HIV-1 has lost fitness over the past 15 years, say Belgian researchers

HIV isolates from the late 1980s infect human cells and kill T-cells much more effectively than HIV isolates gathered in 2002-2003, Belgian researchers report in the October 15^th edition of the journal AIDS. They say that the findings represent the first signs that HIV-1 may eventually become attenuated, or less harmful, in humans in the same way as HIV-2.

The study took viral isolates from 24 untreated patients, matched for viral sub-type, coreceptor tropism and CD4 cell count (all factors that might influence the transmissibility and pathogenicity of HIV).

Half were isolated between 1986 and 1989 from patients at the Institute of Tropical Medicine in Antwerp, half from patients treated at the same clinic in 2002-2003.

Sixteen isolates came from patients with less advanced HIV disease (CD4 count above 400 cells/mm³ and CCR5-tropic virus), the remainder from patients with advanced HIV disease (CD4 count below 200 cells/mm³ and CXCR4-tropic virus).

The researchers ran competitive tests to discover which isolate from a matched pair of old and recent viruses reproduced more readily in human T-cells, and found that the historical HIV-1 isolate out-competed the recent isolate in 176 of 238 pairwise comparisons.

Fitness consistently differed by around 40%, with the 2002-2003 viruses having a mean replicative fitness of around 55% of that found in the 1986-1989 viruses.

Viral fitness is known to be reduced by the accumulation of resistance mutations, often by up to 80%.

However fitness had not been impaired by drug treatment, since all samples came from treatment-naive patients and no evidence of drug resistance mutations could be found in any of the isolates, except for a single 1986-1989 sample, which proved to be more fit than the vast majority of the viruses.

The researchers also found that viruses from 2002-2003 were more sensitive to the antiretroviral drug 3TC (lamivudine, Epivir), and to the experimental CCR5 inhibitor TAK-779. However, the degree of difference in sensitivity was not profound enough to have any clinical implications.

The authors say that they have provided the first experimental evidence suggestive of HIV-1 attenuation over time. They suggest that the process of attenuation may occur due to immune system pressure that forces the virus to sacrifice some replicative fitness in order to evade CD8 cell and antibody responses.