Background:  Few sequence data exist on naturally occurring HIV-1 group M integrase (IN), a new target of inhibitors in advanced clinical development. 

Methods:  HIV-1 group M IN sequences of >90 amino acids were retrieved from GenBank and annotated with data on persons from whom the viruses were obtained. Subtypes were determined using reference sequences of the 9 pure subtypes and CRF01 (AE) and 02 (AG). IN amino acids were considered polymorphic if sequences from ≥1% of persons differed from the Los Alamos database subtype B consensus. Key functional positions were included the catalytic residues (D64, D116, E152) and the extended active site residues (Q62, C65, T66, H67, E92, N120, F121, I141, P142, Y143, Q148, V151, N155, K156, K159). Reported IN inhibitor-resistance mutations were defined as:  T66I, V72I, L74M, E92Q, F1121Y, T125K, A128T, E138K, G140S, Q146K/R, S147G, Q148K, V151I, S153A/Y, M154I, N155S/H, K160D,V165I, V201I, S230R, V249I and C280Y.

Results:  We analyzed 2081 HIV-1 group M IN sequences from 1744 IN inhibitor-naïve persons including 504 persons with subtype C sequences, 288 with subtype A, 274 with subtype B, 160 with subtype AE, 157 with subtype AG, 123 subtype with D, and 238 with viruses belonging to other subtypes or recombinant groups. Mean intra-subtype NA and amino acid distances were 6.3% (range 3.9% to 8.3%) and 5.8% (range 3.8% to 8.4%). Mean inter-subtype NA and amino acid distances were 10.3% and 9.8%. Of 288 positions, 162 were polymorphic. All catalytic residues were non-polymorphic. Among extended active residues, I141V (1.6%), V151I (1.7%), N155H (1.5%), and K156N/Q/H (2.3%, 1.2%, 1.1%) were polymorphic. Among the IN inhibitor-resistance mutations outside of the extended active site, M154I (3.1%), S153A/Y (3.4%), V165I (6.9%), V72I (40.9%), and V201I (83.6%) were polymorphic.

Conclusions:  The catalytic and extended active site IN residues are conserved across HIV-1 group M subtypes with low rates of conservative polymorphisms at positions 141, 151, 155, and 156. Higher rates of polymorphism at several non-active site residues associated with IN inhibitor resistance also occur.