Viral genetic heterogeneity in HIV-1-infected individuals is associated with increasing use of HAART and higher viremia.
OBJECTIVE
To assess the correlation between the outgrowth of mutant viruses (viral genetic heterogeneity), highly active antiretroviral therapy (HAART), and plasma HIV-1 RNA in a population-based observational cohort study.


METHODS
The study population consisted of 42 HIV-1-infected individuals receiving at least two nucleotide reverse transcriptase (RT) inhibitors and one or more protease inhibitors at study entry. There were no restrictions on antiretroviral therapy after enrollment.


METHODS
Plasma samples were obtained from subjects at baseline, at therapy changes, and at quarterly intervals for quantitation of HIV-1 RNA levels and for sequence determination of the entire protease coding region and the first 235 codons of the reverse transcriptase coding region. Data were analyzed using the generalized estimating equation method for longitudinal data and using linear regression analysis.


RESULTS
With increased time on HAART there were significant increases in the number of total HIV-1 mutations in the regions sequenced (P = 0.010). There were significant correlations between the increases in the plasma HIV-1 RNA levels and the numbers of total mutations and reverse transcriptase mutations (P = 0.007 and 0.021, respectively).


CONCLUSIONS
The number of HIV-1 mutations increased over time. Failure of HAART in this study population was correlated with outgrowth of virus with numerous mutations in the reverse transcriptase and protease coding regions. Phenotypic results correlated with genotypic results, showing decreased susceptibility to antiretrovirals over time in the majority of this population during HAART. Both synonymous and non-synonymous mutations were observed, with a higher incidence of non-synonymous mutations occurring at codons associated with drug resistance.
Ross
L
L
Department of Virology, Glaxo Wellcome Inc., Research Triangle Park, North Carolina, 27709, USA. llr8156@glaxowellcome.com
Johnson
M
M
DeMasi
R
R
Liao
Q
Q
Graham
N
N
Shaefer
M
M
St Clair
M
M
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D003062:Codon; D015331:Cohort Studies; D004352:Drug Resistance, Microbial / Q000235:genetics; D004359:Drug Therapy, Combination; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016333:HIV Protease / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D014766:Viremia / Q000821:virology*
D019380:Anti-HIV Agents; D003062:Codon; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016333:HIV Protease