Superinfection with drug-resistant HIV is rare and does not contribute substantially to therapy failure in a large European cohort.

BACKGROUND: Superinfection with drug resistant HIV strains could potentially contribute to compromised therapy in patients initially infected with drug-sensitive virus and receiving antiretroviral therapy. To investigate the importance of this potential route to drug resistance, we developed a bioinformatics pipeline to detect superinfection from routinely collected genotyping data, and assessed whether superinfection contributed to increased drug resistance in a large European cohort of viremic, drug treated patients. METHODS: We used sequence data from routine genotypic tests spanning the protease and partial reverse transcriptase regions in the Virolab and EuResist databases that collated data from five European countries. Superinfection was indicated when sequences of a patient failed to cluster together in phylogenetic trees constructed with selected sets of control sequences. A subset of the indicated cases was validated by re-sequencing pol and env regions from the original samples. RESULTS: 4425 patients had at least two sequences in the database, with a total of 13816 distinct sequence entries (of which 86% belonged to subtype B). We identified 107 patients with phylogenetic evidence for superinfection. In 14 of these cases, we analyzed newly amplified sequences from the original samples for validation purposes: only 2 cases were verified as superinfections in the repeated analyses, the other 12 cases turned out to involve sample or sequence misidentification. Resistance to drugs used at the time of strain replacement did not change in these two patients. A third case could not be validated by re-sequencing, but was supported as superinfection by an intermediate sequence with high degenerate base pair count within the time frame of strain switching. Drug resistance increased in this single patient. CONCLUSIONS: Routine genotyping data are informative for the detection of HIV superinfection; however, most cases of non-monophyletic clustering in patient phylogenies arise from sample or sequence mix-up rather than from superinfection, which emphasizes the importance of validation. Non-transient superinfection was rare in our mainly treatment experienced cohort, and we found a single case of possible transmitted drug resistance by this route. We therefore conclude that in our large cohort, superinfection with drug resistant HIV did not compromise the efficiency of antiretroviral treatment.

HIV-1 Subtype Is an Independent Predictor of Reverse Transcriptase Mutation K65R in HIV-1 Patients Treated with Combination Antiretroviral Therapy Including Tenofovir.

Subtype-dependent selection of HIV-1 reverse transcriptase resistance mutation K65R was previously observed in cell culture and small clinical investigations. We compared K65R prevalence across subtypes A, B, C, F, G, and CRF02_AG separately in a cohort of 3,076 patients on combination therapy including tenofovir. K65R selection was significantly higher in HIV-1 subtype C. This could not be explained by clinical and demographic factors in multivariate analysis, suggesting subtype sequence-specific K65R pathways.

Exercise efficiency relates with mitochondrial content and function in older adults.

Chronic aerobic exercise has been shown to increase exercise efficiency, thus allowing less energy expenditure for a similar amount of work. The extent to which skeletal muscle mitochondria play a role in this is not fully understood, particularly in an elderly population. The purpose of this study was to determine the relationship of exercise efficiency with mitochondrial content and function. We hypothesized that the greater the mitochondrial content and/or function, the greater would be the efficiencies. Thirty-eight sedentary (S, n = 23, 10F/13M) or athletic (A, n = 15, 6F/9M) older adults (66.8 ± 0.8 years) participated in this cross sectional study. V˙O2peak was measured with a cycle ergometer graded exercise protocol (GXT). Gross efficiency (GE, %) and net efficiency (NE, %) were estimated during a 1-h submaximal test (55% V˙O2peak). Delta efficiency (DE, %) was calculated from the GXT. Mitochondrial function was measured as ATPmax (mmol/L/s) during a PCr recovery protocol with (31)P-MR spectroscopy. Muscle biopsies were acquired for determination of mitochondrial volume density (MitoVd, %). Efficiencies were 17% (GE), 14% (NE), and 16% (DE) higher in A than S. MitoVD was 29% higher in A and ATPmax was 24% higher in A than in S. All efficiencies positively correlated with both ATPmax and MitoVd. Chronically trained older individuals had greater mitochondrial content and function, as well as greater exercise efficiencies. GE, NE, and DE were related to both mitochondrial content and function. This suggests a possible role of mitochondria in improving exercise efficiency in elderly athletic populations and allowing conservation of energy at moderate workloads.