Concurrent evolution of regions of the envelope and polymerase genes of human immunodeficiency virus type 1 observed during zidovudine (AZT) therapy

Abstract

Nucleotide sequences of regions of the envelope (env) and polymerase (po/) genes of human immunodeficiency virus type 1 (HIV-1) proviral DNA were obtained from sequential blood and autopsy samples from an AIDS patient who had been treated with zidovudine for 9 months, Phylogenetic analyses showed that a reduction in genetic heterogeneity of the env regions of viruses present in the proviral blood population occurred during therapy, and this coincided with an increased pol gene heterogeneity. Differences were observed in different organs obtained post mortem for both the env and pol coding regions. The cardiac blood proviral population consisted mainly of variants which possessed sequences containing mutations at position 215 of the pol gene, associated with drug resistance. By contrast, the brain population consisted entirely of zidovudine sensitive genotypes, and this organ also harboured variants with genetically distinct env sequences. The lymph tissues obtained after death held more diverse proviral env and pol populations, containing both zidovudine sensitive and resistant genotypes.

Effect of a Protease Inhibitor-Induced Genetic Bottleneck on Human Immunodeficiency Virus Type 1 env Gene Populations

“…The differences we observed between the three groups in our study may explain some of the conflicting observations of previous studies looking at the effect of drug therapy on env populations. First, the observed difference in env heterogeneity between subjects with either weak or strong initial responses to ritonavir are consistent with studies analyzing subjects with a maximum of a 10-fold drop in virus load (or unknown virus loads) where little or no change in env variants was observed (9,11,23,34,36,42). Second, the reappearance of the entry env populations after virus rebound, even as pro goes through further genetic bottlenecks, may help to explain why some of the previous studies observed no differences in env populations after drug therapy, since they studied samples several months after virus load rebound (23,34,42).…”

“…The effect of the drug-induced genetic bottleneck on the population dynamics of other regions of the viral genome has been addressed in several different studies (7,9,11,17,23,28,34,36,42). All of the studies have analyzed the effect of the drug-induced bottleneck on the gene encoding the viral surface glycoprotein (env), since it is the most variable region of the HIV-1 genome, often present as coexisting variants.…”

“…First, in several studies the drop in virus load due to the initiation of therapy was either not shown or was less than 10-fold (9,11,23,34,36,42), making it difficult to assess whether the drug regimen caused a genetic bottleneck. Second, in some of the studies the first sample collected after the initiation of therapy was 6 to 12 months later, making it difficult to determine if the env population changes were due to drug therapy or to selective pressures on env subsequent to rebound (34,36,42). Third, some studies followed subjects for only a few months and were unable to determine if the env population changes due to the bottleneck were transient (9,17,28).…”

“…All of the studies have analyzed the effect of the drug-induced bottleneck on the gene encoding the viral surface glycoprotein (env), since it is the most variable region of the HIV-1 genome, often present as coexisting variants. Several different combinations of transiently suppressive therapy have been studied, such as RT inhibitors (9,23,34,36,42), protease inhibitors (7,17,28), or a combination of both (11). However, the results presented in these studies are conflicting.…”

Patterns of Changes in Human Immunodeficiency Virus Type 1 V3 Sequence Populations Late in Infection

“…Delwart et al showed that there were rapid and dramatic changes in V3 to V5 during the development of resistance to ritonavir or nelfinavir, although the changes were usually transient (9). However, for two groups of subjects on zidovudine (AZT), there was no obvious effect on the evolution of V3 while the virus was developing resistance, presumably because of the weak therapeutic effect of AZT in those subjects (18,32). In a third study with AZT, transient changes in V3 were seen (37).…”