Significant Reductions in Gag-Protease-Mediated HIV-1 Replication Capacity during the Course of the Epidemic in Japan

Abstract

f Human immunodeficiency virus type 1 (HIV-1) evolves rapidly in response to host immune selection pressures. As a result, the functional properties of HIV-1 isolates from earlier in the epidemic may differ from those of isolates from later stages. However, few studies have investigated alterations in viral replication capacity (RC) over the epidemic. In the present study, we compare Gag-Protease-associated RC between early and late isolates in Japan (1994 to 2009). HIV-1 subtype B sequences from 156 antiretroviral-naïve Japanese with chronic asymptomatic infection were used to construct a chimeric NL4-3 strain encoding plasmaderived gag-protease. Viral replication capacity was examined by infecting a long terminal repeat-driven green fluorescent protein-reporter T cell line. We observed a reduction in the RC of chimeric NL4-3 over the epidemic, which remained significant after adjusting for the CD4 ؉ T cell count and plasma virus load. The same outcome was seen when limiting the analysis to a single large cluster of related sequences, indicating that our results are not due to shifts in the molecular epidemiology of the epidemic in Japan. Moreover, the change in RC was independent of genetic distance between patient-derived sequences and wildtype NL4-3, thus ruling out potential temporal bias due to genetic similarity between patient and historic viral backbone sequences. Collectively, these data indicate that Gag-Protease-associated HIV-1 replication capacity has decreased over the epidemic in Japan. Larger studies from multiple geographical regions will be required to confirm this phenomenon.

Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence

“…As described above, transmission of viruses with high replication capacity tends to result in more rapid CD4 decline in the recipient (8) and hence HIV-infected people with low CD4 counts tend to have viruses with high replicative capacity, as observed in this study and several others (14,(17)(18)(19)(20). To examine the plausibility of this hypothesis, we developed a mathematical model, first, to investigate how HIV virulence would be expected to change over the course of the epidemic in the absence of ART; and, second, to examine the anticipated impact that ART would have on virulence (Fig.…”

“…Thus, the true VRC of HIV in each study subject is only partially represented by the assay, and also it is possible that mutations outside of GagProtease may compensate for mutants within Gag-Protease and vice versa. However, the assay has been adopted and validated by several groups, including the demonstration of a correlation between the replication capacities of Gag-recombinant viruses and complete HIV isolates obtained from the same patient samples (31); and, consistently in these studies, the measured VRC correlates with viral set point and, inversely, with CD4 count (14,(17)(18)(19)(20), suggesting that the gag-pro sequence has an important influence on HIV disease outcome, independent of the effects of other genes on VRC. In addition, the CTLs that have been most clearly related to immune control and that dominate the HIV-specific response in subjects expressing the protective HLA alleles HLA-B*57/58:01/27/81:01 are within Gag (9,44), and the escape mutants within these Gag epitopes have been proposed to play a critical role in immune control via a reduction on VRC (9-12).…”

“…In Japan, where HLA-B*51 was initially protective in the early part of the epidemic, increase in the frequency of an escape mutant in the critical CTL epitope to 75% of circulating viruses in the Japanese HIV-positive population was associated with loss of the protective effect associated with HLA-B*51. Recent studies (14) indicate that VRC in Japan has been declining over the same timespan, prompting the question of how viral adaptation to HLA-mediated selection might affect population-level VRC.…”

“…It is well established that transmission of viruses with high VRC tends to result in high viral set points and rapid CD4 decline in the recipient (7,8,15,16). Thus, the viruses in individuals with the lowest CD4 counts tend to have the highest VRC (14,(17)(18)(19)(20). ART initiation along WHO guidelines (21) is in most cases the result of a CD4 count threshold being reached.…”

Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic

“…In particular, in Japan, where the frequency of B*51 exceeds 20%, the frequency of RT I135X exceeds 70%, supporting the spread of the polymorphism at the population level in the country. Studies in Europe (30), Asia (31), and Africa (32) have also reported (or inferred) decreases in HIV-1 replication capacity over the course of their respective epidemics, presumably as a result of HIV-1 adaptation to host pressures. A recent study of HIV-1 Gag and Nef evolution in North America by our group also indicated that HLA-associated polymorphisms have spread in circulation over time (33).…”