Playing With Fire

Superinfection. It is a word that can evoke ironic images of Peter Parker's fateful bite by a radioactive spider, an incident that transformed him into the amazingly strong Spider-Man. Far from conferring superpowers, though, HIV superinfection, in researchers' view, creates a menacing threat to the health of people with HIV. But amid all the talk of drug-resistant strains infecting an already HIV-positive person and neutralizing what had been a successful drug regimen, a cloud of mystery and skepticism has long hung over the question of just how worried people should be about superinfection. Scientists have been piecing the puzzle together slowly, hampered by the immense complexity and expense of successfully analyzing blood samples and by the difficulty of finding research subjects. But over the past two years lots of data has begun to roll in. What it all means, though, is still subject to much debate among HIVers and scientists alike. Just What Is Superinfection? Superinfection occurs when you are infected with one strain of HIV and then become reinfected with a second strain, which in theory could lead to faster disease progression and treatment failure. Some researchers hoped that CD8 cells, also known as 'killer T cells,' could prevent reinfection. Once these immune-system cells realize that HIV has infected CD4 T cells, they are genetically programmed to recognize and kill the virus. And according to Mark Connors, MD, an immunologist at the National Institutes of Health, almost all people with HIV will have high levels of these cells in their blood. Unfortunately, Connors says, he has found that differences between viral strains make it difficult for CD8 cells to recognize and kill off a new strain before it establishes itself in the body. Further, his research leads him to conclude that if CD8 cells cannot control the first virus, there is reason to believe they could not prevent a second infection either. However, his work is countered by Jay Levy, MD, a professor of medicine at the University of California, San Francisco. Levy's research has shown that while superinfection can occur, the CD8 cells do have the ability to effectively control the new infection and keep it at bay. But a vast number of HIV strains complicate the picture a bit more. There are two main types of the virus: HIV-1 and HIV-2. HIV-2 is prevalent in West Africa; HIV-1, in the rest of the world. Within the HIV-1 family are three groups: M, N, and O. The M group is divided into at least 10 further subtypes, or 'clades,' called A through K. In Europe, North America, and Australia, HIV-1, group M, clade B is highly prevalent. This creates a problem because genetic testing may not be sensitive enough to distinguish subtle differences within the same clade. This could lead to trouble identifying whether someone is infected with two genetically similar viruses that are still different enough to negatively affect disease progression. Another worry about dual infections is that the two newly paired viruses may lead to what is known as a recombinant virus. It is possible that two different strains of HIV can enter a single CD4 cell and then combine their DNA to become a new hybrid virus. Scientists are seeing evidence of a growing number of these viruses, especially in Africa. What Do We Really Know? Over the past two years researchers from around the world have published studies establishing with some certainty that superinfection not only exists but also can lead to faster disease progression. A California man was initially infected with a drug-resistant virus and was then reinfected with a drug-sensitive, or 'wild-type' virus, both of the strains from clade B. Since wild types tend to be more virulent, the unmedicated patient saw his viral load increase from 2,400 to 170,000 and his CD4 count drop from 800 to 283 in less than a year. Researchers at the Wadsworth Center at New York's state health department have also found a case of superinfection in a woman who was a part of an ongoing sex-worker cohort in Nairobi, Kenya. The longtime prostitute entered the cohort in 1986 and at the time had subtype A in her blood. By 1995 her blood work showed she had a recombinant virus of the A and C strains, which lead researcher Harold Burger, MD, says was most likely the result of a superinfection with subtype C around 1992. Before the superinfection the woman's CD4 count was in the 700s. Afterward and until her death in 1997 it was never above 150. But just a few superinfected patients out of tens of millions worldwide does not exactly spell statistical disaster for everyone'especially if one of them is a sex worker who rarely uses condoms and has an average of two to three clients a day. Furthermore, as Burger pointed out in January, none of the cases presented up to then demonstrated the ultimate fear'that people can be superinfected with drug-resistant strains. Answers to these lingering questions arrived in San Francisco in February at the Conference on Retroviruses and Opportunistic Infections when a team of scientists led by Davey Smith of the University of California, San Diego, presented a study he says shows that the U.S. HIV population is becoming superinfected at a conservatively estimated rate of 5% each year. The UCSD team studied a cohort of 78 men whose risk factor was unprotected intercourse. The team identified three cases that were superinfected, one of them with a drug-resistant strain. According to Smith, 'The people we identified in this study all had negative consequences of their superinfection: Their CD4 counts went down faster and their viral loads went up faster than the rest of the people in the cohort.' What Does This Mean for Vaccines? Ideally, an HIV vaccine would provide what is known as sterilizing immunity, meaning that the virus would never get into the body and replicate. Or, less ideally, the virus could enter the body and replicate but eventually be eliminated, which is how most vaccines work (by stimulating the CD8 cells to kill off the foreign invaders). Unfortunately, both of these options seem impossible, since the evidence of superinfection leads us to believe that CD8 cells are probably not sensitive enough to recognize the differences between viral strains. 