title: Drug resistance and viral tropism in HIV-1 subtype C-infected patients in KwaZulu-Natal, South Africa: implications for future treatment options.
abstract: BACKGROUND
  Drug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially use CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use, may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy.
  
  
  METHODS
  We sequenced the pol gene of viruses from 45 individuals failing at least 6 months of HAART in Durban, South Africa, to determine the prevalence and patterns of drug-resistance mutations. Coreceptor use profiles of these viruses and those from 45 HAART-naive individuals were analyzed using phenotypic and genotypic approaches.
  
  
  RESULTS
  Ninety-five percent of HAART-failing patients had at least one drug-resistant mutation. Thymidine analog mutations (TAMs) were present in 55% of patients with 9% of individuals possessing mutations indicative of the TAM1 pathway, 44% had TAM2, whereas 7% had mutations common to both pathways. Sixty percent of HAART-failing subjects had X4/dual//mixed-tropic viruses compared with 30% of HAART-naïve subjects (P < 0.02). Genetic coreceptor use prediction algorithms correlated with phenotypic results with 60% of samples from HAART-failing subjects predicted to possess CXCR4-using (X4/dual/mixed viruses) versus 15% of HAART-naïve patients.
  
  
  CONCLUSIONS
  The high proportion of TAMs and X4/dual/mixed HIV-1 viruses among patients failing therapy highlight the need for intensified monitoring of patients taking HAART and the problem of diminished drug options (including CCR5 antagonists) for patients failing therapy in resource-poor settings.
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Ashika
authors.initials: A
authors.lastname: Singh
authors.forename: Henry
authors.initials: H
authors.lastname: Sunpath
authors.forename: Taryn N
authors.initials: TN
authors.lastname: Green
authors.forename: Nagavelli
authors.initials: N
authors.lastname: Padayachi
authors.forename: Keshni
authors.initials: K
authors.lastname: Hiramen
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Lie
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Anton
authors.forename: Richard
authors.initials: R
authors.lastname: Murphy
authors.forename: Jacqueline D
authors.initials: JD
authors.lastname: Reeves
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kuritzkes
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics; D020125:Mutation, Missense; D015728:Receptors, HIV / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013019:South Africa; D056189:Viral Tropism; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D050505:Mutant Proteins; D015728:Receptors, HIV; D054302:pol Gene Products, Human Immunodeficiency Virus