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Genetic Linkage

Do Cats With FIV Foretell HIV’s Future?

Romeo is our third FIV-positive cat.
Since my January 24 blog “My Cat Has AIDS," about my two feline immunodeficiency virus (FIV)-positive cats, we’ve acquired a third, the handsome Romeo. He, too, came to us from Orange Street Cats, on Valentine’s Day.

Romeo was found in an inner city park where people who can barely afford to feed their families nevertheless care for the burgeoning population of stray cats. “His origins are unknown, but I’d been feeding him along with other backyard cats where I live, a short distance from the vet,” said Ethel, the kind woman who saved him. “When Romeo injured his front leg, I trapped him and took him to the vet. The leg wasn't broken, but they determined he is FIV positive, with no symptoms, so I couldn't keep him,” because she already had an adult, indoor cat.

Ethel probably could have kept Romeo, for FIV doesn’t pass easily among indoor adult cats. “A lot of people take a positive FIV result for a death sentence, and it sets off waves of panic,” said my cats’ vet, “Dr. Bart” Forlano. Some infected cats never get sick. Others go through phases similar to a person with AIDS, with initial symptoms and then a long period of stasis, like my #1 FIV cat Juice, star of my January blog. Only a few FIV-infected cats get very sick

Romeo, the sweetest, friendliest cat, apparently not a bit traumatized by his life on the streets, was fine on Valentine’s Day. But yesterday I noticed sores like those that plagued Juice in the weeks after he became infected. Romeo is meeting Dr. Bart as soon as I post this.

In this blog, part 2 of my FIV tale, I’ll cover the here and now – why vets don’t usually offer vaccination for FIV – and the bigger, evolutionary picture that might impact the relationship between humans and HIV.

Vets might never mention an FIV vaccine, while routinely vaccinating against the different disease, feline leukemia, for several reasons.

#1 Logic. Cats most likely to be infected with FIV are outdoor males. “FIV is a disease of young cats with outdoor exposure. That’s the segment of the cat population that should be vaccinated,” explained Arne Zislin, a veterinarian and Technology Manager, Pet Marketing for Boehringer Ingelheim, which produces the vaccine. It’s considered a ”core vaccine” for this group of felines. A captured cat, or pet that goes outdoors, would have an initial vaccine, then yearly boosters, and get a microchip (more on that below), he added. But the homeless outdoor cats are the hardest to catch, says my friend the vet from Texas. “They fight and inoculate each other with bites and scratches. Sexual transmission is an uncommon exposure route.”

#2 An indoor cat wouldn’t need the vaccine. “The chances of a household cat being infected with FIV is virtually nil, and even the chances of a neutered cat allowed outdoors from time-to-time becoming infected is also extremely low. Many FIV-infected pet cats live comfortable lives among non-FIV infected pet cats with a very low risk of passing the infection,” Niels Pedersen, DVM, PhD, director of the Center for Companion Animal Health at the University of California, Davis and co-inventor of the vaccine, told me.

#3 Practicality: Neither Dr. Bart nor my vet friend sees enough FIV-positive cats to justify vaccination. “I go through all my feline leukemia virus vaccine, but have thrown away trays of FIV because it has expired…you do that a few times and it makes you re-evaluate the need,” said TexVet.

#4 Insufficient protection: Like flu vaccine, FIV vaccine only protects against some viral strains. What worked in California in 2002 when the vaccine came on the market might not work in New York, and doesn’t cover my Texas friend’s cat population. Three doses of the vaccine, according to some studies, provide a 0-80% protection rate – too much of a swing for many vets.

#5 Mistaken euthanasia at shelters. An FIV-vaccinated cat makes antibodies against the virus for the rest of its life – as does an infected cat, even one without symptoms. “If you vaccinate a cat it will confound the typical test in a veterinary hospital to determine if a cat has FIV,” said Dr. Zislin. Shelters have euthanized pets testing positive from vaccination.

Because many FIV-positive cats live normal, relatively healthy lifespans, I began to wonder whether most or even all cats are infected, and the ones we know about have enough of a viral load to test positive – and very few cats are tested. “The ability of most naturally-infected cats to keep virus levels so low as not to be detectable and for many years explains why there is not much maternal transmission of the virus in nature and why cats can live such a long proportion of their lives in good health in face of chronic infection,” said Dr. Pedersen. The situation is a little like the baby who made news a few weeks ago for being” "functionally cured" of HIV – the virus is there, but at levels too low to register, and, so far, apparently unable to replicate.

The evidence suggests a taming of FIV, a détente between the cat and viral genomes playing out over time. “In Australia, 30% of cats test positive, and are able to live with the viral infection without severe medical problems. That wouldn’t happen if it hadn’t been in the population a long time,” said Dr. Zislin. The good health of the lions of the Serengeti National Park suggest this is the case -- all are infected, with any of three variants of FIV, and none are sick. The genetic diversity of the virus and dampened response to it suggests that it’s been around a long time, enough to accumulate mutations.

