For many years scientists have probed the question of whether combination antiretroviral therapy (ART) completely inhibits all HIV replication in the body. The preponderance of evidence has suggested that it does, and opinion has generally tilted toward the idea that persistent virus replication in the face of ART is relatively uncommon. The evidence includes studies of ART intensification (adding multiple drugs to standard combinations), which in most—but not all—cases have documented no effect on levels of residual HIV, as well as genetic studies showing a lack of viral evolution over time in people on long-term treatment. The question remains controversial, however, and some scientists continue to believe that low-level ongoing HIV replication on ART may occur in hard-to-access sites in the body.
A paper published online last week by Nature (and published in this week’s issue) has generated substantial debate and media coverage by claiming to provide evidence that HIV replication persists in lymphoid tissue sites where ART penetration may be limited. The study involves a very small sample size of just three people, who had only been taking ART for six months. Complex genetic analyses of HIV sequences sampled from these individuals indicated continuing evolution of several viral lineages, and also provided evidence of trafficking of these viruses from the lymphoid tissue to the blood.
To help explain the findings, the researchers developed a model showing that suboptimal penetration of ART into tissues may allow ongoing low-level HIV replication without necessarily leading to the emergence of drug-resistant viruses (one of the arguments against ongoing replication is based on the expectation that drug resistance would eventually be seen).
The paper’s authors appear confident that these findings are generalizable to most people on ART, but other scientists are skeptical – some vociferously so. In an article about the study by Jon Cohen in Science, longtime HIV researcher John Mellors states that the results contrast with those of his own group, and argues strongly that “the authors should be much more cautious.” Given the small number of individuals included in the Nature paper and the relative short duration of ART, this point seems very reasonable. Larger studies will be needed to resolve the controversy, and will likely be forthcoming soon.
Pending additional data, the implications for cure research are unclear. If persistent HIV replication on ART is sustaining the reservoir of infected cells, as the new paper suggests, then novel strategies may be needed to suppress the virus in tissues. On the other hand, the goal of the “kill” element in the “kick & kill” approach to HIV reservoir reduction (currently being pursued by many scientists) is to eliminate HIV-infected cells that are expressing viral antigens. And theoretically, at least, successful “kill” approaches should also be able to target cells where persistent HIV replication is occurring because they would be expected to display viral antigens.
Nature (2016) doi:10.1038/nature16933
Received 06 July 2015 Accepted 18 December 2015 Published online 27 January 2016
Ramon Lorenzo-Redondo, Helen R. Fryer, Trevor Bedford, Eun-Young Kim, John Archer, Sergei L. Kosakovsky Pond, Yoon-Seok Chung, Sudhir Penugonda, Jeffrey G. Chipman, Courtney V. Fletcher, Timothy W. Schacker, Michael H. Malim, Andrew Rambaut, Ashley T. Haase, Angela R. McLean & Steven M. Wolinsky
Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.