this extraordinary degree of control was only seen in 50% of the CMV vector recipients, it nevertheless represents a great leap forward compared to results obtained in the same model with other candidate vectors.
The researchers ascribe their success to a particular type of CD8 T-cell immune response induced by the vaccine. CD8 T-cells have the ability to identify and kill virus-infected cells (hence their alternate designation: cytotoxic T lymphocyte, or CTL), but the efficiency with which this function is performed can vary. A subset of CD8 T-cells called effector memory cells (or Tem cells, for short) appear to be the most trigger-happy of the killers because they are constantly on high alert; it turns out that the CMV vector is particularly adept at inducing and maintaining a large population of CD8 Tem cells targeting SIV, which correlated with the control of the challenge virus.
So far, so good. But what are the prospects for adapting CMV vectors for use in people? CMV is a member of the herpesvirus family and causes persistent infection; most people on the planet harbor the virus by the time they reach adulthood. Unlike some other vectors, preexisting infection and associated immune responses against the virus do not stop the vector from working, because CMV has evolved the ability to sneak under the immunological radar and reinfect. (All the monkeys described in the Nature article were already infected with rhesus macaque CMV.) Until quite recently, CMV was also thought to be relatively benign, only causing disease in limited settings such as in pregnant women and individuals with severe immune deficiencies (including AIDS, where CMV can reactivate and cause several horrendous opportunistic diseases, including retinitis and colitis).
Over the past decade or so, however, evidence has emerged of another, more insidious long-term impact of CMV on human health. This was first described in a Swedish cohort of much older people ( over 85 years of age) in whom CMV positivity was linked to an array of immune system perturbations (including an inverted CD4:CD8 ratio, diminished naive cell numbers, and poor proliferative responses) and an elevated risk of morbidity and mortality when compared to that of uninfected individuals. It appears that the presence of CMV causes persistent low-level inflammation, which in turn causes accumulated wear-and-tear on the immune system as people age, making CMV a major contributor to a phenomenon that is technically termed “immunosenescence”: the progressive enfeebling of the immune system caused by a lifetime of work against pathogens and other stimuli.
More recent studies have found that CMV may have subtle pernicious effects on health at younger ages, also; infection was associated with a slight but significant increase in risk of all-cause mortality in a large nationally representative sample of individuals in the United States ages 25 and older. As with older individuals, inflammation associated with CMV infection is suggested as the likely explanation.
The literature on the potential dangers of CMV thus represents a cloud of uncertainty hanging over plans to try and advance CMV vectors into human trials. It could be that the very properties of the virus that enable it to induce potent CD8 Tem cells and control a virulent SIV challenge are also those that underlie its apparent harmful long-term effects in humans. Alternatively, it might turn out to be possible to disentangle the effectiveness of CMV as a vector from its negative side; in the press reports on his Nature article, Picker makes it clear that efforts are underway to try and render CMV safe to use, but how this is being accomplished and whether it can be verified in human trials is unclear.