Background:  The clinical development of HIV-1 integrase inhibitors (InI) is proceeding rapidly. The prevalence of amino acid substitutions associated with in vitro resistance to clinically relevant InI is unknown and may occur naturally.

Methods:  We analyzed the IN gene in 102 treatment-naïve patients identified during acute and early infection between 1996 and 2006. Patient peripheral blood mononuclear cells (PBMC) or plasma were used for nucleic acid isolation followed by nested polymerase chain reaction (PCR) to generate a 288-amino acid sequence.  Separately, we analyzed 13 plasma RNA samples from treatment-experienced patients with triple-class resistant virus.

Results:  Proviral DNA from 56 stored PBMC samples and viral RNA from 56 plasma samples were sequenced for the IN gene. Of 288 samples, 117 (61.5%) of the amino acids were variable, indicating greater variability than that found in the protease gene.  However, within this cohort, few of the polymorphisms associated with in vitro InI resistance were identified (9 of 27 possible mutations). Certain natural polymorphisms associated with resistance occurred frequently—V72I was the most common, seen in 58 out of 102 patients. In the multi-drug-resistant treatment-experienced patients (n = 13) the following occurred:  V72I/6, V151I/2, V165I/2, T206S/3, M154I/1, and V201I/5. There was no significant difference between the prevalence of polymorphisms associated with resistance in the multi-drug-resistant treatment-experienced group and in the treatment-naïve group (4.7% vs 4.9%). In contrast to a similar study of InI-naïve patients, we did not identify A128T, E138K, S153Y/A, or N155H in our samples. 

Conclusions:  Amino acid polymorphisms, which may confer resistance to current integrase inhibitors, occur very rarely in recently infected, drug-naive patients.  Furthermore, there has been no significant change in the distribution of polymorphisms since 1996. The clinical significance of these polymorphisms will be revealed as clinical trial results become available.