Is HIV weakening over time? Unlikely, and a sense of déjà vu…
Richard Jefferys, TAG
A little over nine years ago I wrote a blog post with the same title of “Is HIV weakening over time?” about a widely publicised paper claiming that HIV had become less virulent. 
Although it’s grim to be in the position of pouring cold water on optimistic-sounding scenarios, that paper was based on measuring the ability of HIV to replicate using a laboratory test, and other published data raised questions as to whether the test could actually predict differences in disease progression rates. Today, it’s déjà vu, because there has been an explosion of very similar media stories positing that HIV is evolving into a “milder form”.
Once again, the study prompting the coverage relies primarily on laboratory measurements of HIV replication capacity, despite the fact that a prior publication – by several of the same authors – reports that results from this test do not predict the rate of CD4 T cell decline over time.
The new study, by Rebecca Payne and colleagues from the laboratory of Philip Goulder, was published by PNAS in December 2014. Helpfully, the full text has been made freely available. 
Two populations of HIV positive women are compared, from Gaborone, Botswana and Durban, South Africa. The researchers present evidence that in Botswana, where HIV has been circulating for a longer period, there has been greater virus adaptation to immune responses, leading to more escape mutations and a lower replication capacity. HIV replication capacity is compared using samples from 63 study participants in Gaborone and 16 in Durban, with these participants being closely matched for CD4 T cell counts (important because, as the paper reports, HIV replication capacity in a given individual increases as CD4 T cell counts decline). The average result of the replication capacity test was 0.72 in Gaborone and 0.81 in Durban, indicating that the virus in the former population is slightly less fit. The authors create a mathematical model based on these findings suggesting that both immune responses and the increasingly widespread use of antiretroviral therapy may be contributing to a decline in HIV virulence.
The idea that HIV replication capacity can be linked to disease progression rate derives from a documented correlation between the results of the test and both viral load and CD4 T cell count. However, these correlations are based on measurements taken at single timepoints; in other words, cross-sectional analyses. The question of whether measurement of HIV replication capacity can predict subsequent disease progression rate was addressed in a prior study,  which evaluated whether there was a correlation with the rate of CD4 T cell decline over time. No such correlation was found, nor even a hint of one. The discussion section of the Journal of Virology paper containing this result states:
“Therefore, although there may be a benefit to decreased replication capacity (as supported by cross-sectional correlations with viral loads and CD4 counts), the data do not support an enduring benefit or a lasting significant impact of Gag-protease replication capacity on the rate of disease progression, at least once the chronic infection stage has been reached… the long-term clinical impact of immune-driven fitness costs requires further investigation, given the evidence for compensation and the observation that replication capacity does not correlate with the subsequent rate of CD4 decline in chronic infection.”
It is challenging to try and reconcile this prior result with the claim that the difference in replication capacity found in the new PNAS study would equate to an additional 2.5 years in the average time it takes to progress from HIV infection to AIDS (an estimate offered by Phillip Goulder in the BBC’s coverage) . Before concluding that the virulence of HIV is declining, it would be prudent to wait to see if additional studies are able to correlate the apparent differences in HIV replication capacity with differences in CD4 T cell counts and health outcomes over time.
An additional wrinkle is that there are other studies arguing that HIV virulence is increasing over time; a meta-analysis with this finding was published in 2012  and a new analysis presented at CROI 2014 (and just published in the December issue of The Lancet HIV) reached the same conclusion.
There might be explanations for these very disparate results, but – pending additional evidence – it seems reasonable to maintain a healthy scepticism about all of them.
TAG basic science blog. (02 Dec 2014).
- Jefferys R. Is HIV weakening over time? TAG blog. 03 October 2005.
- Payne R et al. Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence. PNAS Published online. December 1, 2014, doi: 10.1073/pnas.1413339111.
- Wright JK et al. Gag-protease-mediated replication capacity in HIV-1 subtype C chronic infection: associations with HLA type and clinical parameters. J. Virol. October 2010 vol. 84 no. 20 10820-10831.
- Gallagher J. HIV evolving ‘into milder form’. BBC news. (01 December 2014).
- Herbeck JT. Is the virulence of HIV changing? A meta-analysis of trends in prognostic markers of HIV disease progression and transmission. AIDS. Jan 14, 2012; 26(2): 193–205. doi: 10.1097/QAD.0b013e32834db418.
- Pantazis N et al. Temporal trends in prognostic markers of HIV-1 virulence and transmissibility. 21st CROI, 3-6 March 2014. Oral abstract 36.
- Pantazis N et al. Temporal trends in prognostic markers of HIV-1 virulence and transmissibility: an observational cohort study. The Lancet HIV. (2014),1(3), e119–e126, December 2014.