ABSTRACT
HIV-1 is characterized by an exceptional level of sequence diversity and a rapid rate of evolution. HIV diversity has implications for reliability of assays designed to detect and monitor infection, pathogenesis, disease progression, response to antiviral therapeutics, resistance pathways, and vaccine development. In the present study, HIV-1 strain diversity was assessed for a small clinical cohort (n = 15) from London, England at risk for infection with non-subtype B strains. Analysis of gag p24, pol IN, and env gp41 IDR revealed the presence of five subtypes (A, B, C, D, H), CRF02_AG, and four unique recombinant forms. Due to the paucity of complete subtype H genomes available, we performed near full-length genome sequence analysis on the candidate subtype H strain, designated as 00GB.AC4001. Phylogenetic analysis revealed that it formed a monophyletic cluster with the three available subtype H reference sequences. Bootscanning analysis confirmed that 00GB.AC4001 represents a new nonrecombinant subtype H genome.
Subject(s)
Genetic Variation , Genome, Viral , HIV Infections/virology , HIV-1/genetics , Cohort Studies , Evolution, Molecular , HIV Envelope Protein gp41/analysis , HIV Envelope Protein gp41/genetics , HIV Infections/blood , Humans , London , Molecular Sequence Data , RNA, Viral/analysis , RNA, Viral/blood , RNA, Viral/genetics , Sequence Analysis, DNA , gag Gene Products, Human Immunodeficiency Virus/analysis , gag Gene Products, Human Immunodeficiency Virus/genetics , pol Gene Products, Human Immunodeficiency Virus/analysis , pol Gene Products, Human Immunodeficiency Virus/geneticsABSTRACT
Escalating drug resistance in treatment-experienced HIV-1-infected patients has made management increasingly difficult. In clinical trials, tipranavir (TPV) has produced potent and durable responses in such patients, although experience in clinical cohorts is limited. A retrospective clinical case review was undertaken of triple-class experienced HIV-1-infected patients receiving optimized boosted TPV-containing regimens and T20 with up to 108 weeks follow-up. Antiretroviral therapy (ART) resistance profiles were characterized using International Aids Society (IAS)-USA scoring and 'TPV resistance score' (TPV-RS) at baseline and failure. Five of 12 patients had undetectable virus (<50 copies/mL) after median 84 weeks (range 60-108), and 1/12 < had 700 copies/mL after 40 weeks. Six of 12 patients failed after 36 (range 12-48) weeks and were more likely to have > or = 3 TPV-RS mutations than non-failures (P = 0.06). Presence of a major IAS-USA mutation at baseline was strongly associated with absence of a 1 log viral load drop at 24 weeks (P = 0.02). TPV-containing regimens showed impressive efficacy and tolerability in this heavily experienced cohort.
Subject(s)
Anti-HIV Agents/therapeutic use , HIV Envelope Protein gp41/therapeutic use , HIV Fusion Inhibitors/therapeutic use , HIV Infections/drug therapy , HIV-1 , Peptide Fragments/therapeutic use , Pyridines/therapeutic use , Pyrones/therapeutic use , Adult , Cohort Studies , Drug Resistance, Multiple, Viral/genetics , Drug Therapy, Combination , Enfuvirtide , Genotype , HIV Infections/genetics , HIV-1/drug effects , HIV-1/genetics , Humans , Middle Aged , Retrospective Studies , Salvage Therapy , Sulfonamides , Treatment OutcomeABSTRACT
BACKGROUND: Guidelines for commencing therapy for HIV infection have been based upon HIV-1 RNA and CD4 lymphocyte thresholds. The influence of confounding factors such as gender, ethnicity and co-infections is unproven. OBJECTIVES: To analyse ethnic discordance in plasma HIV-1 viral load (VL) and CD4+ count and its potential clinical significance in Black and Caucasian groups. STUDY DESIGN: Retrospective, cross-sectional, observational study of 537 antiretroviral nai;ve HIV-1-positive individuals attending two East London clinics. Baseline data were obtained from individuals who registered at the clinic from November 1996 to August 1999. An analysis was performed comparing ethnic differences in plasma HIV-1 VL, CD4+ count, CD8+ count, co-infections, CDC disease category, AIDS-defining illnesses and mode of transmission. RESULTS: Plasma HIV-1 VL was significantly lower in Blacks (4.5 copies/ml versus 4.7 copies/ml; P<0.05) despite lower baseline CD4+ counts and similar rates of disease progression to Caucasian groups. This association remained for patients with less advanced disease after stratification for CD4+ count (CD4+ 200-500, VL 4.5 copies/ml versus 4.7 copies/ml, P<0.01; CD4+ >500, VL 3.4 copies/ml versus 4.3 copies/ml, P<0.001) and disease category (non-AIDS, 4.4 copies/ml versus 4.7 copies/ml; P<0.005). On multivariate analysis, the association persisted following adjustment for gender, age, co-infections, CD4+ count and mode of transmission. CONCLUSIONS: These results suggest that plasma HIV-1 VL is discordantly low in Black compared with Caucasian groups stratified for CD4+ count, in this cohort of antiretroviral nai;ve HIV-1-positive individuals living in London. Although there are a number of possible explanations for this finding, it has considerable clinical relevance for the management of Black HIV-1-infected patients within UK, with significant implications for the decision about when to commence antiretroviral or immune-based therapies.
