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Some people infected by HIV-1, known as long-term-nonprogressors, can live free of AIDS for more than 15 years even without medical treatment. A subgroup of these people are characterized by plasma concentrations of virus so low as to defy measurement by standard clinical techniques. A team of researchers now provides strong evidence that these individuals, dubbed HIV-1 controllers, are indeed suppressing the virus rather than simply playing host to a poorly replicating strain of HIV-1. The research is published in the December 2010 issue of the Journal of Virology.
Studies published in 2007 first showed that virus cultured from HIV-1 controllers could replicate just as competently in the laboratory as well-characterized laboratory strains of HIV-1. That suggested that strains infecting HIV-1 controllers were similar to strains in more typical individuals, and that HIV-1 controllers’ immune systems were doing an unusually good job against the virus. Nonetheless, extrapolating from laboratory studies, where the environment differs so completely from that of the natural host, is risky, says corresponding author Helene Mens of the National Cancer Institute, National Institutes of Health.
A better way to assay replication competency, Mens posited, would be to study genetic change within the virus over time. The virus mutates fairly consistently with each replication. So Mens obtained samples from HIV-1 controllers, and teamed up with John Coffin of the National Cancer Institute, who specializes in quantifying and amplifying HIV-1 from patients with viral loads below the limit of detection in standard assays. Their research showed a rate of genetic evolution in HIV-1 controllers that was similar to that in patients with more typical progression rates. They also found that most HIV-1 controllers had viremia levels that ranged from below 0.2 to 43 copies per ml plasma, well below the limit of detection using clinical techniques--50-75 copies per ml of plasma--and orders of magnitude below typical levels of viremia, which average around 50,000 copies per ml plasma absent therapy.
The research also indicates that the immune system is mounting a strong cellular immune response, in which certain T cells recognize specific antigens on the surface of infected cells, and cause those cells to commit cellular suicide. This “raises hope that an effective HIV vaccine that can delay disease progression and prevent transmission can be developed,” says Mens.
Interestingly, previous studies have suggested that HIV-1 controllers have more immune activation, inflammation, and arteriosclerosis (both of which can be a consequence of ample immune activation) than healthy controls. “It is important to find out of viral replication is driving immune activation and inflammation in HIV-1 controllers, and if they therefore may benefit from antiretroviral therapy,” says Mens.
(H. Mens, M. Kearney, A. Wiegand, W. Shao, K. Schonning, J. Gerstoft, N. Obel, F. Maldarelli, J.W. Mellors, T. Benfield, and J.M. Coffin, 2010. HIV-1 continues to replicate and evolve in patients with natural control of HIV infection. J. Virol. 84:12971-12981.)