The present study clearly revealed that EIPL-IPC therapy significantly improved the 5-year survival span of advanced gastric cancer patients with CY+/P-. Thus, EIPL-IPC therapy is strongly recommended as a standard prophylactic strategy for peritoneal dissemination.
An increasing number of HIV-1-infected patients living in developing countries now have access to antiretroviral drugs. Information regarding the drug-resistant mutations of non-B subtype HIV-1 remains limited, however. The authors cross-sectionally compared patterns of the drug-resistant point mutations in patients infected with either subtype B or CRF01_AE (subtype E) among patients who acquired HIV by sexual transmission in Japan. Protease sequence data were available from 216 patients with a detectable level of RNA copies in plasma. Based on phylogenetic analysis of the protease and the C2V3 regions, 162 subtype B and 45 CRF01_AE cases were identified; 82 subtype B and 24 CRF01_AE patients had a treatment failure with nucleoside reverse transcriptase inhibitors; and 69 subtype B and 19 CRF01_AE patients had a treatment failure with a protease inhibitor. Antiretroviral drug history was similar in subtype B-infected and CRF01_AE-infected patients. The mutations T69N and V75M in reverse transcriptase and L10F, K20I, L33I, and N88S in protease were seen more frequently in patients infected with CRF01_AE than in patients with subtype B. The mutations, D30N, A71V, and N88D were found exclusively in patients with subtype B. Most of the characteristic mutation patterns were associated with a history of receiving nelfinavir. The pattern of drug resistance mutations differs between the subtypes. Data derived from subtype B drug-resistant genotypes may not always be applicable to non-B subtypes.
It is well documented that human immunodeficiency virus type 1 (HIV-1) Gag cleavage site mutations (CSMs) emerge in conjunction with various HIV-1 mutations for protease inhibitor (PI) resistance and improve viral replication capacity, which is reduced by acquisition of the resistance. However, CSMs are not the only mutations that emerge in Gag during treatment; many mutations other than CSMs (non-CSMs) have been found to accumulate in the Gag region. In the present study we demonstrate the important role of Gag non-CSMs with regard to viral fitness recovery. We selected three Gag-protease sequences with different PI resistance-associated mutations and CSMs from patients with antiretroviral treatment failure. To clarify the significance of CSMs and non-CSMs, four types of recombinant viruses with different patterns in each sequence were constructed. These were the GP type (patient-derived Gag and protease), the P type (HXB2 Gag and patient-derived protease), the GP ؊c type (CSMs removed from the GP type), and the P ؉c type (CSMs in the HXB2 Gag frame and patient-derived protease). By comparison of these four types of recombinant viruses in each patient-derived Gag-protease sequence, we found that non-CSMs, which had no systematic pattern, make a significant contribution to viral fitness recovery. Our findings demonstrate a delicate interaction between the in vivo evolution of Gag and protease to evade drug selective pressure and the importance of Gag in evaluating drug-resistant viruses.
We studied the evolutionary relationships between the two protease inhibitor (PI) resistance mutations, D30N and L90M, of human immunodeficiency virus type 1 (HIV-1). The former is highly specific for nelfinavir resistance, while the latter is associated with resistance to several PIs, including nelfinavir. Among patients with nelfinavir treatment failure, we found that D30N acquisition was strongly suppressed when L90M preexisted. Thus, D30N/L90M double mutations not only were detected in a very limited number of patients but also accounted for a minor fraction within each patient. In the disease course, the D30N and L90M clones readily evolved independently of each other, and later the D30N/L90M double mutants emerged. The double mutants appeared to originate from the D30N lineage but not from the L90M lineage, or were strongly associated with the former. However, their evolutionary pathways appeared to be highly complex and to still have something in common, as they always contained several additional polymorphisms, including L63P and N88D, as common signatures. These results suggest that D30N and L90M are mutually exclusive during the evolutionary process. Supporting this notion, the D30N/L90M mutation was also quite rare in a large clinical database. Recombinant viruses with the relevant mutations were generated and compared for the ability to process p55 gag and p160 pol precursor proteins as well as for their infectivity. L90M caused little impairment of the cleavage activities, but D30N was detrimental, although significant residual activity was observed. In contrast, D30N/L90M demonstrated severe impairment. Thus, the concept of mutual antagonism of the two mutations was substantiated biochemically and functionally.
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