Research reported in the Journal of Virology reveals that HIV continues to evolve in the tissues of HIV-positive patients with cancer who have been treated with combined antiretroviral therapy (cART).1

Despite extraordinary advances in cART, there remain two critical issues: Because the virus is not completely eliminated with treatment, patients who discontinue cART experience a rebound; and cART-treated patients have an elevated risk of developing comorbid diseases, including cancer, cardiovascular disease, psychiatric disorders, and liver and lung diseases.2 These phenomena suggest that “during cART, tissue-based HIV may contribute to such pathologies,” wrote the authors of the new study. Of these comorbidities, cancer is the leading cause of death in such patients, though the underlying mechanisms are unclear.

In earlier studies using postmortem tissue samples, the authors of the current research found evolutionary distinctions between the virus in tumors vs nontumor tissues, and they detected the virus in more than 65% of samples of HIV-positive patients with undetectable plasma viral loads (15 of whom had cancer).3,4

In the present investigation, the investigators used single-genome sequencing to obtain DNA, RNA, envnef, and pol sequences from the tissues of 3 HIV-positive cART-treated cancer patients from the same cohort used in the prior studies. Their aim was to explore the possibility of viral dispersal among the tissues and other viral dynamics using time-scaled Bayesian analyses.

The results of their analyses were as follows:

  • cART-treated and cART-naive patients showed similar rates of tissue-based virus evolution.
  • Phylogenetic patterns suggest continual viral evolution and tissue dispersal, and are characterized by “very recently derived clades containing both DNA and RNA sequences from multiple tissues,” the authors reported.
  • HIV-expressing cells were found to be clustered in the cerebellum but dispersed in the lymph node tissues.
  • HIV-expressing cells at both sites were observed in close proximity to infiltrating activated macrophages, some of which appeared to be expressed in the brain.
  • The viral populations found in the patients’ tissues were generally wild-type vs drug-resistant, which indicates the possibility of a mechanism that allows viral replication in the tissues but not in blood T cells.
  • HIV expansion corresponded with cancer onset and metastasis, which suggests a shared mechanism.

Taken together, the results “provide evidence that tissues serve as a sanctuary for wild-type HIV during cART and suggest the importance of macrophages as an alternative reservoir and mechanism of virus spread,” according to the researchers. These findings have implications for the development of novel treatments for HIV.

Future inquiries should potentially expand to patients with a longer postmortem interval, thereby including healthier individuals. Additionally, studies using deep-sequencing techniques and a greater number of patients could further clarify the evolution of the virus during cART. 

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References

  1. Rose R, Lamers SL, Nolan DJ, et al. HIV maintains an evolving and dispersed population in multiple tissues during suppressive combined antiretroviral therapy in individuals with cancerJ Virol. 2016;90:8984-8993. doi: 10.1128/JVI.00684-16.
  2. Lorenc A, Ananthavarathan P, Lorigan J, Jowata M, Brook G. The prevalence of comorbidities among people living with HIV in Brent: a diverse London Borough. London J Prim Care (Abingdon). 2014;6:84-90.
  3. Salemi M, Lamers SL, Huysentruyt LC, et al. Distinct patterns of HIV-1 evolution within metastatic tissues in patients with non-Hodgkins lymphoma. PLoS One. 2009;4:e8153. doi: 10.1371/journal.pone.0008153.
  4. Lamers SL, Rose R, Maidji E, et al. HIV DNA is frequently present within pathologic tissues evaluated at autopsy from combined antiretroviral therapy-treated patients with undetectable viral loads. J Virol. 2016;90:8968-8983. doi: 10.1128/JVI.00674-16.