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HIV Keeps Evolving in Cancer Tissues and Other Tissues During Suppressive ART
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Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston
Mark Mascolini
Antiretroviral therapy (ART) that controlled HIV replication in plasma and often cerebrospinal fluid (CSF) did not slow viral evolution in cancer tissues and other pathologic tissues, according to results of autopsy studies by Michael McGrath (University of California, San Francisco) and colleagues at other sites [1]. They proposed that HIV-infected macrophages may carry virus to these tissue sanctuaries.
Viral rebound promptly follows interruption of suppressive ART, the researchers noted, and risk of certain cancers remains elevated in treated HIV populations. As a result, they hypothesized that viral populations persisting in tissues during suppressive ART "may contribute to both rebound virus and ongoing pathology."
To explore that hypothesis, they analyzed National Neurological AIDS Bank autopsy specimens of 5 people. These people had been infected with HIV from 3.6 to 20 years and had non-Hodgkin lymphoma (3 patients), anal cancer (2 patients), and other cancers. All also had brain pathology. All 5 people had a plasma viral load below 400 copies at their last measure and 3 had final plasma loads below 40 copies. Three had CSF loads below 40 copies; in the other 2 people CSF loads measured 57 and 338 copies.
The researchers used digital-drop PCR and quantitative PCR to detect HIV RNA and DNA in 37 postmortem tissue samples. They used single-genome amplification to assess viral sequences for the env and nef genes and sometimes the pol gene. Tissue sites included lymph nodes, cerebellum, frontal cortex, basal ganglia, liver, kidney, colon, and lung, among others.
HIV genetic diversity in tissues of these antiretroviral responders proved similar to HIV diversity in a comparison group of cancer patients naive to ART. In other words, ART had not slowed viral evolution in tissues from people with low or undetectable plasma and CSF loads. The evolutionary rate of tissue virus in these antiretroviral-treated patients did differ significantly from the evolutionary rate in T cells recovered from a comparison group of antiretroviral-treated patients.
Phylogenetic analysis of HIV in lymph node, brain, spleen, kidney, and pancreas from 3 patients showed two distinct branching patterns—both identical and highly evolved sequences from sample to sample. Sequences in 2 to 4 tissues samples from 3 people yielded two findings: (1) "anatomically dispersed viral populations evolve via different modes of evolution, and (2) periods of increasing lineage diversity correspond to cancer events."
In one antiretroviral-treated cancer patient, RNAscope analysis of cells expressing HIV gag-pol transcripts found HIV RNA associated with invasive macrophages in brain and lymph node tumor cells. Finally, pol sequence resistance mutation analysis indicated that viral evolution in tissue could not be explained by antiretroviral resistance. Only one sequence contained a single-nucleotide resistance motif.
The researchers underlined the "striking" finding that HIV evolutionary rates in tissues from these people with suppressed viremia were no lower than viral evolutionary rates in antiretroviral-naive patients. They suggested that "an alternative site for viral maintenance during ART, apart from memory T cells, must be present in order to explain" these results. McGrath and colleagues noted that lymphatic tissue, tumor tissue, and brain tissue in these patients "are sites of replicating virus as evidenced by RNA sequences and mRNA expression of gag-pol and thus may serve as a [viral] sanctuary."
Because HIV-infected cells in brain and lymph nodes lie close to infiltrating activated macrophages--and because some macrophages appeared to be infected and expressing HIV--the researchers suggested that "macrophages, possibly including tumor-associated macrophages, are the cellular source of the sanctuary and may provide the means of transit for the virus and protection from the effects of ART."
Reference
1. Rose R, Lamers SL, Nolan DJ, et al. Evidence of HIV evolution in lymphatic and cancer tissues in ART+ patients. Conference on Retroviruses and Opportunistic Infections (CROI), February 22-25, 2016, Boston. Abstract 331.
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