Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection
To exclusively examine regardless of whether extended Integrase inhibitor HIV-one suppression resulted in adjustments in amino acid sequences, we investigated nonsynonymous Integrase inhibitor alterations alone in individuals from teams one and 2 for which there ended up more than 7 sequences at time details with <50 copies/ml (Nâ=â8) (Table S2). Effect of cART on HIV-1 population structure and divergence
Divergence of HIV-1 populations during cART could result either from on-going cycles of replication leading to the emergence of new variants or as a consequence of shifts in the viral variants present in the plasma during suppression, indicating a dynamic reservoir. To investigate the possibility of population shift (divergence) during cART, we used a test for panmixia to detect changes in the population structure during therapy compared to pretherapy virus. The panmixia test compares populations of single-genome sequences obtained from longitudinal samples and provides a p-value for the probability that the populations are the same . Probabilities of <10â3 were considered to indicate significantly different populations, taking into account the large numbers of comparisons. Figure 3 and Table 3 show the panmixia results for single-genome sequences from group 1 (Figure 3a, Table 3), group 2, (Figure 3b, Table 3), and group 3 (Figure 3c, Table 3) compared to pretherapy sequences. Panmixia probabilities of virus populations in samples collected from patients on cART compared to pre-therapy populations did not achieve significance (Figure 3a) in 8/10 patients from group 1. These results indicate that there is typically no significant shift in the plasma virus population during the first and second phases of decay after initiating cART despite up to 10,000-fold declines in levels of viremia. Two patients in group 1 (PID 6, 7), however, did show a significant change in population structure after 173 and 193 days on therapy. Additional analyses describing the nature of these changes are presented below. Three of 5 patients in group 2 (long-term cART) showed a significant change in population structure during cART for 4â12 years with no treatment interruptions, suggesting either that new variants emerged during therapy or that the reservoir for persistent viremia is dynamic. Four of 5 patients in group 3 (long-term cART but with brief treatment interruptions) showed a significant shift in population structure using the panmixia test. The results from group 2 and 3 show that, although plasma HIV-1 populations do not typically change in the early phases of viral decay, shifts in virus populations (without a change in overall diversity) are readily detectable after long-term therapy and in rebound viremia. They imply that either a compartment allowing on-going cycles of replication exists during cART or subsets of infected cells expressing virus particles shift over the course of treatment (through proliferation and/or death).
To further determine if the population shifts detected in the plasma of some patients during and after long-term cART were the result of on-going cycles of virus replication or were due to a shift in the population of cells that express virus particles during therapy, we performed phylogenetic analyses and tests for molecular evolution.