Yuko Ichikawa

HIV-1 nef suppression by virally encoded microRNA

BackgroundMicroRNAs (miRNAs) are 21~25-nucleotides (nt) long and interact with mRNAs to trigger either translational repression or RNA cleavage through RNA interference (RNAi), depending on the degree of complementarity with the target mRNAs. Our recent study has shown that HIV-1 nef dsRNA from AIDS patients who are long-term non-progressors (LTNPs) inhibited the transcription of HIV-1.ResultsHere, we show the possibility that nef-derived miRNAs are produced in HIV-1 persistently infected cells. Furthermore, nef short hairpin RNA (shRNA) that corresponded to a predicted nef miRNA (~25 nt, miR-N367) can block HIV-1 Nef expression in vitro and the suppression by shRNA/miR-N367 would be related with low viremia in an LTNP (15-2-2). In the 15-2-2 model mice, the weight loss, which may be rendered by nef was also inhibited by shRNA/miR-N367 corresponding to suppression of nef expression in vivo.ConclusionsThese data suggest that nef/U3 miRNAs produced in HIV-1-infected cells may suppress both Nef function and HIV-1 virulence through the RNAi pathway.

RE: Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial

Recently, Brasky et al. (1) reported an elevated risk of prostate cancer (PC) and high-grade PC, especially in people with high plasma phospholipid compositions (PPLCs) of long-chain (LC) omega-3 (n-3) polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), and a reduced PC risk in individuals with high linoleic acid, a major component of n-6 PUFAs. The observations, although challenging, are incompatible with our hypotheses. Comments should be made in view of PPLCs vs absolute consumption, supplements vs dietary intake, observational epidemiologic findings, and biological plausibility. Although PPLC values may be more accurate than dietary consumption estimated by dietary records/recall/ questionnaire and well correlated with medium-term dietary intakes, they are still relative proportions, not absolute intakes/ concentrations, and although discussed by the authors, they may yield spurious results. The authors did not mention dietary intakes of the subjects. Because Americans only occasionally consume fish/shellfish, the high PPLCs of LC n-3 PUFAs may be presumably attributable to recent intake from supplements. Even though they found a trend between PPLCs of LC n-3 PUFAs and the risk of PC, LC n-3 PUFAs may not be causal factors because the cancer, as is well known, has a long latency period from onset to overt cancer. Sufficiently long past and long-term dietary studies and follow-up are needed to pinpoint the etiologic factors. Because there are certain fallacies in descriptive epidemiologic studies, such as time trend, migration, and ecological studies, they are considered less convincing than analytical research, but they are basic and robust. The recent growing incidence of PC in Japan may be largely attributable not only to the spread of prostate-specific antigen screening but also to the changes in lifestyle, including declining intake of fish/shellfish and soy, and increased intake of deep-fried food and red meat. The latter observations may coincide with findings of migration studies, in which Japanese migrants to the United States have an elevated incidence of PC (2). LC n-3 PUFAs play ultimate competitive inhibitory bioactive roles as n-3 series leukotrienes, thromboxanes, and prostaglandins against respective n-6 family chemicals in lipoxygenase and cyclooxygenase pathways (3). EPA, DPA, and DHA may be milder COX inhibitor analogs without adverse effects, such as gastrointestinal bleeding, bleeding diathesis, and cardiac toxicity, typically caused by aspirin or nonsteroidal antiinflammatory drugs. LC n-3 PUFAs have long been thought to have anti-inflammatory and anticarcinogenic properties, but, as also mentioned by the authors, the findings were counter to their expectations. Although the World Cancer Research Fund/American Institute for Cancer Research (2) has categorized fish as one of the inconclusive factors of PC, we hypothesize that increased dietary consumption of marine food and reduced intake of vegetable oils, yielding lower ratios of n-6 PUFAs/n-3 PUFAs or arachidonic acid/LC n-3 PUFAs (4), may suppress inflammation and prevent the onset of cancers, including PC.

n-6 Polyunsaturated fatty acids and breast cancer.

Rissanen et al. (1) reported that the risk of breast cancer, the postmenopausal type in particular, might be decreased with elevated proportions (wt% of the total fatty acid, FA) of n-6 polyunsaturated fatty acids (PUFAs) and linoleic acid in the serum. It seems, however, incompatible with recent scientific findings (2–9): that is, n-6 PUFAs, possibly along with a high concentration of all FAs, are tumor promoters, as discussed by the authors, whereas n-3 PUFAs are anti–mutagenic/carcinogenic nutrients. The authors should supply information on whether they collected blood under morning fasting conditions or on a spot sampling basis. If the latter, the data should be carefully assessed because the authors mention that they analyzed FAs using whole serum, not the cholesterol fraction. They might also provide values for triglycerides, which are affected by the immediate diet. The authors showed no significant differences in the proportions of n-6 PUFAs between breast cancer cases and controls based on the t-test. However, they exhibited decreased odds ratios in proportion to the percentages of n-6 PUFAs. They could not detect any associations between concentrations of long-chain PUFAs and risk of breast cancer due to the degradation of relevant FAs in serum frozen for 25 yr at –20°C. Are there any plausible reasons that they noted contradictory results only in the comparisons for the first 10 yr? In other words, they may have found an opposite relationship using the remaining subjects because there were no differences in the whole series. Finally, the authors should also provide the relevant data based on the absolute concentrations of FAs (mg/dl or mol/l), rather than percentages, to precisely clarify the effects of n-6 PUFAs, including arachidonic acid, an ultimate bioactive chemical of the eicosanoid cascade; competitive n-3 PUFAs, including α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid; and the ratio of n-6 PUFAs to n-3 PUFAs on mammary carcinogenesis.