HIV Type 1 Polymerase Gene Polymorphisms Are Associated With Phenotypic Differences in Replication Capacity and Disease Progression

The global human immunodeficiency virus type 1 (HIV-1) epidemic is genetically diverse [1]. Group M, the predominant group, is divided into 9 distinct subtypes and 58 circulating recombinant forms [2]. Studies from diverse geographic locations including Africa, North America, and Southeast Asia have documented intersubtype differences in disease progression [3–7]. In a prospective cohort from Rakai, Uganda, with known times of seroconversion, the adjusted hazards of death and progression to AIDS for participants infected with subtype D HIV-1 were 5.7 and 2.1 times, respectively, those for participants infected with subtype A [7]. In Mombasa, Kenya, the hazard of death for subtype D–infected commercial sex workers was 2.3 times that for their subtype A–infected counterparts [3]. It is important to understand the virologic factors underlying intersubtype differences in HIV-1 disease progression, which have associated implications for therapeutic and immune targeting, especially among non-B subtypes. In vivo studies examining virologic factors affecting disease progression have mainly involved Western populations, where subtype B predominates [1]. Previously identified virologic factors influencing disease progression include polymerase gene replication capacity (pol RC), coreceptor tropism switch, and deletions in the nef gene [8–11]. Prior studies in cohorts from the United States have demonstrated an association between high pol RC and increased rates of disease progression, independent of HIV-1 load [8, 10, 11]. Studies to determine in vivo virologic factors explaining intersubtype differences in HIV-1 disease progression are best performed in ethnically homogeneous cohorts, with cocirculation of different subtypes, known dates of seroconversion, and long follow-up periods for subjects involved; thus, they are challenging to conduct. The ethnically homogeneous population in Rakai, Uganda, with a large number of subjects and known dates of seroconversion since 1994, where both HIV-1 subtype A and subtype D cocirculate, provides a unique opportunity to examine the influence of viral factors on intersubtype and intrasubtype differences in disease progression. We examined multiple genomic regions of HIV for association with intersubtype differences in disease progression, tested the influence of phenotypic functionality of a subset of pol genes, and determined whether any amino acid substitutions were correlated with increased pol RC and disease progression in this cohort.