Might this comfortable co-existence between cats and their lentivirus, FIV, come to pass for humanity and its lentivirus, HIV? If so, can we hasten the accommodation? The simian immunodeficiency virus (SIV) story adds evidence that maybe we can.

We can approximate when a virus inserted itself into a host genome by identifying pairs of modern species that carry the virus, and deducing how far back in time they shared an ancestor. (Evolution proceeds in a branching manner from shared ancestors.) Geneticists compare sequences of a gene common to the species – the more DNA base sequence similarities, the more recently the species diverged from an ancestor. Add mutation rates for specific genes, and you have a molecular clock going back thousands or millions of years.

Forty or so species of monkeys and apes harbor SIV, but don’t get sick from it, because SIV is an ancient viral presence. Michael Emerman, PhD, a virologist at the Fred Hutchinson Cancer Research Center in Seattle and graduate student Alex Compton recently traced the origin of SIV infection to 5-6 million years ago by sequencing a host immunity gene called APOBEC3G that has mutated in parallel to a viral gene over time. The results are in the January 2013 PLOS Pathogens.

SIV may be even older than 6 million years. Some of its sequences are tucked into the genomes of ring-tailed lemurs of Madagascar, which are prosimians. Because lemurs branched from the ancestors of primates 12 million years ago, the virus goes back at least that far.

With SIV silently circulating amongst monkeys, apes, and even prosimians, at some point, likely several points, it moved into humans, maybe when they ate their evolutionary cousins. Various researchers have extrapolated the most recent transfer to 1884-1924, the start of HIV/AIDS in humans. I remember the date being repeatedly pushed back, starting in the early 1980s when the CDC began tracking what was then called gay-related immune deficiency (GRID). At first AIDS was thought to be brand new, arising somehow in “patient zero,” a gay flight attendant with many sexual partners. Researchers pushed the origin back a few years at a time, to 1960, then the 1930s.

SIV/HIV might have hopped around Africa for eons, flitting over from SIV in chimpanzee meat to isolated human populations, cloaked against the backdrop of endemic infectious diseases that kill much faster, especially among the immunocompromised. Left were survivors who may have been lucky, or may have been SIV-resistant, like people today who have two mutations in the CCR5 gene; HIV can't bind to their cells. If HIV killed off susceptible individuals in isolated settlements, the infection might only have become noticeable once cities formed and pockets of people with immunodeficiency emerged.

Alfred Roca and his team at the College of Agricultural, Consumer and Environmental Sciences at the University of Illinois are investigating such a possible HIV origin event in people called the Biaka, who live near where SIV may have first appeared in chimp populations. Graduate student Kai Zhao, funded by the Bill and Melinda Gates Foundation, compared single nucleotide polymorphism patterns in Biaka samples and found selection signatures – genome regions that persist because they offer some advantage. Such signatures among the Biaka led to four genes known from other work to confer resistance to HIV infection or progression to AIDS.

(ASIDE: Dr. Roca is an expert in elephants and mammoths and is co-author of one of my favorite papers, The Near Eastern Origin of Cat Domestication. That study compared 979 cats to their wildcat cousins, all subspecies of Felis silvestris, also revealing the origin of Sylvester the cat. Domestic cats split from the wildcats at the dawn of agriculture, about 9,000 years ago, in the Fertile Crescent.)

Evolution is ongoing, always, and so the strain of SIV that came to us from chimps, SIVcpz, is still re-inventing itself. Sandrine Souquière and colleagues at the Center for International Medical Research of Franceville in Gabon reported in late 2012 in PLOS ONE a new strain in wild-born captive chimps from Gabon and Congo. The animals appear healthy, but have much lower CD4+ T cell counts than uninfected animals. There’s also evidence that people may have passed HIV back to chimps.

The SIV/HIV story seems to be recapitulating that of the hardy cat virus. This isn’t a new idea – Robert Olmsted and co-workers wrote in 1992 in the Journal of Virology that “…the transmission of FIV between feline species is infrequent and parallels in time the emergence of HIV from simian ancestors.”

Strains of FIV are less like each other, genetically speaking, than are SIV and HIV. Therefore, perhaps what is happening in today’s domestic cat population foretells what will happen in our own. SIV no longer sickens most wild primates because they’ve had 12 million years to adapt. Cat species around for a long time, like lions, are less likely to get sick from FIV than their more modern relatives, such as our domesticated friends. And then there’s us, who Olmsted et al call “merely the latest unfortunate species to have become infected via another mammalian species.”

Maybe people shouldn’t shun FIV-infected cats, which is how we came to adopt Juice, Artie, and Romeo. For within them may lie clues to hastening evolution in a way that will silence HIV forever.

This blog first appeared at the Public Library of Science "DNA Science" blog.
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