'The superinfection story was a jolt,' says Kent Weinhold, who heads the immunology lab at Duke University for the HIV Vaccine Trials Network. 'But I think it doesn't mean we have to throw up our hands and say, 'Does this mean a vaccine is impossible?' ' Weinhold says researchers are trying to identify components of HIV that do not change between strains and therefore might be vulnerable to a vaccine assault in broad sectors of the world's HIV population. In a 2001 article in the medical journal The Lancet, Levy wrote that vaccine research should focus on simply trying to control the infection and the progression of HIV to AIDS, not stop it altogether. He wrote that such a vaccine 'would be successful not at the individual level but at the population level,' meaning that the vaccine would not initially stop new HIV infections but would hamper the virus's virulence'possibly reducing its infectiousness but not eliminating it. So across the board, the epidemic would be mitigated. The Effects on Actual Lives What does this all mean for real-world HIVers? Unfortunately, as with many issues surrounding HIV disease that have come up over the years, there is a lot of contentious disagreement. We know, for example, where the researchers stand'any risk of becoming reinfected should be avoided. But in 2001, HIV-positive columnist Andrew Sullivan was infamously caught soliciting unprotected sex with other HIVers on the Internet. He reacted to the scandal with incredulity that superinfection was a viable threat. He recently told HIV Plus, 'So far I haven't seen any real evidence [of superinfection]. But I'm open to persuasion.' But even the differences in the mind-sets of HIVers and non-HIVers do not break down so easily. For example, Gordon Mansergh, Ph.D., a behavioral scientist at the Centers for Disease Control and Prevention, researched gay men in San Francisco three years ago and found that of the respondents who had heard of 'barebacking,' 22% of the HIV-positive men had unprotected anal intercourse within the previous two years and only 10% of the HIV-negative men had. However, Grant Colfax, MD, director of HIV prevention studies at San Francisco's department of public health, is about to publish a study in the journal AIDS showing that the vast majority of HIV-positive men believe that superinfection does occur and that those who believe this are much more likely to use condoms when having intercourse. Like almost all doctors, Tony Mills, MD, an HIV specialist in West Hollywood, Calif., is loath to tell his patients that condom-free sex between HIV-positive partners is not the biggest worry'even if the statistical evidence is still cloudy. 'If people are on a nice, easy-to-tolerate regimen and they've got good viral suppression and good immune function, you've sort of won the game at that point,' says Mills, who is HIV-positive himself. 'But if you go muck around with it and introduce another strain of the virus that's resistant to the medications you're on, then all bets are off again.' Indeed, highly active antiretroviral therapy is the defining difference between the old days of AIDS and the new era, which has put the spotlight so brightly on superinfection. During the first 15 years of the epidemic people thought of HIVers as being on their way out. So what was the harm in some wild sex with other infected people? Since 1996, with the greater promise of a long life in mind, HIVers have become more questioning'and are heavily debating'what sexual freedoms they still have and what place latex has in their lives. Juan, an HIV-positive New Yorker, says that while he believes superinfection exists, 'I also believe that individuals who have been positive for many years are tired of being afraid and not being able to enjoy sex the way negative people do.' Complaining of a lack of spontaneity that condoms bring to sex with his partner'she also has HIV'he says the two of them have nixed the rubbers. So far, their blood-work numbers have remained the same. On the flip side of the coin is Henry Menendez, also from New York City, who is troubled by a past he feels may have spoiled some of his chances to fight the virus with HAART. 'I do believe superinfection exists,' he says. 'All I know is that I am the owner of a virus that has mutated greatly, and I have very few options left for drug combinations. Is it because I was infected by [a different viral strain]? Is it because of all my risky behavior? Is it because of my years of drug use? Yes. I think it is a combination of all of the above.' One thing is certain, though. As the debate continues to rage on, so will the effects of HIV infections'and superinfections'whether the result is faster disease progression or not.